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recently , magnetic thin films used in magnetic components , such as inductive devices and magnetic heads , have attracted more and more attention because of the increasing demand for improvement and miniaturization of electromagnetic devices [ 1 - 3 ] .
the basic requirements for these films operated in the ghz range are high resistivity , high permeability , high saturation magnetization ms and appropriate large anisotropy field
hk so as to effectively suppress eddy current loss and to possess high ferromagnetic resonance ( fmr ) frequency fr ( which determines the cut - off frequency for high frequency application ) .
insulator granular films ( migf ) consisting of magnetic metal nano - granules uniformly distributed in an insulator matrix are one of the best candidates for satisfying above demands , because these films have the advantages of high ms and high of magnetic metals and high of insulator .
up to now , soft magnetic properties of granular films composed of magnetic metals ( and their alloys ) and various x-(oxide , nitride and fluoride ) where x is nonmagnetic elements such as hf , al , si , zr , rare earth , etc . have been investigated [ 4 - 8 ] .
the mechanism of the soft magnetic properties of migfs has been confirmed to be the exchange coupling between granules through the intergranular regions .
however , the microscopic origin of exchange coupling has not been totally understood , such as the medium of the exchange coupling for different constitution nano - granular films . by considering the high resistivity of semiconductor oxides , metal semiconductor granular films ( msgf ) consisting of magnetic metal nano - granules uniformly distributed in semiconductor matrix , such as the feco zno systems , may possess good high frequency properties .
as one kind of wide used semiconductor oxides due to the excellent electrical and optical properties , the current carriers of zno may mediate the exchange coupling between magnetic granules and hence favor good soft magnetic properties .
so far , there is no work studying systematically the soft magnetic properties of the feco
zno granule films reported . in order to test whether zno can mediate the exchange coupling , the structure , magnetic properties and electronic transport properties of feco zno msgfs were systematically studied in this work .
( fe65co35)x(zno)1x granular thin films were deposited on water - cooled glass substrates by radio frequency ( rf ) magnetron sputtering at room temperature with a background pressure lower than 4 10 pa . a three - inch fe65co35 alloy disk covered with zno chips ( 5 5 1 mm )
the sputtering power was 100 w , and sputtering ar gas was kept at 0.40 pa .
an external magnetic field obtained by a pair of permanent magnets located on both sides of the substrates was applied during deposition to induce an in - plane uniaxial anisotropy for the samples , and the intensity of external magnetic field is 500 oe . the saturation magnetization 4ms , coercivity hc and in - plane magnetic anisotropy field hk were determined by a vibrating sample magnetometer ( vsm , lakeshore 7304 model ) .
the composition of the samples was measured by energy dispersive x - ray spectroscopy ( eds ) .
the structure and microstructure were analyzed by x - ray diffraction ( xrd ) ( philips xpert model ) with cu - k radiation and high resolution transmission electronic microscopy ( hrtem ) , respectively .
the permeability spectra were carried out with a pna e8363b vector network analyzer using the shorted microstrip transmission - line perturbation method , which works from 100 mhz to 5 ghz .
all the above measurements were performed for as - deposited samples without any post - heat treatment .
figure 1 shows the bright - field hrtem image ( a ) and the corresponding electron diffraction ( ed ) pattern ( b ) , as well as the xrd spectrum ( c ) for a typical sample of x = 0.67 .
it can be seen that the sample consists of bcc fe65co35 particles embedded uniformly in the insulating zno matrix from the image ( a ) .
the average size of fe65co35 particles and the distance between them are about 2 and 4.5 nm , respectively .
figure 1b exhibits the diffraction peaks from ( 110 ) and ( 200 ) planes of bcc fe65co35 alloys , ( 111 ) and ( 103 ) planes of zno , respectively , which are totally consistent with those of xrd shown in fig .
the average diameter of fe65co35 grains calculated by the full width at half maximum ( fwhm ) of the diffraction peak in xrd spectrum through scherrer s equation is about 2.1 nm , which is close to that of fe65co35 granules .
hrtem image ( a ) and the corresponding ed pattern ( b ) as well as the xrd spectrum ( c ) for a typical sample of x= 0.67 figure 2 expresses the x dependence of hc , hk and . it is seen that increases slowly with decreasing x and then increases rapidly after x < 0.64 .
hc is less than 15 oe , and hkis over 43 oe in the range 0.63 < x < 0.72 , which means good soft magnetic properties are obtained in this range .
especially , for the sample with x = 0.67 , its in - plane hysteresis loop shown in fig .
the coercivities in hard and easy axes are 1.43 and 7.08 oe , respectively , 4ms = 9.85 kg , and reaches 2.06 m cm , which is three orders higher than that of pure feco alloy .
these good soft magnetic properties and the high imply that the films are promising for high frequency applications .
h curves for ( fe65co35)0.67(zno)0.33 film figure 4 shows the dependence of complex permeability =
j on frequency f for the film of x = 0.67 , where and represent the real and imaginary parts of complex permeability , respectively .
it can be seen that is more than 100 below 1.83 ghz and then gradually decreases with frequency , while the imaginary part gradually increases to a maximum at f = 2.31 ghz , which can be ascribed to the ferromagnetic resonance ( fmr ) .
lifshitz equations taking account of the coherent spin procession , as shown by the solid lines in fig .
the fmr frequency obtained by this fitting is around 2.31 ghz , consistent with the experimental result .
the high fmr frequency also implies that the granular films are promising for applications in the high frequency range .
permeability spectra ( ~ f ) for the sample of x = 0.67 considering the mechanism of the good soft magnetic properties , we turn to the exchange coupling model . according to the herzer s statement , if the average size d of magnetic particles and the distance s between particles are reduced to be smaller than a characteristic length , namely , the exchange length lex , the exchange interaction between particles may take place , which tends to align the magnetic moments of neighboring particles parallel and so overcome the magneto - crystalline anisotropy and the demagnetization effect of individual particles . as a result ,
the effective magnetic anisotropy of materials is reduced significantly , which leads to the decrease in coercivity and hence the increase in permeability , and then good soft magnetic properties are obtained . for fe65co35 , the characteristic length lex is about 26 nm , while the d and s are 2.3 and 4.5 nm , respectively , based on the results of hrtem spectrum .
thus , ( d + s ) lex holds , exchange coupling can be realized in this film , which is responsible for the good soft magnetic properties . in order to study the microscopic origin of the exchange coupling between granules , the temperature dependence of resistivity
figure 5a depicts thecurve , which exhibits a negative temperature coefficient of resistivity ( tcr ) .
5b , which indicates that the mechanism of electronic transportation of the sample is weak localized electron electron interaction .
these weak localized electrons may also be the medium of exchange coupling between magnetic granules .
resistivity as a function of temperature ( a ) and fitting result ( b ) for a typical sample of x = 0.67
( fe65co35)x(zno)1x granular films were fabricated by magnetron sputtering , and good soft magnetic properties have been obtained in x range from 0.63 to 0.72 with small hc and appropriate large hk . for the typical sample of x = 0.67 ,
the coercivity of 1.43 oe in the hard axis and 7.08 oe in the easy axis are obtained , and the resistivity reaches 2.06 m cm . at a frequency lower than 1.83 ghz , the real part of the complex permeability of this sample is more than 100 , and the fmr frequency reaches 2.31 ghz , which implies that the film is promising for high frequency applications .
the good soft magnetic properties origin from the exchange coupling between magnetic granules and the weak localized electrons existing in films may be the medium of this exchange coupling .
this work was supported by national natural science foundation of china ( grant no.50571041 ) .
this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and source are credited .
this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and source are credited . | a series of nano - granular films composed of magnetic metal ( fe65co35 ) granules with a few nanometers in size and semiconductor oxide ( zno ) have been fabricated by a magnetron sputtering method , and excellent soft magnetic properties have been achieved in a wide metal volume fraction ( x ) range for as - deposited samples due to the exchange coupling between feco granules ( a ferromagnetic interaction in nano - scale ) . in a wide range ( 0.53 < x < 0.71 ) , the films exhibit coercivity hc not exceeding 15 oe , along with high resistivity . especially for the sample with x = 0.67 , coercivities in hard and easy axes are 1.43 and 7.08 oe , respectively , 4ms = 9.85 kg , and reaches 2.06 103 cm . the dependence of complex permeability = j on frequency shows that the real part is more than 100 below 1.83 ghz and that the ferromagnetic resonance frequency reaches 2.31 ghz , implying the promising for high frequency application .
the measured negative temperature coefficient of resistivity reveals that may be the weak localized electrons existing in samples mediate the exchange coupling . | [
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juxtafacet cysts ( jfcs ) are uncommon intraspinal , extradural lesions that arise from the facet joints .
jfcs can be further distinguished as either synovial cysts , if histology confirms the presence of a synovial lining membrane , or alternatively as a ganglion cyst , if no such membrane is present .
however , few differences exist between the two in terms of diagnosis and management.1
2
3
4
5
6
7 their pathogenesis remains unclear , with most authors citing excessive joint mobility leading to synovial fluid herniation through joint capsule defects.2
4
7
calcification in the cyst walls is a common finding on imaging for jfcs , appearing as peripheral areas of high attenuation on computed tomography ( ct ) and peripheral hypointensity on t1- and t2-weighted magnetic resonance imaging ( mri).8
9
10 but although calcification of the cyst walls are commonly reported findings,9
10
11 complete calcification of the cyst is exceedingly rare.11
12
13 we present here an unusual case of a jfc presenting as a giant , multilobular , completely calcified mass with significant extraforaminal extension .
the patient was a 57-year - old woman who presented with a 2-year history of gradually worsening lower back and left leg pain .
she also reported numbness in her left heel and foot and subjective weakness in the left foot .
her past medical history was significant for hypothyroidism , hypertension , mild levoscoliosis , rheumatoid arthritis , and scleroderma managed on weekly methotrexate injection .
her past surgical history was negative for any previous lumbar surgeries , but the patient had received multiple cervical surgeries resulting in c3c7 fusion . on neurologic exam ,
the patient was found to have decreased strength in plantarflexion and dorsiflexion of the left lower extremity but was otherwise nonfocal .
the patient 's imaging was most notable for a large , multilobular mass , measuring 54 31 30 mm , arising from the left l5s1 facet joint that had caused destruction of the joint itself and that showed severe encroachment of the adjoining foramen , with coexisting grade i anterolisthesis of l5 on s1 .
the lesion was hyperdense on plain radiograph ( fig . 1 ) and on ct imaging ( fig
. 2a , 2b , and 2c ) and appeared hypointense on t1- and t2-weighted mri sequences ( fig .
preoperative plain film of the lumbar spine showing a large , completely calcified lesion extending out from the l5s1 intervertebral space .
( a ) axial computed tomography ( ct ) image taken preoperatively , showing the origin of the lesion from the left l5s1 facet joint .
( b ) a preoperative midsagittal ct image demonstrating grade 1 anterolisthesis of l5 on s1 . ( c ) a preoperative sagittal ct image demonstrating foraminal stenosis at l5s1 caused by the lesion .
( a ) t1-weighted magnetic resonance image ( mri ) of the same lesion , which appears uniformly hypointense . ( b )
the patient underwent an l5 laminectomy for excision of the mass along with an l5 to s1 fixation and fusion .
intraoperatively , the lesion was noted to consist of a pastelike material that was compressing the thecal sac and that extended ventrally out of the foramen .
histologic analysis identified the lesion as a mineralized simple pseudocyst , containing mineralized proteinaceous material that did not refract plane polarized light after ethanol fixation ( fig . 4a and 4b ) .
( a ) hematoxylin and eosin stained sections of the resection reveal dense membranous fibrous connective tissue separating spaces associated with dense calcifications as well as smaller loculated spaces filled with calcium ( 20 magnification ) .
( b ) higher magnification ( 40 ) reveals the wall of the spaces to be associated with granular calcifications and no obvious cellular lining .
the patient experienced no intraoperative or postoperative complications , and her postoperative hospital course was unremarkable . by postoperative day 2 , the patient had recovered full strength in her extremities but still had some residual numbness , and she was discharged to home in stable condition on postoperative day 3 . at 2-year follow - up ,
the patient continued to be free of her lower extremity pain and weakness and had not experienced any subsequent postsurgical complications ( fig . 5a and 5b ) .
( a ) postoperative plain film ( anterior - posterior ) showing removal of the mass and placement of fixation hardware .
mineralized , extradural lesions of the lumbar spine arising from the facet joint are uncommon causes of spinal pathology .
the differential diagnosis consists of several uncommon disorders , including synovial osteochondromatosis,14 tumoral calcinosis,15 tumoral calcium pyrophosphate dehydrate crystal deposition disease ( pseudogout),16 and lumbar presentation of ossification of the ligamentum flavum.17 the case we present here represents another potential consideration in that differential diagnosis .
completely calcified jfcs are rare , with only a handful of instances existing in the literature .
almefty et al presented four patients with multiple - level , bilateral , consistently calcified thoracic spinal cysts.12 these lesions were atypical due to their number , location , and mineralization .
kasliwal and deutsch presented on the case of a unilateral lumbar jfc at the l4l5 level.13 similar to our case , the patient presented with radicular symptoms in the setting of a lumbar lesion that appeared hypointense on t1- and t2-weighted mri .
it should be noted that calcification of jfcs can result from treatment as well , as mtellus et al noted a case of a cyst undergoing complete calcification after intracystic steroid injection therapy.11
the case presented here was remarkable not just for its mineralization but also for its size .
jfcs have typically been recorded to be between 10 and 20 mm in diameter at their widest dimension on imaging.10
18 the case we report here , however , measured 54 mm at its widest dimension , showing significant extension into nearby structures .
moreover , although jfcs frequently extend into the spinal canal and cause compression of the thecal sac,2 the majority of the lesion in our case existed outside the spinal canal .
this may explain how the cyst grew to be so large before the patient presented for evaluation .
it should also be noted that our patient 's medical history included rheumatoid arthritis and scleroderma , and systemic inflammatory diseases have been associated with jfcs in the past.1
19 moreover , inflammatory arthritides are known to contribute to the pathogenesis of synovial cysts outside of the spine.20 however , no studies to date have established systemic inflammation as a risk factor for jfc development , and the role of inflammatory joint disease in the pathogenesis jfcs remains unclear .
many methods of treating jfcs have been described , including simple laminotomy with cystectomy and the potential addition of a laminectomy , hemilaminectomy , mesial facetectomy , or foraminotomy.3
4 minimally invasive approaches with tubular retractors have also been described.19
21 in terms of treatment of this patient , it was presumed that the symptoms of back pain were secondary to facet dysfunction and that the left - sided plantar flexion weakness was due to foraminal stenosis . due to the size and mineralization of the lesion
, it was felt that a complete facetectomy was needed to adequately address the underlying pathology , necessitating a concurrent fusion .
our case highlights the significant variation that exists in the size , location , and content of jfcs .
although uncommon , jfcs should be considered in the differential diagnosis of lesions arising from the facet joint , even if they appear calcified and noncystic in nature . |
study design case report .
objective to report the case of one patient who developed a giant , completely calcified , juxtafacet cyst .
methods a 57-year - old woman presented with a 2-year history of progressively worsening lower back pain , left leg pain , weakness , and paresthesias .
imaging showed a giant , completely calcified mass arising from the left l5s1 facet joint , with coexisting grade i l5 on s1 anterolisthesis .
the patient was treated with laminectomy , excision of the mass , and l5s1 fixation and fusion .
results the patient had an uncomplicated postoperative course and had complete resolution of her symptoms as of 1-year follow - up .
conclusions when presented with a solid - appearing , calcified mass arising from the facet joint , a completely calcified juxtafacet cyst should be considered as part of the differential diagnosis . | [
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panax ginseng ( ginseng ) has been used traditionally in eastern asia over thousands of years .
it has been used orally to treat various diseases including hypertension , diabetes mellitus , liver and kidney dysfunction , mental disorders , and postmenopausal disorders .
in addition , topical applications have also been used to heal wounds and reduce skin inflammation . in the past few decades
, it has been proved that ginseng extracts actually show a wide range of effects against human diseases .
their potential therapeutic effects have been mainly attributed to its immunomodulatory , neuroprotective , antioxidative , antitumor , and hepatoprotective activities .
ginseng contains a number of active ingredients including ginsenosides , polysaccharides , phytosterols , peptides , polyacetylenes , fatty acids , and polyacetylenic alcohols , which have different effects on carbohydrate and lipid metabolism , cognition , angiogenesis , and the neuroendocrine , immune , cardiovascular , and central nervous systems . among the active constituents of ginseng ,
ginsenosides are known to be the major biologically active components of ginseng and the most widely studied .
several studies have shown that ginsenosides play important roles in the pharmacological effects of ginseng .
. however , ginseng contains other constituents , including ginsenoyne , phenolic compounds , polyacetylenes , sesquiterpenes , methoxypyrazine , alkylpyrazine derivatives , sesquiterpene alcohols , panasinsanols , and -carboline .
white ginseng is peeled , dried , ginseng root and red ginseng is produced by steaming fresh ginseng root at 98100c for 23 h , and then drying until the moisture content is < 15% .
red and white ginseng have both been shown to have immunomodulatory , anti - inflammatory , antioxidant , and antiatopic activities . moreover ,
red ginseng has been reported to have more potent pharmacological activities than white ginseng in some respects [ 2022 ] .
the differences in biological activities between red and white ginseng are caused by the chemical changes of ginsenosides after the steaming process .
steaming partially converts the original ginsenosides to deglycoslated derivatives . as a result , the species and amounts of ginsenosides are quite different based on the processing method used .
chu et al showed that a total of 53 and 43 compounds were tentatively identified in white ginseng and red ginseng samples , respectively .
the featured compounds are mainly malonyl ginsenosides in white ginseng , and decarboxyl products of mal - ginsenosides and the dehydrated compounds from polar ginsenosides were characteristic in red ginseng .
it is interesting that ginsenosides show a wide variety of biological activities , although the absorption rates from orally administered intact ginsenosides are very low . in the human intestinal tract ,
thus , the pharmacological actions of these ginsenosides have been closely related to their biotransformation by human intestinal bacteria . in this context
several studies showed that the transformation of ginsenosides into deglycosylated ginsenosides is needed to increase ginseng 's effectiveness in vivo
.
abnormal changes in skin color induce significant cosmetic problems with a negative effect on quality of life .
there are two groups of pigmentary disorders : disorders of the quantitative and qualitative distribution of normal pigment and the abnormal presence of exogenous or endogenous pigments in the skin .
hyperpigmentation - related diseases include melasma , lentigines , nevus , ephelis , freckles , postinflammatory hyperpigmentation , and age spots .
postinflammatory hyperpigmentation appears in many skin conditions , including acne , eczema , and contact dermatitis .
skin color is determined by various factors including melanin content , oxygenation state of hemoglobin in capillary vessels , carotenoid content , water content , and organization of collagen fibers in the dermis . among these factors , melanin is the major determinant of skin color . in this context ,
melanogenesis is a biochemical pathway responsible for melanin synthesis that is controlled by complex regulatory mechanisms .
melanogenesis occurs in melanocytes confined in separate cytoplasmic organelles called melanosomes , which contain key enzymes of melanogenesis .
differences in skin color are related to the size , number , shape , and distribution of melanosomes , whereas melanocyte density typically remains relatively constant .
although tyrosinase is the key regulatory enzyme of melanogenesis , tyrosinase - related protein ( trp)-1 , dopachrome tautomerase ( dct / trp2 ) , and melanosomal matrix proteins ( pmel17 , mart-1 ) carry out important roles in regulating melanogenesis .
the genes of tyrosinase , trp-1 , and dct contain common transcription starting sites , the microphthalmia - associated transcription factor ( mitf ) binding sites .
the intracellular signal transduction pathways of protein kinase c , cyclic amp ( camp ) , and nitrogen oxide are involved in the regulation of melanogenesis .
various endogenous and exogenous factors , such as estrogen and ultraviolet ( uv ) radiation , affect melanogenesis via signal transduction pathways .
these endogenous / exogenous factors exert their actions directly on melanocytes or indirectly via surrounding skin cells .
melanocytes , keratinocytes , dermal fibroblasts , and other skin cells communicate with each other by factors that are secreted and cell cell contacts .
it has been shown that the interactions between keratinocytes and melanocytes are critical in the regulation of melanogenesis .
in addition , dermal factors have been found to be involved in the regulation of melanogenesis . at the same time , stimulated melanocytes secret a number of signal molecules targeting not only keratinocytes but also skin immune cells .
soluble factors released by melanocytes include proinflammatory cytokines and chemokines such as interleukin ( il)-1/1 , il-6 , il-8 il-10 , tumor necrosis factor ( tnf)- , transforming growth factor ( tgf)- , catecholamines , eicosanoids , serotonin , -melanocyte stimulating factor ( -msh ) , and nitric oxide ( no ) .
a variety of hypopigmenting agents including hydroquinone , arbutin , tretinoin , kojic acid , azelaic acid , vitamin c , n - acetylglucosamine , niacinamide , linoleic acid , ellagic acid , methimazole , dioic acid , soy extract , licorice extract , rucinol , and glycolic acid have been used alone or in combination to treat abnormal hyperpigmentation .
these agents can interfere with the pigmentation process at several different steps of skin pigmentation .
however , the treatment of hyperpigmented conditions still remains challenging and the results are often discouraging .
thus there is a need for novel skin - whitening agents that are highly effective and tolerable . in this article
, we review recent reports investigating the skin - whitening effect of ginseng and its components and the underlying mechanisms of action , and then discuss their potential as candidates for novel skin - whitening agents .
p. ginseng is one of the most widely used medicinal plants in traditional oriental medicine . over thousands of years
, it has been used to improve the overall condition of skin , as well as to treat a wide variety of diseases . however
, genuine scientific approaches to clarify the efficacy of ginseng in skin have only been made in recent years .
several reports have shown that ginseng extract , powder , or some other constituents could inhibit melanogenesis in vitro and in vivo . table 1 summarizes the direct effects of ginseng and its components on skin color and key enzymes involved in melanogenesis .
song et al reported that red ginseng powder improved melasma in a human clinical trial .
they orally administered korean red ginseng powder for 24 weeks to female patients with melasma .
after 24 weeks , the melasma area and severity index score decreased and melasma quality of life scale showed improvement in 91% of patients .
in addition , 74% of the patients showed some improvement on the patient- and investigator - rated global improvement scales .
most of reports investigating the antimelanogenic effect of ginseng were conducted in vitro used purified tyrosinase or melanocyte cell lines . in melan - a cells treated with ethanol extract of ginseng seeds , melanin content and
in addition to the crude extract or powder , several studies tested the effects of specific constituents of ginseng . the phenol compounds inhibited tyrosinase activity while ginsenoside prevents uvb - induced intracellular increase of reactive oxygen species [ 4648 ] . in some reports , ginsenosides alone exerted antimelanogenic effects .
aglycone of ginsenoside rh4 inhibited melanin synthesis in b16 melanoma cells , possibly by involvement of protein kinase a pathway .
it significantly reduced melanin content and tyrosinase activity in -msh and forskolin - stimulated b16 melanoma cells .
it reduced the camp level and camp response - element binding protein level in b16 melanoma cells , and this might be responsible for the downregulation of mitf and tyrosinase .
in addition , ginsenoside rb1 inhibited melanogenesis through the inhibition of tyrosinase activity in -msh - stimulated b16 cells in a dose - dependent manner .
the crude methanol extract of the fresh leaves of p. ginseng showed inhibitory activity on mushroom tyrosinase , and p - coumaric acid was characterized as the principal tyrosinase inhibitor in the extract .
p - coumaric acid inhibited melanogenesis in b16f10 melanoma cells stimulated by -msh , and was suggested to interfere with melanogenesis by its structural similarity with tyrosine .
interestingly , p - coumaric acid showed weaker inhibition against mushroom tyrosinase but more strongly inhibited human or murine tyrosinase in comparison with kojic acid and arbutin .
enzyme kinetics analysis indicate that p - coumaric acid is a mixed type ( for tyrosine ) or competitive inhibitor ( for dopa ) of human tyrosinase .
in addition , p - coumaric acid potently inhibits melanogenesis in human epidermal melanocytes exposed to uvb .
cinnamic acid , one of the major components of cinnamomum cassia blume , is found in the root and seed of p. ginseng
.
cinnamic acid significantly reduced melanin production , tyrosinase activity , and tyrosinase expression in the melan - a cells .
in addition , cinnamic acid showed depigmenting activity on the uvb - tanned skin of brown guinea pigs .
it is already known that the pharmacological actions of these ginsenosides have been closely related to their biotransformation by human intestinal bacteria . although the contents of total ginsenosides in red ginseng and fermented red ginseng using lactobacillus brevis were not significantly different , the ginsenoside metabolite content was higher in fermented red ginseng compared to red ginseng .
the tyrosinase inhibitory activity of fermented red ginseng extract was more potent compared with red ginseng extract in a test using mushroom tyrosinase .
as reviewed above , crude extract or some components of ginseng and its components showed antimelanogenic activities by direct inhibition on key enzymes of melanogenesis , such as tyrosinase .
moreover , ginseng and its components could exert antimelanogenic activity via action on the several factors related in melanocyte physiology . among a large number of soluble factors produced from melanocytes , keratinocytes , fibroblasts , and immune cells in skin , adrenocorticotropic hormone ( acth ) , -msh , endothelin-1 , prostaglandin e2 , prostaglandin f2 , no , and histamine are well - known stimulators of melanogenesis [ 37,5963 ] .
il-1/1 and granulocyte - macrophage colony - stimulating factor ( gm - csf ) stimulate melanogenesis , while il-6 , tgf-1 , and tnf- downregulate melanin production .
gm - csf has been reported to be involved in regulating the proliferation and differentiation of epidermal melanocytes .
treatment of melan - a cells with conditioned media from uv - irradiated sp-1 keratinocytes increased melanocyte proliferation , and the proliferative effect of the conditioned media was blocked by anti - gm - csf antibody treatment . when uv - irradiated sp-1 keratinocytes were treated with red ginseng extract or saponin of red ginseng , the increased melanocyte proliferation by the conditioned media was blocked . in that report ,
red ginseng extract or saponin of red ginseng treatment decreased the expression of gm - csf induced by uv - b irradiation in sp-1 keratinocytes .
as mentioned above , inflammatory cytokines such as il-1 and tnf- take part in the regulation of melanogenesis .
ginseng extracts and ginsenosides have been reported to have anti - inflammatory activities in several different studies .
ginsenosides inhibit different inducer - activated signaling protein kinases and transcription factor nuclear factor ( nf)-b , and then decrease the production of proinflammatory cytokines and mediators of inflammation .
korean red ginseng extracts decreased tnf- and il-8 production in lipopolysaccharide ( lps)-stimulated hacat keratinocytes and show radical scavenging and antioxidant activity in human dermal fibroblasts .
these findings suggest that ginseng extracts and ginsenosides might affect melanogenesis through their anti - inflammatory activities . the effect of ginseng on no production is still questionable .
sun ginseng , a new processed ginseng prepared by steaming at high temperature , reduced uv - b - induced cell damage and decreased no production by inhibition of inducible no synthase mrna synthesis in hacat keratinocytes and human dermal fibroblasts .
red ginseng marc oil inhibited inducible no synthase and cyclooxygenase-2 via nf-b and p38 pathways in lps - stimulated raw264.7 cells .
in addition , ginsenjilinol , a protopanaxatriol - type saponin obtained from the roots of p. ginseng , shows inhibitory activity on no production in lps - stimulated raw264.7 cells .
by contrast , there are some controversial reports that ginseng extract enhanced no production or no signaling .
hong et al reported that ginseng extract administration stimulated nongenomic endothelial no synthase activation and enhanced no production in spontaneously hypertensive rats . in another report , water extract of korean red ginseng exerted vasoprotective effects through augmentation of no production by inhibiting arginase .
therefore , the effect of ginseng on melanogenesis via no signaling remains to be clarified by further study .
considerable numbers of immune cells including langerhans cells , macrophages , mast cells , and t cells are working actively in skin tissue . because the immunostimulatory activities of many ginsenosides are known , it is not surprising that ginsenosides could enhance the reactivity of skin immune cells . in a recent paper ,
a cream containing 0.1% ginsenoside f1 ( a metabolite of ginsenoside rg1 ) showed a significant whitening effect on artificially tanned human skin .
however , ginsenoside f1 did not directly inhibit mrna expression of tyrosinase or dct in normal human epidermal melanocytes .
instead , ginsenoside f1 enhanced production of il-13 from human epidermal t cells , and il-13 significantly reduced the mrna expression and protein amount of both tyrosinase and dct resulting in visible brightening of normal human epidermal melanocyte pellets .
these results suggest that ginsenosides might be able to regulate melanogenesis via their effect on skin immune cells .
recently , several reports have shown that extract , powder , or some constituents of ginseng could inhibit melanogenesis in vivo or in vitro
. the underlying mechanisms of the antimelanogenic effect of ginseng or its components included the direct inhibition of key enzymes of melanogenesis ( tyrosinase and dct ) , inhibition of transcription factors ( mitf , nf-b ) or signaling pathways ( protein kinase a pathway and protein kinase c pathway ) involved in melanogenesis , decreasing the production of inducers of melanogenesis ( camp , gm - csf ) , and enhancing production of antimelanogenic factor ( il-13 ) . fig .
although issues surrounding the antimelanogenic activity of ginseng still remain controversial , especially in its effect on the production of proinflammatory cytokines and no , these recent findings suggest that ginseng and its constituents might be potential candidates for novel skin - whitening agents . | abnormal changes in skin color induce significant cosmetic problems and affect quality of life .
there are two groups of abnormal change in skin color ; hyperpigmentation and hypopigmentation .
hyperpigmentation , darkening skin color by excessive pigmentation , is a major concern for asian people with yellow brown skin .
a variety of hypopigmenting agents have been used , but treating the hyperpigmented condition is still challenging and the results are often discouraging .
panax ginseng has been used traditionally in eastern asia to treat various diseases , due to its immunomodulatory , neuroprotective , antioxidative , and antitumor activities . recently
, several reports have shown that extract , powder , or some constituents of ginseng could inhibit melanogenesis in vivo or in vitro .
the underlying mechanisms of antimelanogenic properties in ginseng or its components include the direct inhibition of key enzymes of melanogenesis , inhibition of transcription factors or signaling pathways involved in melanogenesis , decreasing production of inducers of melanogenesis , and enhancing production of antimelanogenic factor .
although there still remain some controversial issues surrounding the antimelanogenic activity of ginseng , especially in its effect on production of proinflammatory cytokines and nitric oxide , these recent findings suggest that ginseng and its constituents might be potential candidates for novel skin whitening agents . | [
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] |
aneuploid strains were generated by sporulation of the above polyploid strains , followed by karyotype stability tests and determination as described in fig .
qpcr assays were designed with primers in non - coding regions on each chromosome arm ( supplementary table 1 lists primer sequences ) .
dna samples were prepared by alkaline lysis , and qpcr reactions were performed in 384-well plates using a biomek fx ( beckman coulter ) to assemble 10 l reactions and an abi 7900ht ( applied biosystems ) for cycling .
equal amounts ( od600 ) of aneuploid and euploid control cultures were spotted , using the biomek fx robot , onto omnitrays containing various solid media and grown under conditions listed in supplementary table 2 .
omnitrays representing three biological replicates of each tested condition were scanned on an hp scanjet 4070 desktop scanner .
whole - cell lysates were prepared from 50 ml cycling yeast cultures by bead - beating .
the ms / ms datasets were searched using sequest23 against a database of 11,986 sequences , consisting of 5,816 s. cerevisiae non - redundant proteins ( ncbi ) , 177 contaminants and 5,993 decoy sequences .
all statistical analyses were performed in the r environment25 using standard packages and custom scripts .
aneuploid strains were generated by sporulation of the above polyploid strains , followed by karyotype stability tests and determination as described in fig .
qpcr assays were designed with primers in non - coding regions on each chromosome arm ( supplementary table 1 lists primer sequences ) .
dna samples were prepared by alkaline lysis , and qpcr reactions were performed in 384-well plates using a biomek fx ( beckman coulter ) to assemble 10 l reactions and an abi 7900ht ( applied biosystems ) for cycling .
equal amounts ( od600 ) of aneuploid and euploid control cultures were spotted , using the biomek fx robot , onto omnitrays containing various solid media and grown under conditions listed in supplementary table 2 .
omnitrays representing three biological replicates of each tested condition were scanned on an hp scanjet 4070 desktop scanner .
whole - cell lysates were prepared from 50 ml cycling yeast cultures by bead - beating .
the ms / ms datasets were searched using sequest23 against a database of 11,986 sequences , consisting of 5,816 s. cerevisiae non - redundant proteins ( ncbi ) , 177 contaminants and 5,993 decoy sequences .
all statistical analyses were performed in the r environment25 using standard packages and custom scripts . | aneuploidy , referring here to genome contents characterized by abnormal numbers of chromosomes , has been associated with developmental defects , cancer , and adaptive evolution in experimental organisms19 .
however , it remains unresolved how aneuploidy impacts gene expression and whether aneuploidy could directly bring phenotypic variation and improved fitness over that of euploid counterparts . in this work
, we designed a novel scheme to generate , through random meiotic segregation , 38 stable and fully isogenic aneuploid yeast strains with distinct karyotypes and genome contents between 1n and 3n without involving any genetic selection . through phenotypic
profiling under various growth conditions or in the presence of a panel of chemotherapeutic or antifungal drugs , we found that aneuploid strains exhibited diverse growth phenotypes , and some aneuploid strains grew better than euploid control strains under conditions suboptimal for the latter . using quantitative mass spectrometry - based proteomics ,
we show that the levels of protein expression largely scale with chromosome copy numbers , following the same trend observed for the transcriptome .
these results provide strong evidence that aneuploidy directly impacts gene expression at both the transcriptome and proteome levels and can generate significant phenotypic variation that could bring about fitness gains under diverse conditions .
our findings suggest that the fitness ranking between euploid and aneuploid cells is context- and karyotype - dependent , providing the basis for the notion that aneuploidy can directly underlie phenotypic evolution and cellular adaptation . | [
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] |
the chemistry of metallocenes rapidly expanded in the 1970s with organozircocene emerging as one of the most useful classes of transition metal derivatives for use in organic synthesis .
one important reagent belonging to this class of organometallic compounds is the chlorobis(cyclopentadienyl)hydrido - zirconium 1 , also called zirconocene hydrochloride but better known as schwartz 's reagent .
wailes and weigold
were the first to prepare 1 and , subsequently , schwartz
and many other scientists exploited its potential in the functionalization of organic compounds .
selected examples of the utility of this reagent in organic synthesis are depicted in figure 1 .
schwartz 's reagent is most often used in the hydrozirconation of triple and double bonds ( figure 1 , reaction a ) .
however , its use in this reaction is sometimes hampered by the functional group compatibility of the process that is limited by the oxophilic , hard lewis - acid character of the schwartz reagent .
this characteristic has been therefore exploited in other useful synthetic organic transformations such as the chemoselective reduction of tertiary amides to aldehydes ( figure 1 , reaction b ) ,
and the reduction of secondary amides to n - substituted imines ( figure 1 , reaction c ) .
the latter transformation , when performed with most other metal hydride reagents , results either in over - reduction of the imine to give the corresponding amine or in the reductive cleavage of the amide .
interestingly , 1 has also been employed as a reducing agent for phosphine oxides to the corresponding phosphines ( figure 1 , reaction d ) .
recently , bhat and co - workers reported a very mild and useful deacetylation procedure of acetamides involving reagent 1 .
the methodology proved to be very efficient for aromatic , heteroaromatic , and aliphatic amides and moreover no epimerization was observed during the n - deacetylation of chiral acetamides .
the amine functionality is present in many compounds of biological interest ,
for instance natural products and pharmaceuticals .
nucleoside and nucleotide chemistry frequently involves protecting procedures at the amine and hydroxyl groups and benefit of selective deprotection methods , in order to obtain the target compound efficiently without any side reactions .
n - acetyl protection is one of the most widely used in nucleoside and nucleotide chemistry .
however , the requirement of strong base or acid and/or high reaction temperatures
during the deprotection step ( n - deacetylation ) is often not compatible with some nucleosidic substrates and especially their prodrugs .
harsh conditions are also likely to yield fully deprotected products , an outcome often undesired .
zinc bromide
and hydrazine hydrate
were initially reported as selective and mild n - deacetylating agents for nucleosides , although their compatibility with other protecting groups was not explored broadly .
our goal was the identification of a selective n - deacetylation methodology involving mild reaction conditions that could be applied to a broad spectrum of differently protected nucleosides .
therefore , we became immediately interested in bhat 's methodology
and in its possible application in nucleoside chemistry .
to the best of our knowledge , no attempt to use schwartz 's reagent in the n - deacetylation of nucleosides and their prodrugs has been previously reported .
herein , we would like to report our efforts directed at deacetylation of n - acetyl purine and pyrimidine nucleoside analogues bearing a variety of protecting groups ( pgs ) at the hydroxyl moiety , commonly used in nucleoside chemistry , such as o - acetyl , o - tert - butyloxycarbonyl , o - tert - butyldimethylsilyl , o - tetrahydropyranyl , o - benzoyl , and o - isopropylidene groups , with the aim of evaluating the ability of reagent 1 to selectively remove the acetyl group from the amino moiety , leaving the other pgs untouched .
our investigation began with the preparation , according to literature procedures , of differently substituted n - acetyl-2-deoxycytidine ( 2a - c ) and n - acetylcytidine ( 2d - g ) , as indicated in table 1 . with all the o - protected nucleosides in hand , we proceeded to test the deacetylation reaction .
first , compound 2a was subjected to the action of three equivalents of reagent 1 in a thf solution , under a nitrogen atmosphere , for 30 minutes ( table 1 , entry 1 ) .
pleasingly , we were able to isolate after aqueous work - up and column chromatography compound 3a in 57% yield , where only the n - acetyl group was removed .
application of these conditions to 2b , once again , led to the selective removal of the acetyl group from the amino moiety without affecting the silicon protected hydroxyl groups and yielding 3b in 49% yield ( table 1 , entry 2 ) .
table 1 deacetylation reaction of differentially protected n - acetyl-2-deoxycytidines and n - acetylcytidines , promoted by schwartz reagententrycpdr1r2r31 ( eq)temp ( c)time ( h)prod.yield ( % ) recovered sm ( % ) 12ahacac3rt0.53a574022bhtbdmstbdms3rt0.53b493332chthpthp3rt33c682042dohbocboc3rt0.53d395552eoacacac3rt33e702362fobzbzbz3rt33f534172gcme2 h3rt33g553882ahacac6rt33a554292ahacac370123a4839
similar results were obtained testing the compatibility of schwartz 's reagent with other protecting groups such as tetrahydropyranyl , tertbutoxycarbonyl , benzoyl , and isopropylidene ( table 1 , entries 37 ) . in all examples ,
the o - protecting groups were unaffected by this procedure , and only the acetyl group on the nucleobase was removed , affording the desired compounds in moderate to good yields ( 3970% ) , along with the recovery of unreacted starting material .
attempts to increase the yield of the desired n - deacetylated nucleoside either by increasing the equivalents of 1 ( up to six ) or by adding it portionwise over a period of three hours , proved to be unsuccessful and some amount of starting material was always recovered ( table 1 , entry 8) .
incrementing the temperature up to 70c did not enhance the yield ( table 1 , entry 9 ) .
subsequently , we decided to broaden the scope of the methodology by testing it on examples of other pyrimidine and purine nucleoside derivatives bearing different pgs ( table 2 ) .
lamivudine was acetylated on both oxygen and amine groups and the resulting n , o - diacetylated compound 2h was then submitted to the deacetylating protocol ( table 2 , entry 1 ) .
as expected , the acetyl group was removed only from the nitrogen on the nucleobase , leaving the o - acetyl group untouched .
table 2
n - deacetylation of protected pyrimidine and purine nucleosides , promoted by schwartz 's reagententrycompoundproductyield ( % ) 1 56 5 53 2 25 3 47 4 76
n - acetyl - o - trityl - lamivudine 2i was found to be a poor substrate for this protocol ( table 2 , entry 2 ) .
the desired product 3i was obtained only in 25% isolated yield , most probably due to the partial trityl group instability to the reaction conditions .
no starting material was isolated in this case . when the protocol was tested on purine nucleoside analogues , reagent 1 proved efficient in removing the acetyl group selectively from the amine group on both the guanine ring of peracetylated acyclovir 2j and the adenine ring of n - acetyl-5-o - acetyl-2,3-o - isopropylidene adenosine 2k , affording 3j and 3k respectively in 47% and 76% isolated yields ( table 2 , entries 3,4 ) . finally ,
n , n - diacetyl-2,3-isopropylidene adenosine 2l was submitted to the optimized protocol . in this case schwartz 's reagent was able to remove both n - acetyl groups , affording compound 3k in 53% yield , with only traces of mono - n - acetylated derivative 2k .
.
reported a practical method to generate schwartz 's reagent in situ using li(ot - bu)3alh , demonstrating the advantage of this procedure both in reducing tertiary amides to aldehydes and in hydrozirconation reactions , in comparison to the use of the commercial schwartz 's reagent .
we , therefore , decided to assess this efficient procedure in the deacetylation of nucleoside 2 g in order to be able to compare the in situ methods with the use of the preformed 1 ( scheme 1 ) .
therefore , to a thf solution of 2 g and 1.5 equivalents of cp2zrcl2 in thf , solid li(ot - bu)3alh was added in one portion and the mixture was stirred for 40 minutes .
aqueous workup , followed by column chromatography , afforded compound 3 g in 80% isolated yield , demonstrating a yield improvement from the previous 55% , possibly due to the partial air , light , and moisture sensitivity of 1 , which are reported to be responsible for the reduction of its effectiveness with time .
figure 1
n - deacetylation of n - acetyl-2,3-o - isopropylidene cytidine 2 g with in situ generated schwartz 's reagent 1 .
nucleoside analogues ( nas ) are an important class of molecules accounting for half of all antiviral drugs currently on the market and a number of anticancer agents that are widely used .
unfortunately , many nucleoside analogues are not phosphorylated effectively in vivo , and thus their therapeutic potential is often quite limited . using various approaches ,
the ionizable phosphate group can be masked by derivatization , generating prodrugs with increased biological activity .
among different nucleoside monophosphate prodrug strategies
is the phosphoroamidate prodrug approach ( protide ) , consisting of an amino acid ester promoiety linked via p
gilead has just launched on the market its anti - hcv protide , sofosbuvir ( psi-7977 ) ,
whereas nucana biomed has taken to trial a gemcitabine protide ( nuc-1031 ) , for patients with advanced solid tumours .
considering the importance that the protide technology is assuming in the antiviral and anticancer scenarios , we were interested in checking if schwartz 's reagent is compatible with the phosphoramidate motif and whether this protocol can be used at later stage in the synthesis of this class of prodrugs .
figure 2 synthesis and deacetylation of n - acetyl-2,3-o - isopropylidene- cytidine-5-o-[napthyl ( cyclohexyl - l - alanyl ) ] phosphate ( 5 ) promoted by schwartz reagent .
phosphoroamidate 5 was synthesized from 2 g and ( 2s)-cyclohexyl 2-((chloro(naphthalen-1-yloxy)phosphoryl)amino)propanoate 4 in 40% yield ( scheme 2 ) , according to a previously described method .
phosphoroamidate 5 was then treated with three equivalents of the schwartz 's reagent , yielding the corresponding deacetylated prodrug 6 in 65% isolated yield .
at the same time we were conducting our investigations , snieckus et al .
reported a practical method to generate schwartz 's reagent in situ using li(ot - bu)3alh , demonstrating the advantage of this procedure both in reducing tertiary amides to aldehydes and in hydrozirconation reactions , in comparison to the use of the commercial schwartz 's reagent .
we , therefore , decided to assess this efficient procedure in the deacetylation of nucleoside 2 g in order to be able to compare the in situ methods with the use of the preformed 1 ( scheme 1 ) .
therefore , to a thf solution of 2 g and 1.5 equivalents of cp2zrcl2 in thf , solid li(ot - bu)3alh was added in one portion and the mixture was stirred for 40 minutes .
aqueous workup , followed by column chromatography , afforded compound 3 g in 80% isolated yield , demonstrating a yield improvement from the previous 55% , possibly due to the partial air , light , and moisture sensitivity of 1 , which are reported to be responsible for the reduction of its effectiveness with time .
figure 1
n - deacetylation of n - acetyl-2,3-o - isopropylidene cytidine 2 g with in situ generated schwartz 's reagent 1 .
nucleoside analogues ( nas ) are an important class of molecules accounting for half of all antiviral drugs currently on the market and a number of anticancer agents that are widely used .
nas mostly require phosphorylation to be active . unfortunately , many nucleoside analogues are not phosphorylated effectively in vivo , and thus their therapeutic potential is often quite limited .
using various approaches , the ionizable phosphate group can be masked by derivatization , generating prodrugs with increased biological activity .
among different nucleoside monophosphate prodrug strategies
is the phosphoroamidate prodrug approach ( protide ) , consisting of an amino acid ester promoiety linked via p
gilead has just launched on the market its anti - hcv protide , sofosbuvir ( psi-7977 ) ,
whereas nucana biomed has taken to trial a gemcitabine protide ( nuc-1031 ) , for patients with advanced solid tumours .
considering the importance that the protide technology is assuming in the antiviral and anticancer scenarios , we were interested in checking if schwartz 's reagent is compatible with the phosphoramidate motif and whether this protocol can be used at later stage in the synthesis of this class of prodrugs .
figure 2 synthesis and deacetylation of n - acetyl-2,3-o - isopropylidene- cytidine-5-o-[napthyl ( cyclohexyl - l - alanyl ) ] phosphate ( 5 ) promoted by schwartz reagent .
phosphoroamidate 5 was synthesized from 2 g and ( 2s)-cyclohexyl 2-((chloro(naphthalen-1-yloxy)phosphoryl)amino)propanoate 4 in 40% yield ( scheme 2 ) , according to a previously described method .
phosphoroamidate 5 was then treated with three equivalents of the schwartz 's reagent , yielding the corresponding deacetylated prodrug 6 in 65% isolated yield .
in conclusion , we have demonstrated that the general and mild method for the deacetylation of n - acetyl group developed by bhat et al . can be successfully applied to purine and pyrimidine nucleosides , with diverse o - protection .
moreover , we have shown that schwartz 's reagent is compatible with the phosphoramidate moiety and can be used for n - deacetylation reaction in the later stages of the synthesis of this class of nucleoside monophosphate prodrugs .
lastly , we have proved that modification of the reported procedure
involving in situ generation of schwartz 's reagent leads to yield improvement and is promising of similar results on other nucleoside substrates .
schwartz reagent was purchased from sigma - aldrich or prepared in situ as described and all nucleosides used as starting materials were purchased from carbosynth .
h nmr ( 500 mhz ) , c nmr ( 125 mhz ) , and p nmr ( 202 mhz ) spectra were recorded on a bruker avance 500 mhz spectrometer at 25c .
chemical shifts ( ) are quoted in parts per million ( ppm ) relative to internal cd3od ( 3.34 h nmr , 49.86 c nmr ) and cdcl3 ( 7.26 h nmr , 77.36 c nmr ) or external 85% h3po4 ( 0.00 p nmr ) .
the following abbreviations are used in the assignment of nmr signals : singlet ( s ) , doublet ( d ) , triplet ( t ) , quartet ( q ) , quintet ( qn ) , multiplet ( m ) , broad singlet ( bs ) , doublet of doublet ( dd ) , and doublet of triplet ( dt ) . high and low - resolution mass spectrometry analyses were performed on a bruker microtof - lc system .
to a stirred solution of n - acetyl nucleoside ( 100 mg ) in anhydrous thf ( 2 ml ) , schwartz 's reagent ( 36 eq . )
is added at room temperature and the reaction mixture is stirred for 0.53 hours .
the combined organic layer is washed with brine solution and dried over anhydrous na2so4 , filtered and evaporated to afford the crude product , which is purified by silica gel column chromatography to finally afford pure deacetylated nucleoside .
n - deacetylation reaction via in situ generation of schwartz 's .
to a solution of n - acetyl nucleoside ( 100 mg ) and cp2zrcl2
( 1.5 equiv ) in thf ( 2 ml ) at rt , solid lialh(otbu)3 ( 1.5 equiv ) was rapidly added .
the resulting solution was stirred at rt for 40 minutes and the reaction was monitored by tlc analysis .
the combined organic layer is washed with brine solution and dried over anhydrous na2so4 , filtered and evaporated to afford the crude product , which is purified by silica gel column chromatography to finally afford pure deacetylated nucleoside .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3a
as a white solid ( 0.050 g , 57% yield ) .
h nmr ( 500 mhz ) cdcl3 h 2.08 ( 3h , s , ococh3 ) , 2.09 ( 3h , s , ococh3 ) , 2.192.12 ( 1h , m , h-2a ) , 2.58 ( 1h , dd , j = 4.0 , 14.0 hz , h-2b ) , 4.244.26 ( 1h , m , h-4 ) , 4.32 ( 2h , d , j = 12.5 hz , h-5 ) , 5.185.19 ( 1h , m , h-3 ) , 6.11 ( 1h , d , j = 6.5 hz , h-5 ) , 6.22 ( 1h , t j = 6.5 hz , h-1 ) , 7.57 ( 1h , d , j = 6.5 hz , h-6 ) .
c nmr ( 125 mhz ) cdcl3 c 20.90 , 20.98 ( ch3 ) , 38.24 ( ch2 - 2 ) , 63.82 ( ch2 - 5 ) , 74.12 ( c-3 ) , 82.63 ( c-4 ) , 88.18 ( c-1 ) , 95.87 ( c-5 ) , 140.21 ( c-6 ) , 170.32 ( c - o ) , 155.15 ( c-2 ) , 164.90 ( c-4 ) ; ms ( es+ ) m / z ( 312 ) [ m+1 ] ; hrms ( es ) m / z found 312.1192 [ calcd for c13h18n3o6
( m+h ) 312.1190 ] .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3b
as a white solid ( 0.044 g , 49% ) .
h nmr ( 500 mhz ) cdcl3 h 0.12 ( 6h , s , 2 ch3 ) , 0.15 ( 6h , s , 2 ch3 ) , 0.91 ( 9h , s , c(ch3)3 ) , 0.98 ( 9h , s , c(ch3)3 ) , 2.092.13 ( 1h , m , h-2a ) , 2.352.40 ( 1h , m , h-2b ) , 3.83 ( 1h , dd , j = 2.5 , 11.5 hz , h-5a ) , 3.92 ( 1h , dd , j = 3.0 , 11.0 hz , h-5b ) , 3.933.96 ( 1h , m , h-4 ) , 4.474.49 ( 1h , m , h-3 ) , 5.89 ( 1h , d , j = 7.5 hz , h-5 ) , 6.24 ( 1h , t j = 6.0 hz , h-1 ) , 7.97 ( 1h , d , j = 7.5 hz , h-6 ) ; c nmr ( 125 mhz ) cdcl3 c 4.92 , 4.58 ( sich3 ) , 17.93 , 18.94 ( c(ch3)3 ) 26.04 , 26.22 ( c(ch3)3 ) , 42.13 ( c-2 ) , 62.04 ( c-5 ) , 70.44 ( c-3 ) , 85.80 ( c-1 ) , 87.25 ( c-4 ) , 94.26 ( c-5 ) , 141 ( c-6 ) , 155.94 ( c-2 ) , 165.87 ( c-4 ) ; ms ( es+ ) m / z 456 [ m+1 ] ; hrms ( es ) m / z found 456.2710 [ calcd for c21h42n3o4si2
( m+h ) 456.2708 ] .
3,5-o - bis(tetrahydropyranyl)-2-deoxycytidine ( 3c ) . prepared from 2c
according to standard procedure for the n - deacetylation reaction .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3c as a white solid ( 0.061 mg , 68% ) .
h nmr ( 500 mhz ) cd3od h 1.441.48 ( 8h , m , ch2 py ) , 1.611.76 ( 4h , m , ch2 py ) , 2.342.50 ( 1h , m , h-2b ) , 1.952.12 ( 1h , m , h-2a ) , 3.433.47 ( 2h , m , ch2o py ) , 3.51 ( 0.25h , dd , j = 3.0 , 11.0 hz , h-5b ) , 3.53 ( 0.25h , dd , j = 3.0 , 11.5 hz , h-5b ) , 3.543.61 ( 0.5h , dt j = 3.9 , 16.5 hz , h-5b ) , 3.713.82 ( 2h , m , ch2o py ) , 3.803.86 ( 0.5 , m , h-5a ) ,
3.903.95 ( 0.5h , m , h-5a ) , 4.074.11 ( 0.5h , m , h-4 ) , 4.134.15 ( 0.25h , m , h-4 ) , 4.174.19 ( 0.25h , m , h-4 ) , 4.294.31(0.25h , m , h-3 ) , 4.344.36 ( 0.5h , m h-3 ) , 4.404.41 ( 0.25h , m , h-3 ) , 4.554.67 ( 2h , m , cho py ) , 5.775.80 ( 1h , m , h-5 ) , 6.116.16 ( 1h , m , h-1 ) , 7.88 ( 0.25h , d , j = 7.5 hz , h-6 ) , 7.89 ( 0.25h , d , j = 7.5 hz , h-6 ) , 7.94 ( 0.25h , d , j = 7.5 hz , h-6 ) , 7.97 ( 0.25h , d , j = 7.0 hz , h-6 ) ; c nmr ( 125 mhz ) cd3od c 20.47 , 20.50 , 20.68 , 20.77 ( ch2 py ) , 26.51 , 26.55 ( ch2 py ) , 31.69 , 31.75 , 31.94 , 32.01 ( ch2 py ) , 39.54 , 39.71 , 40.82 , 40.98 ( c-2 ) , 63.69 , 63.73 , 63.75 , 63.92 ( ch2o ) , 68.30 , 68.42 , 68.49 , 68.80 ( c-5 ) , 77.39 , 77.82 , 78.25 ( c-3 ) , 85.41 , 85.47 , 85.97 , 85.18 ( c-4 ) , 87.65 , 87.83 , 87.87 , 87.97 ( c-1 ) , 95.80 , 95.90 ( c-5),99.29 , 99.36 , 99.79 , 99.88 , 100.14 , 100.33 , 100.97,101.03 ( ch py ) , 142.38 , 142.81 ( c-6 ) , 158.17 ( c-2 ) , 167.63 ( c-4 ) ; ms ( es+ ) m / z = 396 [ m+1 ] .
hrms ( es ) m / z found 396.2127 [ calcd for c19h30n3o6
( m+h ) 396.2129 ] .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3d as a white solid ( 0.035 g , 39% yield ) .
h nmr ( 500 mhz ) cd3od h 1.47 ( 9h , s , c(ch3)3 ) , 1.50 ( 9h , s , c(ch3)3 ) , 3.77 ( 1h , dd , j = 3.0 , 12.5 hz , h-5 ) , 3.88 ( 1h , dd , j = 2.5 , 12.5 hz , h-5 ) , 4.224.20 ( 1h , m , h-4 ) , 5.27 ( 1h , dd , j = 5.5 hz ,
j = 5.5 hz , h-3 ) , 5.32 ( 1h , dd , j = 4.0 , 4.0 hz , h-2 ) , 5.90 ( 1h , d , j = 7.5 hz , h-5 ) , 6.10 ( 1h , d , j = 4.5 hz , h-1 ) , 8.0 ( 1h , d , j = 7.5 hz , h-6 ) ; c nmr ( 125 mhz ) cd3od c 27.96 , 28.02 ( c(ch3)3 ) , 31.70 ( c(ch3)3 ) , 61.96 ( c-5 ) , 74.17 ( c-3 ) , 77.25 ( c-2 ) , 83.93 ( c-4 ) , 89.94 ( c-1 ) , 96.64 ( c-5 ) , 143.07 ( c-6 ) , 153.61 , 153.89 ( coc(ch3)3 ) , 158.01(c-2 ) , 167.56 ( c-4 ) ; ms ( es+ ) m / z = 444 [ m+1 ] . hrms ( es ) m / z found 444.1973 [ calcd for c19h30n3o9
( m+h ) 444.1977 ] .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3e
as a white solid ( 0.063 g , 70% yield ) .
h nmr ( 500 mhz ) cd3od h 2.10 ( 3h , s , coch3 ) , 2.11 ( 3h , s , coch3 ) , 2.12 ( 3h , s , coch3 ) , 4.344.40 ( 3h , m , h4 , h5 ) , 5.41 ( dd , j = 5.0 , 5.9 hz , 1h , h3 ) , 5.48 ( dd , j = 4.6 , 6.0 hz , 1h , h3 ) , 5.96 ( 1h , d , j = 7.5 hz , h5 ) , 5.98 ( 1h , d , j = 4.6 hz , h1 ) , 7.69 ( 1h , d , j = 7.5 hz , h6 ) ; c nmr ( 125 mhz ) cd3od c 20.40 ( coch3 ) , 20.45 ( coch3 ) , 20.69 ( coch3 ) , 64.32 ( c5 ) , 71.68 ( c3 ) , 74.69 ( c2 ) , 80.99 ( c4 ) , 91.09 ( c1 ) , 96.76 ( c5 ) , 143.23 ( c6 ) , 157.91 ( c4 ) , 167.82 ( c2 ) , 171.35 ( coch3 ) , 171.39 ( coch3 ) , 172.19 ( coch3 ) ; ms ( es+ )
. hrms ( es ) m / z found 370.1243 [ calcd for c15h20n3o8
( m+h ) 370.1245 ] .
cytidine 2 , 3 , 5-tribenzoate ( 3f ) . prepared from 2f
according to standard procedure for the n - deacetylation reaction .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 96/4 to give 3f
as a white solid ( 0.049 g , 53% yield ) .
h nmr ( 500 mhz ) cd3cl h 2.12 ( 3h , s , coch3 ) , 4.63 ( 1h , dd , j = 3.9 , 12.2 hz , h5 ) , 4.724.68 ( 1h , m , h4 ) , 4.76 ( 1h , dd , j = 2.8 , 12.2 hz , h5 ) , 5.745.78 ( 1h , m , h2 ) , 5.795.84 ( 1h , m , h3 ) , 6.31 ( 1h , d , j = 4.2 hz , h1 ) , 7.317.24 ( 5h , m , ph , h5 ) , 7.377.42 ( 2h , m , ph ) , 7.437.49 ( 2h , m , ph ) , 7.507.55 ( 1h , m , ph ) , 7.817.89 ( 5h , m , ph , h6 ) , 7.988.08 ( 2h , m , ph ) , 9.58 ( 1h , br s , nhcoch3 ) .
c nmr ( 125 mhz ) cd3cl c 63.92 ( c5 ) , 71.20 ( c3 ) , 74.45 ( c2 ) , 80.15 ( c4 ) , 89.25 ( c1 ) , 95.45 ( c5 ) , 128.46 ( ch ar ) , 128.49 ( ch - ar ) , 128.68 ( ch - ar ) , 128.75 ( c - ar ) , 129.40 ( c - ar ) , 129.71 ( ch - ar ) , 129.85 ( ch - ar ) , 129.97 ( ch - ar ) , 133.49 ( ch - ar ) , 133.61 ( ch - ar ) , 133.62 ( ch - ar ) , 141.36 ( c6 ) , 155.28 ( c5 ) , 165.33 ( coph ) , 165.37 ( coph ) , 165.39 ( c4 ) , 166.14 ( coph ) ; ms ( es+ ) m / z ( 556 ) [ m+1 ] ; hrms ( es )
m / z found 556.1711 [ calcd for c30h26n3o8
( m+h ) 556.1714 ] .
2 , 3-o - isopropylidene - cytidine ( 3 g ) . prepared from 2 g
according to standard procedure for the n - deacetylation reaction .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3 g
as a white solid ( 0.043 g , 49% yield ) .
prepared according to the in situ schwartz 's reagent generation procedure for the deacetylation reaction .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3 g as a white solid ( 0.070 g , 80% yield ) .
h nmr ( 500 mhz ) cd3od h 1.25 ( 3h , s , ch3 ) , 1.45 ( 3h , s , ch3 ) , 3.62 ( 1h , dd , j = 4.5 , 12.0 hz , h-5a ) , 3.69 ( 1h , dd , j = 3.5 , 12.0 hz , h-5b ) , 4.114.13 ( 1h , m , h-4 ) , 4.724.74 ( 1h , m , h-3 ) , 4.784.80 ( 1h , m , h-2 ) , 5.75 ( 1h , s , h-1 ) , 5.81 ( 1h , d , j = 7.5 hz , h-5 ) , 7.73 ( 1h , d , j = 7.5hz , h-6 ) ; c nmr ( 125 mhz ) cd3od c 25.55 ( cch3)2 ) , 27.55 ( cch3)2 ) , 63.19 ( c5 ) , 82.25 ( c3 ) , 86.40 ( c2 ) , 88.69 ( c4 ) , 95.45 ( c1 ) , 96.20 ( c5 ) , 115.03 ( cch3)2 ) , 144.42 ( c6 ) , 154.90 ( c2 ) , 167.82 ( c4).ms ( esi+ ) m / z = ( 284 ) [ m+1].hrms ( es ) m / z found 284.1243 [ calcd for c12h18n3o5
( m+h ) 284.1241 ] .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3h
as a white solid ( 0.048 g , 56% yield ) .
h nmr ( 500 mhz ) cd3od h 1.90 ( 3h , s , coch3 ) , 2.95 ( 1h , dd , j = 3.0 , 12.5 hz , h-4 ) , 3.35 ( 1h , dd , j = 5.5 , 12.5 hz , h-4 ) , 4.20 ( 1h , dd , j = 3.0 , 12.5 hz , ch2oh ) , 4.35 ( 1h , dd , j = 5.0 , 12.5 hz , ch2oh ) , 5.20 ( 1h , dd , j = 3.5 , 5.0 hz , h-2 ) , 5.70 ( 1h , d , j = 7.5 hz , h-5 ) , 6.10 ( 1h , dd , j = 3.5 , 5.5 hz , h-5 ) , 7.68 ( 1h , d , j = 7.5 hz , h-6 ) ; c nmr ( 125 mhz ) cd3od c 20.62 ( ch3 ) , 38.15 ( c-4 ) , 65.64 ( ch2oh ) , 84.44 ( c-2 ) , 89.11 ( c-5 ) , 96.03 ( c-6 ) , 142.49 ( c-5 ) , 157.83 ( c-2 ) , 167.72 ( c-4 ) , 172.08 ( coch3 ) ; ms ( esi+ ) m / z = 272 [ m+1 ] . hrms
( es ) m / z found 272.0701 [ calcd for c10h14n3o4s ( m+h ) 272.0700 ] .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3i as a white solid ( 0.023 g , 25% yield ) .
h nmr ( 500 mhz ) cdcl3 h 3.09 ( 1h , dd , j = 2.5 , 12.5 hz , h-4 ) , 3.44 ( 1h , dd , j = 5.5 , 12.5 hz , h-4 ) , 3.49 ( 2h , d , j = 3.5 hz , ch2oh ) , 5.19 ( 1h , t , j = 3.5 hz , h-2 ) , 5.38 ( 1h , d , j = 7.0 hz , h-5 ) , 6.27 ( 1h , dd , j = 3.0 , 5.5 hz , h-5 ) , 7.267.15 ( 10h , m , ph ) , 7.397.37 ( 5h , m , ph ) , 7.93 ( 1h , d , j = 7.0 hz , h-6 ) ; c nmr ( 125 mhz ) cdcl3 c 36.72 ( c-4 ) , 61.31 ( ch2oh ) , 83.90 ( c-2 ) , 84.75 ( c-5 ) , 84.88 ( c - ph ) , 91.12 ( c-5 ) , 124.39 , 125.59 , 126.23 ( ch - ph ) , 139.06 ( c-6 ) , 140.08 ( c - ph ) , 153.01 ( c-2 ) , 163.16 ( c-4 ) ; ms ( esi+ ) m / z = 472 [ m+1 ] . hrms ( es+ ) m / z found 472.1685 [ calcd for c27h26n3o3s ( m+h ) 472.1689 ] .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3j
as a white solid ( 0.041 g , 47% ) .
h nmr ( 500 mhz ) ( cd3)2so h 1.95 ( 3h , s , coch3 ) , 3.65 ( 2h , dd , j = 7.0 , 7.5 hz , ch2o ) , 4.10 ( 2h , dd , j = 5.0 , 6.0 hz , ch2o ) , 6.55 ( 2h , s , nch2o ) , 7.80 ( 1h , s , h-8 ) , 10.65 ( 1h , brs , nh ) ; c nmr ( 125 mhz ) ( cd3)2so c 20.53 ( ch3 ) , 62.70 ( nch2 ) , 66.48 ( ch2o ) , 71.80 ( nch2o ) , 116.45 ( c-5 ) , 137.62 ( c-8 ) , 151.39 ( c-4 ) , 153.92 ( c-2 ) , 156.71(c-6 ) , 170.22 ( coch3 ) ; ms ( esi+ ) m / z = 268 [ m+1 ] . hrms ( es ) m / z found 268.1044 [ calcd for c10h14n5o4
( m+h ) 268.1040 ] .
prepared from 2k
or 2l
according to standard procedure for the n - deacetylation reaction .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 3k as a white solid ( 0.068 g , 76% from 2k ; 0.034 g , 53% from 2l ) .
h nmr ( 500 mhz ) cd3cl h 1.33 ( 3h , s , ch3).1.55 ( 3h , s , ch3 ) , 1.92 ( 3h , s , coch3 ) , 4.15 ( 1h , dd , j = 6.2 hz , 11.7 hz , h5 ) , 4.29 ( 1h , dd , j = 4.4 hz , 11.7 hz , h5 ) , 4.434.38 ( 1h , m , h4 ) , 4.99 ( 1h , dd , j = 3.4 hz , 6.3 hz , h3 ) , 5.41 ( 1h , dd , j = 2.0 hz , 6.3 hz , h2 ) , 5.94 ( 2h , br s , nh2 ) , 6.04 ( 1h , d , j = 2.0 hz , h1 ) , 7.82 ( 1h , s , h8 ) , 8.28 ( 1h , s , h2 ) ; c nmr ( 125 mhz ) cdcl3 c 20.68 ( coch3 ) , 25.41 ( cch3 ) , 27.14 ( cch3 ) , 64.09 ( c5 ) , 81.73 ( c4 ) , 84.23 ( c3 ) , 85.04 ( c2 ) , 91.06 ( c1 ) , 114.59 ( c5 ) , 120.35 ( cch3 ) , 139.71 ( c8 ) , 149.27 ( c4 ) , 153.22 ( c2 ) , 155.71 ( c6 ) , 170.41 ( coch3 ) .
ms ( es+ ) m / z ( 350 ) [ m+1 ] ; hrms ( es ) m / z found 350.1451 [ calcd for c15h20n5o5
( m+h ) 350.1459 ] .
n - acetyl-2,3-o - isopropylidene-5-o-[napthyl ( cyclohexyl - l - alanyl ) ] pho - sphate cytidine ( 5 ) . to a solution of 2 g
( 0.5 g , 1.53 mmol ) and ( 2s)-cyclohexyl 2-((chloro(naphthalen-1-yloxy)phosphoryl)amino)propa - noate ( 4
, 1.02 g , 3.073 mmol ) in anhydrous thf ( 10ml )
, 1 m bumgcl ( 3.08 ml , 3.073 mmol ) is added dropwise and the reaction mixture is stirred at room temperature overnight . after this period
the crude is purified by column chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 .
the compound 5 is recovered as a white solid
( 0.420 , 40% yield ) .
h nmr ( 500 mhz ) cd3od h 1.281.40 ( 11h , m , chch3 , ch3 , 2 ch2-chex ) , 1.521.58 ( 4h , m , ch3 , ch2-chex ) , 1.691.78 ( 4h , m , 2 ch2-chex ) , 2.15 , 2.18 ( 3h , s , coch3 ) , 3.994.02 ( 1h , m , chch3 ) , 4.404.52 ( 3.5h , m , ch-2 , h-4 ,
h-5 ) , 4.684.72 ( 2h , m , h-2 , h-3 ) , 4.90 ( 0.5h , m , h-3 ) , 5.80 ( 1h , d , j = 2.5 hz , h1 ) , 7.25 ( 0.5h , d , j = 7.5 hz , h-5 ) , 7.35 ( 0.5h , d , j = 7.5 hz , h-6 ) , 7.397.42 ( 1h , m , naph ) , 7.477.49 ( 1h , m , naph ) , 7.527.58 ( 2h , m , naph ) , 7.707.72 ( 1h , m , naph ) , 7.877.89 ( 1.5h , m , naph , h-5 ) , 7,96 ( 0.5h , d , j = 7.5 hz , h-5 ) , 8.088.10 ( 0.5h , m , naph ) , 8.138.15 ( 0.5h , m , naph ) ; c nmr ( 125 mhz ) cd3od c 20.45 ( d , jcp = 7.5 hz , chch3 ) , 20.62 ( d , jcp = 7.5 hz , chch3 ) , 24.57 ( coch3 ) , 24.60 , 24.62 ( ch2-chex ) , 25.42 , 25.52 , ( ch3 ) , 26.38 ( ch2-chex ) , 27.37 , 27.43 ( ch3 ) , 32.35 , 32.45 ( ch2-chex ) , 51.89 , 51.97 ( chch3 ) , 68.01 , 68.02 ( d , jcp = 7.5 hz , c-5 ) , 75.00 ( cho ) , 82.22 , 82.24 ( ch3 ) , 86.57 ( ch2 ) , 87.51 ( d , jcp = 2.5 hz , c-4 ) , 87.57 ( d , jcp = 2.5 hz , c-4 ) , 96.58 , 96.65 ( c-1 ) , 98.02 , 98.12 ( c-6 ) , 115.06 , 115.21 ( c - naph ) ,
116.22 ( d , jcp = 3.7 hz , ch - naph ) , 116 .
49 ( d , jcp = 3.7 hz , ch - naph ) , 122.60 , 122.68 , 126.15 , 126.53 ( ch - naph ) , 126.59 , 127.60 , 127.70 , 127.80 , 127.85 , 127.93 , 128.97 ( ch - naph ) , 136.28 ( c - naph ) , 147.20 , 147.35 ( c5 ) , 147.85 ( d , jcp = 7.5 hz , ipsoc - naph ) , 148.00 ( d , jcp = 7.5 hz , ipsoc - naph ) , 157.55 , 157.59 ( c-2 ) , 164.57 ( c-4 ) , 172.85 , 172.91 ( coch3 ) , 174.32 ( d , jcp = 3.7 hz , co2 ) , 174.63 ( d , jcp = 3.7 hz , co2 ) ; p nmr ( 500 mhz ) meod p 3.92 , 4.15 . ms ( esi+ ) m / z = 685 [ m+1 ] .
hrms ( es+ ) m / z found 685.2631 [ calcd for c33h42n4o10p ( m+h ) 685.2633 ] .
2,3-o - isopropylidene-5-o-[napthyl ( cyclohexyl - l - alanyl ) ] phosphate cytidine ( 6 ) . prepared from 5
according to standard procedure for the n - deacetylation reaction .
the crude compound is purified by flash chromatography on silica gel gradient elution of ch2cl2/meoh from 98/2 to 95/5 to give 6 as a white solid ( 0.061 g , 65% yield ) .
h nmr ( 500 mhz ) cd3od h 1.321.41 ( 12h , m , chch
3 , ch3 , 3 ch2-
chex ) , 1.54 ( 3h , s , ch3 ) , 1.551.84 ( 4h , m , ch2-chexyl ) , 4.004.05 ( 1h , m , chch3 ) , 4.344.44 ( 3h , m , h-4 , h-5 ) , 4.644.77 ( 2h , m , h-2 , h-3 ) , 4.814.84 ( m , 1h , cho ) , 5.74 ( 0.5h , d , j = 7.5 hz , h-6 ) , 5.785.81 ( 1.5h , m , h-1 , h-6 ) , 7.437.48 ( 1.5h , m , ch - naph . ) , 7.507.53 ( 1.5h , m , ch - naph ) , 7.557.59 ( 2h , m , ch - naph , h-5 ) , 7.73 ( 1h , d , j = 5.0 hz , ch - naph ) , 7.907.92 ( 1h , m , ch - naph ) , 8.168.20 ( 1h , m , naph ) ; c nmr ( 125 mhz ) cd3od c 20.45 ( d , jcp
= 7.5 hz , chch3 ) , 20.60 ( d , jcp
= 7.5 hz , ch3 ) , 24.61 ( ch2-chex ) , 25.50 , 25.56 , ( ch3 ) , 26.39 ( ch2-chex ) , 27.45 , 27.47 ( ch3 ) , 32.36 , 32.45 ( ch2-chex ) , 51.91 , 51.96 ( chch3 ) , 68.11 , 68.13 ( d , jcp = 5.0 hz , c-5 ) , 74.98 ( cho ) , 82.23 , 82.27 ( c-3 ) , 86.04 , 86.09 ( c-2 ) , 86.63 ( d , jcp = 2.5 hz , c-4 ) , 86.70 ( d , jcp = 2.5 hz , c-4 ) , 95.65 ( c-1 ) , 96.24 ( c-6 ) , 115.24 , 115.31 ( c - naph ) , 116.31 ( d , jcp = 3.7 hz , ch - naph ) , 116 .
48 ( d , jcp = 3.7 hz , ch - naph ) , 122.74 , 126.08 , 126.54 , 126.58 , 127.55 , 127.60 , 127.84 127.87 , 128.93 ( ch - naph ) , 136.33 ( c - naph ) , 144.19 ( c-5 ) , 147.85 ( d , jcp = 7.5 hz , ipsoc - naph ) , 148.00 ( d , jcp = 7.5 hz , ipsoc - naph ) , 157.84 ( c-2 ) , 167.84 ( c-4 ) , 174.32 ( d , jcp = 3.7 hz , co2 ) , 174.63 ( d , jcp = 3.7 hz , co2 ) ; p nmr ( 500 mhz ) cd3od p 3.96 , 4.11 ; ms ( es+ ) m / z = 643 [ m+1 ] .
hrms ( es+ ) m / z found 643.2521 [ calcd for c31h40n4o9p ( m+h ) 643.2527 ] .
supplementary file includes experimental procedures for the synthesis of protected nucleosides and analytical data for all new compounds .
go to the publisher 's online edition of nucleosides , nucleotides and nucleic acids to view the free supplementary files . | protection and deprotection strategies involving the n - acetyl group are widely utilized in nucleoside and nucleotide chemistry .
herein , we present a mild and selective n - deacetylation methodology , applicable to purine and pyrimidine nucleosides , by means of schwartz 's reagent , compatible with most of the common protecting groups used in nucleoside chemistry . | [
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in order to assess sexual well - being and provide treatment or education for iranian women 's sexuality , it is necessary to understand their sexuality and the meanings they give to sexual behaviors .
sexual behavior is a complex concept that is difficult to measure . according to webster 's online dictionary ,
the manner of conducting oneself and sexual simply means whatever relates to sex , the sexes or
sexual reproduction. thus , sexual behavior would be an act by someone that expresses their sexuality . in the archive for sexology , erwin j. haeberle introduces
sexual as a word with double meaning , referring to human anatomy as well as to human behavior . he defines sexual behavior as erotic behavior .
therefore , in contrast with webster , the critical dictionary in the archive for sexology defines human reproduction as asexual behavior because it concentrates on the biological facts without reference to the erotic feelings of the man and the woman involved .
the functional analysis of sexual behaviors has led researchers to develop instruments to gather observable data . in order to change subjective meanings to observable data ,
the researchers need to extract meanings from the contexts and populations they seek to measure .
many sexually related measures and instruments have been published ; they measure perceptions , attitudes , beliefs and so on . however , the contexts from which the concepts and meanings were extracted to develop these instruments vary .
doubtless , their reliability in measuring sexual behaviors as socially constructed , complex and dynamic phenomena can be questioned . in order to determine a research approach for the context of iranian women 's sexuality , review and assessment of existing instruments was essential . after a brief overview of the existing instruments measuring
non - risky sexual behaviors among heterosexual women , we look at their cultural appropriateness to measure sexual behaviors within an iranian context .
finally , because we find these instruments insufficient , we suggest criteria for cultural - specific sexually related measures in the iranian settings .
for the purpose of this paper , we searched literature using medline , pub - med , psychinfo and cinahl from june 2006 to june 2011 .
the mesh terms used to search title and abstract included sexuality , sexual behavior , questionnaire and sexual behavior and questionnaire or
sexually related measure , sexually related tools limited to human , female , english and reproductive age . focused exclusively on the concept of sexual behavior , we screened titles and abstracts . considering that not all abstracts highlighted the specified population and name of the applied tools ,
these articles were found in full , and methods sections were reviewed to identify populations and the tools used .
retrieved articles were included if they used a structured instrument(s ) to measure sexual behaviors of the female population .
we excluded those studies whose outcome of interest included risky sexual behaviors or sexual behaviors measured among same sex relationships .
we excluded same sex relationships because this form of relationships is illegal and deniable in iran .
if the original paper was unavailable , we selected the article that used the given tool to measure the study outcomes . in this stage , tools in languages other than english , those employed just for menopausal women and those not related to sexual behaviors were excluded . using gagnon and simon sexual script theory as the theoretical framework ,
cultural appropriateness ( i.e. understanding and language of sexuality , ethics , and morality ) was our selection criteria for the instruments .
evaluation of the 143 articles revealed that a majority of them ( 65% ) had utilized the female sexual function index ( fsfi ) in their research .
the second most used scale was the pelvic organ prolapsed / urinary incontinence sexual function questionnaire ( pisq-12 ) , utilized in 10.4% of the final articles .
the golombok - rust inventory of sexual satisfaction ( griss ) and the arizona sexual experience scale ( asex ) were the next most used instruments by 6.9% and 5.6% of articles , respectively .
we reviewed all instruments and determined the subscales as well as measurement types [ table 1 ] .
we categorized these instruments into three groups based on their working definitions of sexual behavior and theoretical frameworks .
these instruments were reviewed by the authors , who are iranian experts in sexology , reproductive health , and epidemiology .
of 50 instruments , we found 19 tools applicable in the iranian culture [ table 2 ] .
the third group included those which were focused on a specific sexual problem rather than looking at sexual behaviors overall [ table 4 ] .
the multidimensional derogatis sexual functioning inventory ( dsfi ) did not fit into any of those three categories . with this overview
, it appears that there are significant challenges to using these instruments in iranian contexts .
instruments features including the subscales compatible scales for iranian culture instruments incompatible with iranian culture problem - focused instruments
inspiring gagnon and simon 's description of sexual behaviors defined with social scripts , understanding and language of sexuality , ethics , and morality are the main cultural determinants of sexual norms in the iranian society . in her linguistic analysis of sexuality expression of iranian women ,
merghati - khoei has revealed the ways of developing terminology and cultural explanations , which are juxtaposed with the exploration of the development of women 's sexuality .
iranian women expressed their sexuality differently from western women even though they understood and talked about the same issues .
there is , however , a hesitation when it comes to discussing or reporting the emotional aspects of sexual encounters .
the power of culture in dictating daily language for females has been highlighted in morocco as an arab - islamic context .
similarly , culturally meaningful ambiguity in language guides iranian people 's behavior . even though persian vocabulary ,
concepts and expressions about sexual matters exist in art , poetry and the beauty of nature , these linguistic resources are not applied in daily life to express sexuality .
for example , the sexual attitude scale ( sas ) , certainly a well - designed tool for use within many cultures measures a person 's awareness toward her / his sexual interests and needs as well as sexual - self judgment .
communication of sexual needs or interests with others is another feature of this tool . as a neglected subject matter in the iranian culture , questioning people about their sexual needs and interests or sexual - self concept seems impractical .
sexuality is an unspoken issue , and individuals might not be linguistically skilled to communicate their sexuality with an interviewer . in sum , the art of using a rich vocabulary of metaphors and euphemisms is a characteristic of iranian speech , used to communicate and encapsulate matters not normally spoken explicitly .
for example , for fluent english speakers phrase marital life may indicate all kinds of relationships within a marital framework , while in farsi zendegi - e - zanashoyi ( literally marital life ) has sexual connotations and is usually understood to mean the sexual relationship between husband and wife .
another difficulty in asking about sexuality during a study is the struggle between conscious embarrassment and sexual talk . by conscious embarrassment , we mean the shame , prohibition and modesty about sex .
the majority of the women who participated in merghati - khoei 's qualitative study pointed out that they were not culturally expected to be straightforward or frank in expressing sexual matters .
for example , the sexual desire inventory tends to measure sexual desire as a biologic factor . out of 14 items ,
4 focus on masturbation and 2 items ask about having interest in casual sex . in iranian contexts ,
none of these 6 items would be posed by researchers or responded to by the participants .
why human have sex ? ( ysex ) is another example , which measures number of variables .
for instance , some of the items focus on motivations leading people to out - of - wedlock or casual sex .
although casual or extra marital sex happens in every society , questioning iranians about these behaviors is not ethically and religiously possible or feasible .
this assertion is based on the common assumptions . in iran , people strongly hold onto the traditional culture of sexuality based on purity ( paki ) ,
chastity ( nejabat ) , honour ( aberoo ) and honesty ( sedagat ) underlying the family structure .
there is also the belief commonly permeating iranian society that people are fairly innocent in terms of sexuality compared with non - muslim or western societies .
however , with these assumptions we can not minimize the impact of factors such as modernization , worldwide communication and cultural transformations in younger generations and the way they learn about sex , practice and develop their sexual understandings . undoubtedly , these factors change behaviors and attitudes .
social conduct and religiosity define the ethical aspect of sexuality in the iranian culture . in iran
the teachings of islamic principles tie strongly to shia interpretations , which form the basis for iranians understandings of sexuality .
the expression of sexuality is considered legitimate only within the framework of islamic marriage ( nikah ) . moreover , as shown in merghati et al .
study , sexual obedience was seen as the primary goals of the committed muslim woman .
the concept of nejabat ( modesty ) is the most important ethical code applied to an iranian woman who is not sexually expressive .
in contrast , islamic scholar morteza motahari pointed out the islamic clear guidelines toward sexuality , leading neither to any sense of sexual deprivation and frustration , nor to any repressed or inhibited sexual desire .
however , in the islamic doctrine freeing sexual desire and lifting of traditional moral restraints is not accepted . as a criterion ,
religiosity has significant effects on iranian women 's sexual understandings ; and that experts working in the fields of gender and sexuality need to be sensitive to the notion that some muslim women may not speak out their sexuality as an indicator of submission to religious codes , of modesty and of being an idealized muslim wife .
in her linguistic analysis of sexuality expression of iranian women , merghati - khoei has revealed the ways of developing terminology and cultural explanations , which are juxtaposed with the exploration of the development of women 's sexuality .
iranian women expressed their sexuality differently from western women even though they understood and talked about the same issues .
. there is , however , a hesitation when it comes to discussing or reporting the emotional aspects of sexual encounters .
the power of culture in dictating daily language for females has been highlighted in morocco as an arab - islamic context .
even though persian vocabulary , concepts and expressions about sexual matters exist in art , poetry and the beauty of nature , these linguistic resources are not applied in daily life to express sexuality .
for example , the sexual attitude scale ( sas ) , certainly a well - designed tool for use within many cultures measures a person 's awareness toward her / his sexual interests and needs as well as sexual - self judgment .
communication of sexual needs or interests with others is another feature of this tool . as a neglected subject matter in the iranian culture , questioning people about their sexual needs and interests or sexual - self concept seems impractical .
sexuality is an unspoken issue , and individuals might not be linguistically skilled to communicate their sexuality with an interviewer . in sum , the art of using a rich vocabulary of metaphors and euphemisms is a characteristic of iranian speech , used to communicate and encapsulate matters not normally spoken explicitly .
for example , for fluent english speakers phrase marital life may indicate all kinds of relationships within a marital framework , while in farsi zendegi - e - zanashoyi ( literally marital life ) has sexual connotations and is usually understood to mean the sexual relationship between husband and wife .
another difficulty in asking about sexuality during a study is the struggle between conscious embarrassment and sexual talk . by conscious embarrassment , we mean the shame , prohibition and modesty about sex .
the majority of the women who participated in merghati - khoei 's qualitative study pointed out that they were not culturally expected to be straightforward or frank in expressing sexual matters .
for example , the sexual desire inventory tends to measure sexual desire as a biologic factor . out of 14 items ,
4 focus on masturbation and 2 items ask about having interest in casual sex . in iranian contexts ,
none of these 6 items would be posed by researchers or responded to by the participants .
for instance , some of the items focus on motivations leading people to out - of - wedlock or casual sex .
although casual or extra marital sex happens in every society , questioning iranians about these behaviors is not ethically and religiously possible or feasible .
this assertion is based on the common assumptions . in iran , people strongly hold onto the traditional culture of sexuality based on purity ( paki ) , chastity ( nejabat ) , honour ( aberoo ) and honesty ( sedagat ) underlying the family structure .
there is also the belief commonly permeating iranian society that people are fairly innocent in terms of sexuality compared with non - muslim or western societies .
however , with these assumptions we can not minimize the impact of factors such as modernization , worldwide communication and cultural transformations in younger generations and the way they learn about sex , practice and develop their sexual understandings .
undoubtedly , these factors change behaviors and attitudes . social conduct and religiosity define the ethical aspect of sexuality in the iranian culture .
in iran the teachings of islamic principles tie strongly to shia interpretations , which form the basis for iranians understandings of sexuality .
the expression of sexuality is considered legitimate only within the framework of islamic marriage ( nikah ) . moreover , as shown in merghati et al .
study , sexual obedience was seen as the primary goals of the committed muslim woman .
the concept of nejabat ( modesty ) is the most important ethical code applied to an iranian woman who is not sexually expressive .
in contrast , islamic scholar morteza motahari pointed out the islamic clear guidelines toward sexuality , leading neither to any sense of sexual deprivation and frustration , nor to any repressed or inhibited sexual desire .
however , in the islamic doctrine freeing sexual desire and lifting of traditional moral restraints is not accepted . as a criterion ,
religiosity has significant effects on iranian women 's sexual understandings ; and that experts working in the fields of gender and sexuality need to be sensitive to the notion that some muslim women may not speak out their sexuality as an indicator of submission to religious codes , of modesty and of being an idealized muslim wife .
to investigate sexual behaviors in an iranian context , we recognize the importance of identifying or developing an instrument to assess sexual behavior domains among women in the particular context of iranian culture .
we thought that such an instrument would be essential tool for achieving a more systematic and in - depth understanding of iranian women 's sexuality , may be useful in applied settings , and would advance sexuality research as a whole . no matter the context or use
, however , measuring a construct such as sexual behavior is subjective and therefore entirely dependent on self - report .
it has been argued that iranian women may not report properly if they believe sexuality has nothing to do with health .
for example , a woman 's inability to gain sexual pleasure due to painful intercourse might not be defined as a sexual health problem to be reported , whereas other people would consider it as a sexual health problem for the woman .
this suggests the idea that the culture of sexuality affects people 's interpretations of sexually related problems .
developing a contextualized instrument to measure the domains of sexual behavior would allow sexuality and gender researchers to better answer questions related to the influence of culture in those domains , sexual scripts across diverse cultures , and other factors influencing sexual health outcomes . in the 1970s , gagnon and simon 's sexual conduct represented the first truly sociological analysis of sexual behavior .
gagnon and simon defined sexual behavior within a new theoretical framework of social scripts. they produced a critique that moved us beyond the objective definition of sexual behavior : our concern here is to understand sexual activities of all kinds as the outcome of a complex psychological process of development , and it is only because they are embedded in social scripts that the physical acts themselves become possible it is neither fixed by nature or by the organs themselves .
the very experience of sexual excitement that seems to originate from hidden internal sources is in fact a learned process and it is only our insistence on the myth of naturalness that hides these social components from us . the
character through a cultural scenario in which they take up , internalize and enact culturally prescribed normative roles ; interpersonal scripts in which they make a suitable identity based on desired expectations and intrapsychic scripting in which they make the self in relation to social life .
thus , sexual practice is separated from the biology of the body and one 's sexuality is strongly formed by the very complex social world .
having investigated the history of human sexuality , we believe sexuality is influenced by the society , culture and era in which people live . within an iranian context , we therefore recognized existing instruments targeting
non - risky sexual behaviors among heterosexual women are insufficient to measure sexual behaviors .
we categorized instruments as culturally compatible or incompatible based on the sexuality domains they tend to measure .
the instruments , by which the biological aspects of sexual behaviors are measured were found applicable for any given community or population , the iranian context included .
alternatively , those measuring outcomes related to subjects attitudes , understanding or sexual scripts were identified as culturally incompatible .
most of the tools seem reasonable candidates for use in the iranian culture and society with minor revisions [ table 1 ] .
review of these instruments shows that most of them are functional based , such as the most used scale in literature , ( fsfi ) .
other well known tools , such as the arizona sexual experience scale ( asex ) and the golombok - rust inventory of sexual satisfaction ( griss ) , are also functional based .
some other tools are problem - focused [ table 3 ] and specific to measure only disorder - based outcomes .
we argue that the medically oriented instruments employed in the field are drawn from concepts and meanings based on investigations conducted in western societies .
yet as researchers , we sometimes found ourselves disappointed by the level of difficulty , which we professionals encountered in fitting our participants into those biomedical frameworks .
the culture - bound nature of sexuality limits the research - based information in iran . in our society
, the lack of information in the sexual domain will be most productively addressed first through research attention to subjective concepts .
lack of sufficient knowledge in the field of sexuality in iranian contexts , makes it important to identify normative sexual behaviors qualitatively before applying problem - oriented tools in research .
there are social and cultural challenges arising from the recognition that iranians use culturally specific sexual expressions .
these expressions may construct different ways of perceiving sexuality that are not easily translatable or even understandable by outsiders .
this means that sexuality is a complex phenomenon embedded in various meanings and understandings , not merely objective and measurable behavior . explaining those meanings and perceptions makes sexuality a dynamic phenomenon through one 's life time . how we know what we know changes periodically and therefore , creating an epistemological crisis in knowledge as well as the research process .
however , scholars in science and human behavior such as skinner have powerfully questioned the reliability of subjective measures of private events such as sexual behaviors .
we concluded that the published instruments are well - designed and used worldwide ; however , we must also acknowledge that the sexual scripts of iranian women define sexual behaviors differently , limiting their communication in the research setting and compromising the compatibility of these instruments .
therefore , exploring and analyzing the lexicon and expressions used by the iranian women creates a ground for developing a culturally comprehensive measure , which can adequately examine how these women explain their sexual behaviors . | the cultural compatibility of sexually related instruments is problematic because the contexts from which the concepts and meanings were extracted may be significantly different from related contexts in a different society .
this paper describes the instruments that have been used to assess sexual behaviors , primarily in western contexts .
then , based on the instruments working definition of sexual behavior and their theoretical frameworks , we will ( 1 ) discuss the applicability or cultural compatibility of existing instruments targeting women 's sexual behaviors within an iranian context , and ( 2 ) suggest criteria for sexually related tools applicable in iranian settings .
iranian women 's sexual scripts may compromise the existing instruments compatibility .
suggested criteria are as follows : understanding , language of sexuality , ethics and morality .
therefore , developing a culturally comprehensive measure that can adequately examine iranian women 's sexual behaviors is needed . | [
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a level of pain that completely incapacitates one individual may cause only a minor annoyance in another .
characterizing the genetic factors affecting susceptibility to chronic pain could lead to novel treatment or prevention strategies , which are desperately needed . a recent paper by costigan et al .
the authors performed a multi - dimensional analysis using rat gene expression and human genetic association that identified a new genetic factor affecting susceptibility to chronic pain .
this study was initiated by analysis of gene expression changes within rat dorsal root ganglia obtained after nerve damage was induced in three different models of chronic pain .
the mrna for a potassium channel alpha subunit ( kcns1 ) was constitutively expressed in sensory neurons , but was downregulated after three types of nerve injury in these models .
other studies have successfully identified a human genetic susceptibility factor on the basis of a candidate gene emerging from analysis of a rodent model .
costigan and colleagues therefore examined snp alleles within the human homolog ( kcns1 ) in five independent cohorts ( two with chronic low back pain , two after limb amputation and one after mastectomy ) that have a high incidence of chronic pain . in four of
the five cohorts studied , there was a significant association of the val allele at a nonsynonymous snp ( rs734784 , val / ile ) with increased risk for chronic pain .
for example , homozygous val / val individuals had a 2.4-fold increased relative risk of failing to achieve pain improvement 1 year after back surgery .
the proportion of individuals without phantom limb pain after leg amputation was 45% in those without the val allele , but fell to 22% in val / val homozygotes . among healthy volunteers that were subjected to multiple experimental pain stimuli ,
although experimental studies demonstrating an allelic effect were not presented , which is a substantial limitation of this study , these results make it likely that kcns1 alleles contribute to susceptibility to chronic pain .
although kcns1 by itself does not have potassium channel function when tested in heterologous expression systems , its expression has been shown to modulate the currents formed by other channels [ 3 - 5 ] .
voltage - gated potassium channels have important effects on neuronal function , including altering the resting membrane potential and the shape and frequency of the action potential
. similarly , gain - of - function mutations in the nav1.7 sodium channel cause syndromes associated with increased pain sensitivity .
chronic pain has a huge impact on our society , and its treatment is a major driver for the increasing cost of health care . an estimated 76 million people in the us have chronic pain , which costs the us public over $ 100 billion per year .
approximately 25% of chronic pain is neuropathic ( caused by nerve damage ) , which is characterized by spontaneous pain that is burning or stabbing in nature .
this can develop after limb amputation , mastectomy or lower back injury , or in individuals with a long history of diabetes .
although multiple kinds of treatment can be used , they often have limited efficacy , and chronic pain is often managed by administration of opioids ( morphine and related synthetic compounds , including hydrocodone ) .
the increased focus on pain management resulted in a six - fold increase in the per capita sales of prescription opioid medications in the us between 1997 and 2006 .
hydrocodone - acetaminophen is prescribed over 100 million times per year in the us , which is far more than any other medication , including lipid - lowering and blood - pressure - lowering agents .
this has led to a dramatic increase in the incidence of opioid misuse , emergency room visits due to opioid analgesic poisoning , and fatal opioid overdose .
prescription opioids have now surpassed marijuana as the drug that is most commonly abused among the newly initiated .
because of the enormity of this public health problem , we desperately need new approaches for the prevention or treatment of chronic pain conditions .
it is likely that genetic discoveries can lead to new approaches for chronic pain , because genetic discoveries have catalyzed new approaches for related clinical conditions .
for example , haplotype - based computational genetic analysis has identified causative genetic factors affecting analgesic medication and inflammatory pain responses , and it has identified four genes affecting narcotic drug responses [ 11,14 - 16 ] in mice .
the latter genetic discovery generated a new treatment strategy for preventing narcotic drug withdrawal symptoms , which was shown to be effective in humans .
moreover , the variable response to multiple classes of analgesic medications among inbred mouse strains was shown to be due to genetic variation within a genetic locus ( kcnj9 ) that also encodes a potassium channel ( girk3 ) .
hopefully , characterizing the functional role of kcns1 in neuronal responses and pain perception , and the impact of the allelic differences , could lead to new approaches for treatment of chronic pain .
although the tractability of kcns1 ( or other potassium channels ) as a therapeutic target remains to be determined , small molecules targeting potassium channels have been produced ( reviewed in ) , and one has attenuated neuropathic pain in animal models . although the kcns1 val allele explains only a small percentage of the total variance ( 4.6 to 7.8% ) in the chronic pain endpoints in the cohorts studied , the identification of an initial genetic factor for chronic pain is an important achievement for two reasons .
first , it shows that genetic factors can be identified for this condition , and this study provides a template for subsequent studies .
second , it is likely that a greater percentage of the genetic susceptibility to chronic pain can be explained by combining this genetic factor with other subsequently identified factors .
moreover , pain is a subjective sensory symptom ; it is difficult to measure ; and there are substantial psychological and emotional components that contribute to the perception of pain .
it has recently been found that there are different subtypes of chronic pain , which are distinct from the causative disease ( diabetic neuropathy , radicular back pain and so on ) .
it is likely that genetic factors determine whether a chronic pain syndrome will develop and the specific subtype that emerges after exposure to a triggering cause .
thus , the impact of a single genetic factor could be much larger if a specific pain subtype is examined relative to that measured in a large cohort of individuals with different types of chronic pain .
beyond finding new drug targets , identification of genetic factors affecting susceptibility to chronic pain syndromes could be the lever that drives advances in this difficult clinical area .
a genetic risk factor could have a substantial impact on clinical practice because individuals at increased risk for developing a chronic pain syndrome could be identified before a surgical procedure or immediately after a traumatic incident . the genetic information could be used to develop proactive methods for prevention of chronic pain syndromes , enabling interventions to be targeted to the high - risk subset . because of the great inter - individual variation in the response to painful stimuli and to analgesic drugs , knowledge of genetic risk factors could enable better stratification of chronic pain patients or aid in the selection of the appropriate therapy . rather than focusing on the disease that is etiologically associated with the chronic pain ,
study is hopefully one of the first of many subsequent genetic studies that could lead to entirely new ways to approach chronic pain syndromes .
clearly , the clinical and research communities have a long way to go before genetically targeted therapies for chronic pain become a reality .
however , kcns1 ( or other channels ) could perhaps become the next target for a new class of analgesics that are selectively used in the 20% of the population that are homozygous for the val alleles of kcns1 .
the day might soon come when we no longer think of ' chronic pain ' as a single clinical entity , but have the tools to characterize the specific ' channelopathy ' that underlies the clinical presentation and targeted treatments for each subgroup .
gp is a professor and mz is the director of statistical research in the department of anesthesia at stanford university medical school . | a recent publication that combined rat gene expression data and a human genetic association study has identified the first genetic risk factor for chronic pain in humans . in four of
the five cohorts studied , there was a significant association of an allele within a gene ( kcns1 ) encoding a potassium channel ( kv9.1 ) with an increased risk for chronic pain .
identification of genetic risk factors for chronic pain could catalyze new advances in this difficult clinical area that has become a major public health problem .
genomic - medicine - based advances for chronic pain could include the development of a mechanism - based classification system for chronic pain , new treatment options , improved methods for treatment selection and targeted prevention strategies for high - risk individuals . | [
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] |
optical coherence tomography ( oct ) is a noninvasive method that evaluates biological tissues by in vivo imaging.1 since its introduction , oct has undergone several improvements and revolutionized the diagnostic , monitoring , and therapeutic approaches to many retinal diseases and glaucoma .
computerized algorithms can be used on the high - resolution images obtained by modern oct devices in order to identify and measure the thicknesses of discrete retinal layers , including the retinal nerve fiber layer ( rnfl ) , macular ganglion cell complex ( gcc ) , and choroid.2,3 the choroid is the most vascular tissue in the eye and is known to have an important role in ocular nutrition , volume regulation , and temperature control.4 choroidal abnormalities are critical to the onset and progression of many chorioretinal disorders such as age - related macular degeneration ( amd ) , polypoidal choroidal vasculopathy , vogt - kayanagi - harada disease , and central serous chorioretinopathy.5 with the recent development of enhanced depth imaging ( edi ) , in vivo assessment of the choroid has become an area of interest .
edi allows better visualization and quantitative evaluation of the choroid , which was not possible before .
information about the choroidal thickness ( ct ) is useful in many clinical situations for decision making regarding the management and monitoring of disease progression.6 neurodegenerative diseases such as glaucoma preferentially affect the gcc , which is the sum of the three innermost layers : the rnfl , the retinal ganglion cell layer , and the inner plexiform layer .
these contain the axons , cell bodies , and the dendrites of the retinal ganglion cells , respectively.7,8 recent studies have shown that measurement of macular gcc thickness has the same diagnostic potential for glaucoma as rnfl thickness.911 moreover , it has been reported that measurements of average gcc thickness had better sensitivity in detecting changes in retinal thickness in multiple sclerosis neurodegeneration than rnfl thickness measured by oct.12 both ct and gcc thickness measurements can be affected by several factors such as pupil size , scan quality , and cataract . in this study
, we aimed to evaluate the effect of uneventful cataract surgery on subfoveal ct and gcc thickness measured by edi - oct .
this prospective study included consecutive patients who had undergone uneventful phacoemulsification surgery for senile cataract at sakarya university medical education and research hospital between november 2013 and june 2015 .
the present study was approved by the institutional review board of sakarya university medical education and research hospital and adhered to the tenets of the declaration of helsinki and all patients signed informed consent after they received an explanation of the nature and possible consequences of the procedure .
exclusion criteria included a history of prior ocular surgery and systemic / ocular diseases such as diabetes mellitus , hypertension , glaucoma , amd , diabetic retinopathy , retinal vein occlusion , uveitis , or other inflammatory and vascular pathologies .
patients with unstable fixation or dense cataracts leading to a poor scan quality of oct images and eyes with increase in postoperative intraocular pressure ( iop ) or cystoid macular edema were also excluded .
all patients had a full ophthalmic examination , including best - corrected visual acuity ( bcva ) assessment , as well as slit - lamp biomicroscopy and dilated fundoscopy evaluation , and iop measurement by goldmann applanation tonometry .
axial length ( al ) was measured by immersion echography ( axis ii ; quantel medical inc . , cedex , france ) and central corneal thickness ( cct ) was measured by ultrasonographic pachymetry ( pacline ; optikon 2000 spa , rome , italy ) .
prior to the operation , tropicamide 1% and phenylephrine hydrochloride 2.5% were applied to patients eyes for pupil dilation .
phacoemulsification was performed by one experienced surgeon ( ec ) using infiniti vision system ( alcon laboratories , inc . ) . a clear corneal incision of 2.8 mm , 600 mmhg vacuum , an aspiration flow rate of 30 ml / min , bottle height of 75 cm , and quick - chop technique were used in all surgeries .
two different dispersive viscoelastics ( viscoat and bivisc ) and two different cohesive viscoelastics ( healon and bio - hyalur ) were used during cataract surgery .
one - piece hydrophobic acrylic intraocular lens ( sensar model : aab00 ; abbott medical optics inc . , santa ana , ca , usa ) was used in all surgeries .
viscoelastics were cleaned out with marked attention , even behind the intraocular lenses . the procedure ended with intracameral cefuroxime axetil 1 mg/0.1 ml for prophylaxis for endophthalmitis .
the operative times ( ots ) and effective phaco times ( epts ) were recorded in each case .
postoperatively , all patients were treated with topical antibiotics ( ofloxacin 0.3% ) for 1 week and topical steroid drops ( prednisolone acetate 1% ) for 4 weeks .
cirrus edi - oct ( carl zeiss meditec ag , jena , germany ; software version 6.5.0.772 ) was used to obtain subfoveal ct and gcc thickness measurements using high - definition one - line raster and ganglion cell analysis ( macular cube 512128 ) scan protocols , respectively .
scans with misalignment , segmentation failure , decentration of the measurement circle , and poor illumination , or those out of focus , were also excluded .
the one - line raster is a 6 mm line consisting of 4,096 a - scans .
scan 3 of the five scans taken , which passes through the fovea , was used for all measurements .
ct was defined as the vertical distance from the outer portion of the hyperreflective line corresponding to bruch s membrane beneath the retinal pigment epithelium to the outermost hyperreflective line of the inner scleral border . to avoid the effects of mydriatic agents or diurnal changes ,
the ct was measured from the subfoveal region by using the cirrus linear measurement tool .
when there was a discrepancy of > 10% of the mean of the two values between the observers in two eyes in the study , observers discussed and repeated the measurements , and the average results from the two observers were determined as the final ct readings .
the cirrus oct device allows a quantitative assessment of the ganglion cell and inner plexiform layers ( gcipl ) in six circular sectors centered in the fovea .
it also gives information on the mean and minimum gcipl thickness for each eye and compares these figures with a normative database .
macular cube 512128 acquisition protocol generates a cube through a 6 mm square grid of 128 b - scans , each composed of 512 a - scans .
a built - in gcipl analysis algorithm detects and measures the thickness of the macular gcipl within a 662 mm elliptical annulus area centered on the fovea .
the annulus has an inner vertical diameter of 1 mm , which was chosen to exclude the portions of the fovea where the layers are very thin and difficult to detect accurately , and an outer vertical diameter of 4 mm , which was chosen according to where the ganglion cell layer again becomes thin and difficult to detect .
the ganglion cell analysis algorithm identifies the outer boundaries of the rnfl and the inner plexiform layer .
the difference between the rnfl and the inner plexiform layer outer boundary segmentations yields the combined thickness of the retinal gcipl .
similar to other cirrus printouts , it provides gcipl measurements in six wedge - shaped sectors with a pseudocolor scheme .
those that are abnormal at the < 5% and at the < 1% level are represented by yellow and red backgrounds , respectively .
the primary objective of this study was to evaluate the subfoveal ct and average gcc thickness changes ; however , central macular thickness ( cmt ) and peripapillary rnfl thickness were also obtained by the macular cube 512128 and optic disc cube 200200 protocols , respectively , using the cirrus oct device .
statistical analysis was performed using spss statistics for windows , version 20.0 ( ibm corporation 2011 , armonk , ny , usa ) .
paired - samples t - test was used for equality of means , and analysis of variance regression and pearson correlation analysis were used for correlations between parameters .
this prospective study included consecutive patients who had undergone uneventful phacoemulsification surgery for senile cataract at sakarya university medical education and research hospital between november 2013 and june 2015 .
the present study was approved by the institutional review board of sakarya university medical education and research hospital and adhered to the tenets of the declaration of helsinki and all patients signed informed consent after they received an explanation of the nature and possible consequences of the procedure .
exclusion criteria included a history of prior ocular surgery and systemic / ocular diseases such as diabetes mellitus , hypertension , glaucoma , amd , diabetic retinopathy , retinal vein occlusion , uveitis , or other inflammatory and vascular pathologies .
patients with unstable fixation or dense cataracts leading to a poor scan quality of oct images and eyes with increase in postoperative intraocular pressure ( iop ) or cystoid macular edema were also excluded .
all patients had a full ophthalmic examination , including best - corrected visual acuity ( bcva ) assessment , as well as slit - lamp biomicroscopy and dilated fundoscopy evaluation , and iop measurement by goldmann applanation tonometry .
axial length ( al ) was measured by immersion echography ( axis ii ; quantel medical inc . , cedex , france ) and central corneal thickness ( cct ) was measured by ultrasonographic pachymetry ( pacline ; optikon 2000 spa , rome , italy ) .
prior to the operation , tropicamide 1% and phenylephrine hydrochloride 2.5% were applied to patients eyes for pupil dilation .
phacoemulsification was performed by one experienced surgeon ( ec ) using infiniti vision system ( alcon laboratories , inc . ) . a clear corneal incision of 2.8 mm , 600 mmhg vacuum , an aspiration flow rate of 30 ml / min , bottle height of 75 cm , and quick - chop technique were used in all surgeries .
two different dispersive viscoelastics ( viscoat and bivisc ) and two different cohesive viscoelastics ( healon and bio - hyalur ) were used during cataract surgery .
one - piece hydrophobic acrylic intraocular lens ( sensar model : aab00 ; abbott medical optics inc . , santa ana , ca , usa ) was used in all surgeries .
viscoelastics were cleaned out with marked attention , even behind the intraocular lenses . the procedure ended with intracameral cefuroxime axetil 1 mg/0.1 ml for prophylaxis for endophthalmitis .
the operative times ( ots ) and effective phaco times ( epts ) were recorded in each case .
postoperatively , all patients were treated with topical antibiotics ( ofloxacin 0.3% ) for 1 week and topical steroid drops ( prednisolone acetate 1% ) for 4 weeks .
cirrus edi - oct ( carl zeiss meditec ag , jena , germany ; software version 6.5.0.772 ) was used to obtain subfoveal ct and gcc thickness measurements using high - definition one - line raster and ganglion cell analysis ( macular cube 512128 ) scan protocols , respectively .
scans with misalignment , segmentation failure , decentration of the measurement circle , and poor illumination , or those out of focus , were also excluded .
the one - line raster is a 6 mm line consisting of 4,096 a - scans .
scan 3 of the five scans taken , which passes through the fovea , was used for all measurements .
ct was defined as the vertical distance from the outer portion of the hyperreflective line corresponding to bruch s membrane beneath the retinal pigment epithelium to the outermost hyperreflective line of the inner scleral border . to avoid the effects of mydriatic agents or diurnal changes ,
the ct was measured from the subfoveal region by using the cirrus linear measurement tool . when there was a discrepancy of > 10% of the mean of the two values between the observers in two eyes in the study , observers discussed and repeated the measurements , and the average results from the two observers
the cirrus oct device allows a quantitative assessment of the ganglion cell and inner plexiform layers ( gcipl ) in six circular sectors centered in the fovea
. it also gives information on the mean and minimum gcipl thickness for each eye and compares these figures with a normative database .
macular cube 512128 acquisition protocol generates a cube through a 6 mm square grid of 128 b - scans , each composed of 512 a - scans .
a built - in gcipl analysis algorithm detects and measures the thickness of the macular gcipl within a 662 mm elliptical annulus area centered on the fovea .
the annulus has an inner vertical diameter of 1 mm , which was chosen to exclude the portions of the fovea where the layers are very thin and difficult to detect accurately , and an outer vertical diameter of 4 mm , which was chosen according to where the ganglion cell layer again becomes thin and difficult to detect .
the ganglion cell analysis algorithm identifies the outer boundaries of the rnfl and the inner plexiform layer .
the difference between the rnfl and the inner plexiform layer outer boundary segmentations yields the combined thickness of the retinal gcipl .
similar to other cirrus printouts , it provides gcipl measurements in six wedge - shaped sectors with a pseudocolor scheme .
those that are abnormal at the < 5% and at the < 1% level are represented by yellow and red backgrounds , respectively .
the primary objective of this study was to evaluate the subfoveal ct and average gcc thickness changes ; however , central macular thickness ( cmt ) and peripapillary rnfl thickness were also obtained by the macular cube 512128 and optic disc cube 200200 protocols , respectively , using the cirrus oct device .
statistical analysis was performed using spss statistics for windows , version 20.0 ( ibm corporation 2011 , armonk , ny , usa ) .
paired - samples t - test was used for equality of means , and analysis of variance regression and pearson correlation analysis were used for correlations between parameters .
a total of 30 eyes of 30 patients ( 16 male and 14 female ) , with a mean age of 60.24.2 years were included in this study .
mean bcva improved in all eyes , and this improvement was statistically significant ( 0.460.15 logarithm of minimum angle of resolution [ logmar ] units preoperatively and 0.060.49 logmar units postoperatively ; p<0.001 ) .
mean preoperative al was 22.80.6 mm ( range : 21.524.1 mm ) and mean cct was 551.522.1 m .
mean ot was 8.62.7 minutes and mean ept was 6.92.5 seconds ( table 1 ) .
the mean subfoveal ct was 294.439.2 m ( range : 201356 m ) preoperatively and 301.439.9 m ( range : 231367 m ) postoperatively .
the mean gcc thickness was 85.04.4 m ( range : 7894 m ) preoperatively and 89.25.3 m ( range : 8199 m ) postoperatively .
the mean cmt was 247.917.6 m preoperatively ( range : 211280 m ) and 249.017.8 m ( range : 213278 m ) postoperatively .
the mean rnfl thickness was 97.45.4 m preoperatively ( range : 87110 m ) and 101.75.6 m ( range : 91113 m ) postoperatively .
regression analysis showed that age , sex , al , cct , ot , and ept were not associated with ct changes ( p=0.834 , p=0.129 , p=0.203 , p=0.343 , p=0.547 , and p=0.147 , respectively ) and gcc thickness changes ( p=0.645 , p=0.542 , p=0.152 , p=0.664 , p=0.448 , p=0.268 , respectively ) after cataract surgery .
in this study , we investigated the effect of cataract surgery on subfoveal ct and gcc thickness , as measured by edi - oct , and we found that both subfoveal ct and gcc thickness increased slightly after cataract surgery .
cmt and peripapillary rnfl thicknesses were also evaluated as a secondary objective , and we observed statistically significant increases in cmt and rnfl thickness .
our results indicate that cmt , subfoveal ct , as well as rnfl and gcc thicknesses are slightly affected after phacoemulsification surgery .
although our study included a small group ( only 30 eyes ) , we assume that our data reliability is high because of the homogeneous nature of the patients ( similarities of age , cataract type and severity , cct , al , ot , ept and so on ) and the careful / detailed oct examinations performed by two observers , avoiding the effects of diurnal changes and mydriatic agents .
zhao et al13 revealed significant diurnal variations of the ct at the macular region in young healthy female individuals .
cataract surgery by phacoemulsification is one of the most common intraocular surgeries that improve the quality of vision .
however , it is an invasive procedure leading to an inflammatory response mostly induced by the release of prostaglandins in the retina and choroid and , in many patients , can lead to worsening of preexisting retinal diseases such as diabetic macular edema.15,16 recent studies have shown subclinical increase of cmt and peripapillary rnfl thickness after uneventful cataract surgery.1719 however , the morphologic changes that this inflammatory insult produces in the choroid have not been studied well because of the lack of detailed imaging techniques for the choroid .
after the introduction of edi , changes in ct in several pathologic ( central serous chorioretinopathy , choroidal neovascularization , and high myopia ) and physiologic ( age , sex , and al ) conditions can be easily assessed.2022 therefore , ct is being measured increasingly often and is becoming an accepted procedure for clinical and research applications .
falco et al23 evaluated the effect of uneventful phacoemulsification on the subfoveal ct and cmt , and they reported that phacoemulsification induced nonpathologic increases in cmt ; however , these changes were not accompanied by significant changes in ct .
they claimed that the inflammatory insult due to phacoemulsification mainly affects at the retinal level and seems to be independent of ct changes.23 by contrast ; our results support the recent studies by ohsugi et al24 and noda et al,25 which report significant increases in ct after uneventful phacoemulsification .
ohsugi et al24 evaluated 100 eyes and emphasized that the al and changes in iop were critical for evaluating the changes in ct after cataract surgery .
noda et al25 evaluated 29 eyes and observed that the increase in subfoveal ct did not subside to baseline even at 6 months postoperatively .
they also found that male sex and thicker baseline ct predicted a larger magnitude of increase in ct after cataract surgery.25 in our study , interestingly , the parameters of age , sex , al , baseline ct , and cct did not influence the postoperative ct statistically in regression analysis .
we also analyzed the effect of ot and ept on postoperative ct and we did not find any relationship .
this may be explained by the short / similar results in terms of ots and epts , as well as the experience of the surgeon conducting a quick surgery with less anterior segment manipulation , thus reducing the inflammatory response after cataract surgery .
a speculation is that it may be related to postoperative inflammation because proinflammatory prostaglandins and cytokines are considered to explain macular edema after cataract surgery , and inflammatory disorders are also known to increase the ct.26,27 another speculation is that cataract surgery introduces more light into the eyes , leading to greater metabolic activation in the retinal pigment epithelium , causing angiogenesis and inflammation.28,29 in the beaver dam and blue mountains eye studies,3032 it has been suggested that cataract surgery is associated with the onset of amd , resulting in visual impairment due to neovascularization originating from the choroid .
noda et al25 report that cataract surgery influences the ct and this influence persists for as long as 6 months postoperatively and may affect the process of amd .
choroidal abnormalities are central to chorioretinal disorders such as amd , polypoidal choroidal vasculopathy , and central serous chorioretinopathy .
furthermore , it has been claimed that pathologic choroidal blood supply is an important factor in open - angle glaucoma leading to optic nerve damage.33,34 cts of glaucomatous eyes have been reported to be thinner in postmortem histologic studies .
in addition , significant increases in choroidal extravascular volume have been confirmed in many primary angle - closure glaucoma eyes and abnormal ct has been hypothesized to be a contributing feature in these eyes.35,36 however , it is unclear whether these findings represent a risk factor or a consequence of these diseases .
the hallmark of glaucoma is the loss of the retinal ganglion cell axons , which leads to a typical optic neuropathy .
qualitative and quantitative evaluations of the optic nerve head and rnfl have been used to detect evidence of glaucomatous damage.911 in a recent study,8 it has been suggested that the gcc thickness may be the most relevant parameter to measure in glaucoma .
nouri - mahdavi et al37 also reported that regional gcc measurements derived from cirrus hd - oct performed as well as regional rnfl outcomes for the detection of early glaucoma .
moreover , macular gcc thickness has been found to have better structure function correlations than rnfl thickness with both visual function and central nervous system findings in multiple sclerosis neurodegeneration.12 as oct uses near - infrared light and is based on interferometry , its image quality is influenced by opacities in the optical path .
loss of oct image quality is caused by attenuation of the light in the oct scanning spot on the retina.17,18 several studies have shown that lens opacity decreased image quality and postoperative rnfl thickness measurements increased significantly.3840 the more advanced the cataract , the less is the signal quality and the thinner are the recorded rnfl and gcc thicknesses .
the coexistence of neurodegenerative diseases such as glaucoma and cataract among elderly patients is not unusual , and cataract may decrease the quality of fundus images , leading to an incorrect evaluation in the diagnosis and follow - up of these patients .
nakatani et al7 examined the effect of cataract on the measurements of gcc and rnfl thicknesses , and they reported that all thickness parameters in gcc and rnfl increased slightly after phacoemulsification surgery .
therefore , we decided that the presence of cataract may lead to an underestimation of the thicknesses of gcc and rnfl , and this should be taken into account when analyzing progression in glaucoma and/or neurodegenerative diseases such as multiple sclerosis .
after cataract surgery , the examiners should consider obtaining new baseline measurements , as suggested in previous studies .
this study has many limitations such as short follow - up time , relatively small sample size , and lack of eyes with glaucoma and neurodegenerative diseases .
in addition , we analyzed just mean subfoveal ct and mean thickness of gcc and rnfl , leading to lack of segmentation of these parameters .
scleral interface and measured ct with cirrus linear measurement tool . although we used scans with signal strength 6 for analysis and excluded poor images , the effect of signal strength index on measurements was not investigated .
furthermore , we used postoperative topical steroids after cataract surgery ; thus , the true effect of phacoemulsification on oct parameters could not be evaluated and we could not determine whether and when the increased ct can return to baseline measurements .
phacoemulsification surgery increased ct and it should be kept in mind that the small changes in ct may affect the onset of amd , which is a serious disease that results in central visual impairment .
although the mechanism is unclear , it has been postulated that ct changes may also play a role in glaucoma .
we suggest establishment of new baseline measurements after cataract surgery for monitoring patients with glaucoma and neurodegenerative diseases .
further studies with a greater number of patients and longer duration of follow - up and conducted using new computerized oct algorithms are needed . | purposewe aimed to evaluate the effect of cataract surgery on subfoveal choroidal thickness ( ct ) and ganglion cell complex ( gcc ) thickness , as measured by enhanced depth imaging - optical coherence tomography ( oct).methodsthis prospective study included 30 eyes of 30 patients who had undergone uneventful phacoemulsification surgery for senile cataract but had no previous ocular surgery or other ocular abnormality .
best - corrected visual acuity , slit - lamp biomicroscopy , intraocular pressure , axial length , and central corneal thickness were measured preoperatively .
the operative times ( ots ) and effective phaco times were also recorded in each case .
oct measurements were performed at the preoperative visit and 1 month after cataract surgery .
study of ct and gcc thickness changes was the primary objective , but central macular thickness ( cmt ) and peripapillary retinal nerve fiber layer ( rnfl ) thicknesses were also obtained by oct.resultsthe mean subfoveal ct was 294.439.2 m preoperatively and 301.439.9 m postoperatively ( p<0.001 ) .
the mean gcc thickness was 85.04.4 m preoperatively and 89.25.3 m postoperatively ( p<0.001 ) .
the mean cmt was 247.917.6 m preoperatively and 249.017.8 m postoperatively ( p=0.029 ) .
the mean rnfl thickness was 97.45.4 m preoperatively and 101.75.6 m postoperatively ( p<0.001 ) .
regression analysis showed that age , sex , axial length , central corneal thickness , operative time , and effective phaco time were not associated with ct changes ( p=0.834 , p=0.129 , p=0.203 , p=0.343 , p=0.547 , and p=0.147 , respectively ) and gcc thickness changes ( p=0.645 , p=0.542 , p=0.152 , p=0.664 , p=0.448 , and p=0.268 , respectively ) after cataract surgery.conclusionour results indicate that all subfoveal ct , cmt , as well as rnfl and gcc thicknesses are slightly affected after uneventful phacoemulsification surgery .
after cataract surgery , the examiners should consider obtaining new baseline measurements . | [
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only 2030% of patients with group a beta hemolytic streptococcus ( gabhs ) pharyngitis presents with classical symptoms of the disease .
reliance on clinical judgment alone has a poor predictive value and results in 80% to 95% overestimation of disease [ 2 , 3 ] .
diagnostic strategies for acute gabhs pharyngitis are thus based on epidemiological factors , signs , and symptoms , as well as the result of throat cultures ( tcs ) .
several studies have shown that the use of throat culture leads to more judicious use of antibiotics [ 57 ] .
physicians prescribe antibiotics for acute pharyngitis as they are concerned that patients with this complaint may be suffering from gabhs infection that if left untreated might develop suppurative complications , such as , tonsillar abscess or nonsuppurative complications , such as , rheumatic fever [ 6 , 8 ] . antibiotics , however ; confer only minor symptomatic benefits for gabhs sore throat .
they shorten the duration of symptoms by merely half a day on average [ 8 , 9 ] .
more recent studies have shown that antibiotic use only reduced the incidence of rheumatic fever by a mere 0.5 cases per 100,000 .
the importance of preventing rheumatic fever has lessened as the incidence of rheumatic fever and rheumatic heart disease has declined significantly in the last 20 years , from a mean annual incidence of 13.4 per 100,000 to 5 per 100,000 .
prevalence has decreased as well from 5.7 per 1,000 in the eighties to 0.5 per 1,000 in 2000 [ 8 , 10 , 11 ] .
this failure probably stems from the fact that about 20% of children with gabhs is infected with bacteria which contain m protein , a virulence factor located on the surface of the bacterial wall that confers resistance to commonly used antibiotics .
newer beta - lactamase - resistant antibiotics did not prevent this treatment failure [ 13 , 14 ] .
review of the literature from 1945 to 1999 , which includes 10,484 cases of gabhs sore throat , found that antibiotic treatment reduced the occurrence of acute otitis media , a common complication of this disease , by a mere 25% , compared to the placebo group and sinusitis by only 50% .
rheumatic fever , a nonsuppurative complication , was reduced by less than 33% , compared to placebo [ 8 , 10 , 11 , 15 ] .
in addition to the uncertainly in the scientific literature , parents seem to be uncertain regarding the benefits of antibiotic treatment for acute gabhs pharyngitis and tend to stop treatment earlier than prescribed . in a pilot study
, we randomly followed 75 children with gabhs pharyngitis for 6 months and have found that more than 75% of them did not complete ten days of antibiotics .
this finding led us to conduct a multisite , prospective cohort observational study , the results of which are reported here .
the goal of this study was to determine whether noncompliance with antibiotic treatment affects short - term or long - term complications .
two central , primarily rural , and agricultural regions of the largest health maintenance organization ( hmo ) in israel , comprising approximately one million patients . using a standard protocol
, we located from our computerized data base 107,840 patients , aged 6 months to 18 years , who were examined by their primary care physician for upper respiratory tract infection , tonsillitis , pharyngitis , sore throat , tonsillopharyngitis , neck pain , cervical lymphadenopathy , pta , rpa , from january 1 , 1999 until december 31 , 2000 .
we then accessed the charts of 78,473 of these children who were diagnosed with infected throat or one of the differential variants , excluding all children diagnosed as having viral upper respiratory infections .
47,000 of these patients were formally diagnosed with acute pharyngitis or acute tonsillitis and received a prescription for antibiotics , indicating that their physician suspected bacterial disease . in the index visit , 35,000 of these children had at least four out of five symptoms in the modified centor criteria used for this study and nadir modified breese epidemiological and clinical score card ( ecsc ) that has 91% sensitivity and 98% specificity when the score was above 15 ( score between 4 and 36 ) for the diagnosis of gabhs [ 1719 ] .
colonies yielding beta - hemolysis were grouped for surface carbohydrate assessment by using a latex bead agglutination test ( figure 1 ) . of the 6336 children ( with positive cultures with 4 or more centor criteria and 15 or higher ecsc ) , 4,775 parents consented to enroll their children to the study ( figure 1 ) . excluded from the study were children who were diagnosed as gabhs chronic carriers or who had suffered from post - gabhs complications ; had any chronic illness , such as , renal or hepatic impairment ; had bleeding disorder ; had congenital or acquired immunodeficiency or suffered from malignancy .
initial patient / parent contact was made by one of the authors ( m. sarrell ) within 3 to 5 days of the initial positive throat culture . at that time , initial information regarding the illness and whether a prescription for antibiotics was given by the primary care physician .
the attending physicians of the two thousand study patients were contacted by email within 48 hours of the enrollment by one author ( m. sarrell ) .
the physicians were requested to inform the authors of any additional cultures taken during therapy , and to request that they obtain two additional throat cultures and engage in improve adherence strategies by providing information , counseling , reminders , reinforcement , and if needed personal attention or supervision .
while repeated cultures are not routinely recommended for asymptomatic patients who have completed a course of antimicrobial therapy , in light of the poor compliance with treatment in the pilot study , performance of such follow - up cultures was considered important for the purposes of the study .
the first follow - up culture was performed within 10 to 14 days of the initial positive culture regardless of treatment status .
the purpose of this culture was verification of antibiotics treatment failure or persistence of gabhs in the oropharynx of the untreated patients .
the second additional throat culture was taken between days 21 and 30 after the initial positive culture , regardless of treatment status , to ascertain the presence of residual gabhs or recurrences . treating physicians
were also requested to obtain blood for liver enzymes , renal function tests , and urine analysis from all the participants and to perform annual follow - up evaluation thereafter .
a second patient / parent contact was made by our study coordinator within 10 to 14 days of initiation of antibiotic treatment .
she collected information about demographic characteristics , past medical history , febrile status , need for repeat throat culture during the treatment period ( that was not part of the study protocol ) , and type of medication prescribed . during this contact she obtained information about the number of days of actual treatment , omission compliance and complications , the patients / parents perceived as deriving from the treatment ( or lack thereof ) .
the computerized charts of the participants were searched within 2 to 4 weeks of the second patient / parent contact for additional information , including demographic characteristics , medical and environmental history , initial clinical data , such as , in - office fever evaluation , results of the physical examination , additional culture taken , type of antibiotics used , and disposition of prescription received .
a second search of the computerized medical charts was performed by our research assistant between 30 and 90 days of initiation of medical treatment , to ascertain that the 2 requested throat cultures were obtained . relapse or recurrence of clinical or bacterial pharyngitis ,
suppurative or nonsuppurative complication , or even whether the participants complained of any sore throat within 30 days of completion of treatment were also evaluated . in order to assure that all possible short - term complications that occurred within 90 days of the index case were obtained ,
an additional comprehensive search of the hmo database was done within 120 days of the second computer search .
we ascertained that findings that were either not available on the original computerized chart or were seen by other than their primary care physician , ( e.g. , emergency departments , patients that relocated ) , were not overlooked .
the charts of the participants were then reviewed by one of the authors on a yearly basis , from january 2000 to january 2010 , noting possible late nonsuppurative complications of gabhs infection .
no patients were lost to followup , even if they had changed physicians , due to our ability to track them through the centralized database to their new physician or another hmo .
the children that were enlisted to the army ( and thus not members of any hmo during their military service ) were contacted either through their former attending physician or the military physician .
minor treatment failure was defined as any clinical or bacterial recurrence of pharyngitis during the short - term follow - up period and its correlation to compliance with treatment .
major treatment failure was defined as retropharyngeal or peritonsillar abscess or long - term complications , such as rheumatic fever .
suppurative complications were chosen as a model , because the nonsuppurative complications ( rheumatic heart disease , arthritis , carditis ) have been practically eradicated in our region .
this cohort study was designed to analyze rare events ( according to the cioms classification 110 events per 10,000 children years ) .
the annual incidence of peritonsillar abscess ( pta ) in our region is 24 cases per 100,000 and the incidence of retropharyngeal abscess ( rpa ) is 57 cases per 100,000 .
power calculations suggested 6,500 to 7,000 person - years of intervention would be needed to detect a 22% difference in pta and rpa between the fully treated ( ft ) and partially treated ( pt ) arms of the study population .
furthermore , one - sided alpha of 0.025 , a statistical power of 95% , and the pta / rpa incidence given above showed that approximately 19,000 children - years would be needed to show the noninferiority of ft versus pt . since the primary outcome of interest is the pta / rpa hazard ratio between ft and pt .
the null hypothesis to be tested is hr pta / rpa > 2 ( i.e. , the pta / rpa hazard ratio for ft versus pt is higher or equal to 2 ) .
the pta / rpa hazard ratio was calculated for ft versus pt . for purposes of analysis ,
participants were divided into four subgroups based on length of treatment : 1st subgroup ( untreated ) , those who did not receive any treatment , 2nd subgroup ( partially treated ) , children that received antibiotics for 1 to 3 days , 3rd subgroup ( mostly - treated ) , children treated for 4 to 6 days , and 4th subgroup ( fully - treated ) children treated between 7 to 10 days .
data are presented as proportions ( with 99% confidence intervals [ cis ] ) , means ( with sds ) , or medians ( with interquartile ranges ) , using pearson tests , student 's tests , or fisher exact test .
comparisons of length of treatment according to time and treatment were assessed using the repeated measures and analysis of variance and the paired t test .
a 2-tailed p value of.05 was used to determine the statistical significance of differences observed between groups and to calculate confidence intervals around differences in sample means and odds ratios .
we used the mcnamara test to measure the changes between the groups and their subgroups regard to the length of antibiotic treatment .
over half of their children ( 1023 , 51% ) were between the ages of 6 months and 6.9 years , and over half 1,039 ( 52% ) were female .
the majority of children ( 1,821 , 91% ) were prescribed penicillin or amoxicillin , allergic or intolerant to penicillin were treated with cephalosporin 25 ( 1.5% ) , erythromycin 109 ( 5.5% ) , and azithromycin 45 ( 2.5% ) , all medication were prescribed twice daily for 10 days , except azithromycin once daily for 5 days .
no statistical correlation was found between the type of antibiotics , the children received , or the demographic characteristics and the complications found in the later medical examinations .
only 196 children ( 9.8% ) actually completed 10 days of antibiotic treatment . despite having received a prescription from their physician , two hundred and thirteen participants ( 11% )
did not start taking any treatment whatsoever , including those who did not even purchase antibiotics .
as shown in table 1 a no statistical correlation was found concerning length frequency and duration , palatability , number of daily dose of treatment , but a statistically significant difference was found between all the subgroups concerning the length of antibiotics treatment ( p <
the majority of children ( 1192 , 59.6% ) had 3 days or less of fever , defined as any rectal temperature less than 38.5c or oral temperature less than 37.8c .
the majority of children ( 1591 , 80% ) received medication for four to six days at the most ( partially treated subgroup ) .
as illustrated in table 1 , the association between the duration of fever and the number of days of treatment was statistically significant ( p < .0001 ) .
of the 306 ( 15.3% ) children with clinically diagnosed recurrent tonsillopharyngitis , only 236 ( 12.3% ) had positive gabhs findings on the throat culture taken within 10 to 14 days after conclusion of the primary infection .
an additional thirty - four ( 1.7% ) had a positive second study culture ( taken 2130 days after the index positive gabhs culture ) .
of note is the fact that the majority ( 156 , 66% ) of the positive study culture at 1014 days were found among the subgroup treated for 7 to 10 days .
no such positive results were found in the subgroup treated for 1 up to 3 days .
furthermore , no positive gabhs throat cultures were found on the second study culture in the untreated group .
the majority ( 26 , 76% ) of positive gabhs cultures were in the mostly treated subgroups .
as illustrated in table 2 , these findings were both statistically significant ( p < .0001 ) ( table 2 ) .
cervical lymphadenitis , acute otitis media , and impetigo were the only suppurative complications noted .
110 ( 5.5% ) children developed cervical lymphadenitis , most ( 52 , 47% ) among the 6 to 7 days treatment subgroup and 33 ( 33% ) among the 4 to 5 days treatment subgroup , a significant difference among the treatment subgroups ( p < .0001 ) .
additionally , no children developed nonsuppurative complications during 10 years of followup nor did any of the children develop iga nephropathy during the follow - up period .
furthermore , they were no association between the five modified centor criteria and development of complication , even when stratified by type of antibiotics or the season of the year . altogether , 304 ( 15% )
new onset cases of acute otitis media ( aom ) were diagnosed within 30 days of the initial diagnosis .
however , only 31 ( 10% ) of those were in the untreated subgroup , as compared to 141 ( 46% ) in the 7 to 10 days treatment subgroup , 98 ( 38% ) in the 4 to 6 days treatment subgroup and 98 ( 33% ) in the 1 to 3 days subgroup , a statistically significant difference among the all treatment subgroups ( p < .0001 ) . attempting to elucidate the possible causes for the differences between the recurrence of gabhs and the length of antibiotic treatment or clinical score on enrolment or illness severity , a multivariate stepwise logistic analysis was performed .
the duration of fever was the most significant predictor for such recurrence , age under 6 years being less significant , while treatment for 7 to 10 days had no significant influence on the recurrence of gabhs .
of note is that the contribution of the duration of fever was apparent even after controlling for the concomitant influence of age , gender , medical history , single- or two - parent home , type of antibiotics or the season of the year , and concomitant illnesses , such as , conjunctivitis , otitis media , upper respiratory infection , gastroenteritis , or lymphadenitis , which may have otherwise explained the influence of the length of treatment in relation to those illnesses ( table 3 ) .
this study found a very poor parent / child compliance to antibiotic treatment prescribed for symptomatic , culture - positive gabhs tonsillopharyngitis .
11% of children did not start taking any treatment at all , and only 10% completed a full course of treatment .
the reason for this low rate of compliance is unclear , but it coincides with other reported studies [ 14 , 16 ] . we speculate that a large proportion of lack of compliance is the parent 's sensation that antibiotics are potentially dangerous and overprescribed [ 18 , 19 ] . despite this poor compliance , in our study as in others , there was a very low rate of suppurative complications .
furthermore , despite the poor compliance , we found no increase in the incidence of acute rheumatic fever , the most dreaded complication of gabhs , in our patients .
in fact , since the year 2000 , the incidence of rf in our region has declined from 2.2 per 100,000 to 0.2 per 100,000 in 2008 , according to the epidemiological department of the israeli ministry of health .
this is in concordance with other developed countries , including , the united states , where the original recommendation for 10 days of antibiotic treatment of gabhs originated . in that country ,
currently there are only 10 cases of rf per 100,000 patients with gabhs pharyngitis , and only 1 case per 10,000 patients with acute rheumatic fever develop rheumatic heart disease [ 2022 ] .
in fact , concomitant with the increased use of antibiotics , recurrence of gabhs in the usa rose from 9% and 10.7% in the years 1975 to 1979 , respectively , to 25.9% and 37.5% in the years 1995 to 1996 , despite the decline in acute rheumatic fever .
14% of patients in our study had a recurrent infection , proven by a gabhs - positive throat cultures .
this percentage is similar to other studies which found that penicillin failed to eradicate gabhs from the throat in approximately 13% to 26% of the patients evaluated [ 23 , 24 ] .
the majority of recurrences in our study were in the younger group ( mean age of 10.2 years , and 60% of them younger than 9.9 years ) .
this is consistent with other published studies where such recurrences were more frequent among children aged 1 to 8 years than among children aged between 13 and 19 years [ 24 , 25 ] . historically ,
prescribing 10 days of oral penicillin began in the 1950s , substituting the intramuscular injections of long - acting parenteral penicillin , based on surrogate markers of eradication of gabhs from the tonsillopharynx . however , no study has conclusively proven that this practice unequivocally prevents acute rheumatic fever [ 26 , 27 ] . even though orally prescribed penicillin appeared to be equally effective for clinical and laboratory resolution of signs and symptoms , it is difficult to administer and expensive , considering the staggering financial burden of approximately 140 office visits per annum per 1,000 children younger than 15 years [ 28 , 29 ] . substituting azithromycin or cephalosporins for penicillin was found to produce better bacteriological and clinical results and also required a shorter course of treatment [ 30 , 31 ] .
our results may not apply to adults , sick people , or chronic gabhs carriers .
it does not address the optimal length of treatment required to achieve appropriate eradication of the microbe or whether complete eradication is required at all .
the method of pill / doses counts is not a good measure of adherence , but due to it simplicity and empiric nature it was found adequate for this study .
we were unable to assess the true variation of the incidence of acute rheumatic fever , due to the fact that this disease has been practically eradicated from our population .
our data suggest that the large majority of parents / patients stop administering antibiotics to their children who suffer from gabhs prior to the completion of the recommended course .
a more judicious use of antibiotics would promote and improve compliance , cut costs , and prove more convenient to parents and children alike . |
background .
uncertainty exists concerning the necessity of 10-day antibiotic treatment of group a beta hemolytic streptococcus ( gabhs ) pharyngitis . objective . to assess the incidence of gabhs recurrence and suppurative and nonsuppurative complications in relation to compliance
. methods .
( design ) . prospective cohort observational study .
( subjects ) .
2,000 children aged 6 months to 18 years with sore throat and positive gabhs culture .
( main outcome measures ) .
recurrence of symptomatic culture positive gabhs pharyngitis , incidence of suppurative , and long - term , regional , nonsuppurative complications of gabhs pharyngitis , over a ten year period . results .
213 ( 11% ) of the children received no treatment .
most children received antibiotics for only 46 days ( in correlation with the duration of fever , which in most cases lasted up to 3 days ) .
three hundred and six ( 15.3% ) children had clinically diagnosed recurrent tonsillopharyngitis ; 236 ( 12.3% ) had positive gabhs findings within 10 to 14 days and thirty - four ( 1.7% ) within 2130 days after the index positive gabhs culture .
the remaining 1.3% had no positive culture despite the clinical findings .
almost all recurrences [ 236 ( 11.6% ) ] occurred within 14 days and 156 ( 7.6% ) in the fully treated group .
the presence of fever during the first 3 days of the disease was the most significant predictor for recurrence .
other predictors were the age younger than 6 years and the presence of cervical lymphadenitis .
no increase in the incidence of nonsuppurative or suppurative complications was noted during the 10-year follow - up period , compared to the past incidence of those complications in israel .
conclusions .
our data suggests that the majority of children discontinue antibiotics for gabhs tonsillopharyngitis a day or two after the fever subsides .
the incidence of complications in our study was not affected by this poor compliance . | [
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neurofibromatosis affects 1:3,000 individuals , and characterized by largely benign but often debilitating tumors that grow in the nervous system .
its course is unpredictable : it can cause a variety of benign nerve tumors including plexiform , dermal , and optic glioma tumors ; in some cases malignant peripheral nerve sheath tumors can develop in the plexiform tumours .
down 's syndrome is one of the most common and easily recognized genetic conditions in humans .
the estimated prevalence in the united states is approximately 15 per 10,000 live births ( ie , 1 out of every 700 )
most often , it is the result of nondisjunction on chromosome 21 during maternal meiotic division .
we herein present the case of a 17-year - old boy with complaints of skin lesions over the back associated with mild itching since 3 months .
he was a known case of down 's syndrome with a history of seizures in childhood [ figure 1 ] .
the lesions gradually increased in size and number , and similar lesions started developing over his forehead since 23 weeks . on examination , multiple skin colored papules of varying size were present over the entire back and the forehead .
velvety thickening of the skin and hyperpigmentation of the axillae suggestive of acanthosis nigricans was present .
the characteristic features of down 's syndrome , including simian crease , mongoloid facies , and mental retardation were present .
canities and a solitary keloid over the chest were also seen apart from the clinical features of down 's syndrome . on oral examination , scrotal tongue , abnormal dentition , and
other investigations such as ct scan brain , 2d echo , and ecg were normal .
histopathology of the nodule from the back revealed focally thinned out epidermis with intact basal layer ; the papillary dermis showed a mild perivascular infiltrate .
deeper dermis showed a benign spindle cell proliferation suggestive of neurofibromatosis [ figure 3 ] .
physical appearance of down 's syndrome ( a ) neurofibromas ( b ) sebaceous cyst ( c ) acanthosis nigricans , and axillary freckling ( d ) scrotal tongue focally thinned out epidermis with intact basal layer with the papillary dermis showing a mild perivascular infiltrate .
the presentation of a patient with two unrelated genetic disorders is uncommon , although not statistically impossible .
however , in two of these reports , a third medical condition was also present . in one report , breast cancer was reported . in the other ,
our patient had down 's syndrome , neurofibromatosis , dental anomalies , and ocular defects and keloids . in the large majority of cases , trisomy 21
there is no current evidence to support the idea that this is anything other than a chance occurrence .
the two conditions are not related , and the likelihood of a person being born with these two conditions is approximately 1 in 2,700,000 births .
they however overlap in their manifestations . both are associated with intellectual impairment to differing degrees .
macroglossia occurs in both conditions , as may facial , dental , and occlusal abnormalities .
hearing and speech are affected in both conditions , as may the ability to maintain an acceptable level of oral hygiene .
mutations in the gene results in abnormal control of cell growth , differentiation , and aberrant myelination . our patient with of neurofibrmatosis type 1 with down 's syndrome is the first such to have a keloid and sebaceous cyst apart from myopia and dental anomalies . the unpredictable nature and course of the two genetic disorders along with multiple acquired conditions in this patient make it difficult for patients , teachers , care givers , and medical / dental providers to create and maintain long - term care plans . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . | we report a patient with down 's syndrome and neurofibromatosis who presented with a keloid , sebaceous cyst and acanthosis nigricans , along with dental and ophthalmological defects .
the coexistence of neurofibromatosis type 1 and down 's syndrome which are two unrelated genetic conditions is itself a rarity . | [
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a 48-year - old man presented with acute lower extremity weakness and back pain developed while he was working in a crawl space hyper extending his back .
muscle strength was 4/5 in right iliopsoas and hamstrings , and 0/5 in the remaining muscles of right and all muscles of the left lower limb . bilateral knee and ankle reflexes
pinprick sensation was decreased over left leg up to t12 level , and right l3 through s2 dermatomes .
vibration and proprioception sensation were normal . at a peripheral hospital , spine mri was unremarkable on day 1 .
spine mri on day 2 showed a non - enhancing intra - axial bright t2-weighted signal preferentially involving the anterior part of the cord extending from the conus to t11 ( figure 1a&b ) . on day 4 , ncs showed normal sensory and motor studies except an unrecordable right peroneal motor response ( chronic , post ankle fracture ) .
f - waves were not obtainable over the peroneal and tibial nerves ( figure 2a - c ) .
cerebrospinal fluid protein , glucose , cell count , cytology and flow cytometry were normal . extensive metabolic , infectious , vasculitis , cardiac , malignancy and thrombophilia workup were unremarkable .
he initially received intravenous methylprednisolone and plasma exchange for a presumed transverse myelitis . on day 10 , mri showed smooth enhancement of the ventral nerve roots and conus ( figure 1c&d ) .
the diagnosis was revised to conus medullaris infarct based on the distribution and evolution of mri findings .
. left peroneal and bilateral tibial compound muscle action potential ( cmap ) amplitudes decreased .
left peroneal f waves reappeared with poor persistence ( 6.7% ) and prolonged latency ( 64 ms ) .
although cmap amplitudes remained decreased , all f - waves were obtainable with a slightly prolonged latency and normal persistence ( figure 2g - i ) .
spine mri axial ( a ) and sagittal ( b ) t2-weighted mri obtained 2 days after symptoms onset demonstrating t2 hyperintense signal within the conus extending to t11 .
axial t2-weighted ( c ) and contrast enhanced ( d ) mri obtained 10 days after symptom onset demonstrating contrast enhancement of the anterior part of the conus and nerve roots .
f - waves ( a - c ) f responses recorded by stimulating the left peroneal and bilateral tibial nerves at day 4 , ( d - f ) day 18 , and ( g - i ) day 56 after disease onset .
m - direct motor response ; ml - minimal latency ; mv - millivolt , nr - no response ; ms - millisecond
f - wave is not considered part of the workup in conus medullaris infarct . however , in the absence of upper motor neuron signs , especially with a normal early spine mri and absent f - wave , confusion about the diagnosis may arise . in a previous case report , f waves were absent in the hyperacute stage ( first 4 hours ) of anterior spinal cord infarct.2 in our patient , f waves were absent at the time of the first nerve conduction studies ( ncs ) ( day 4 ) and they may have been absent from the onset .
hiersemenzel et al3 described reappearance of f waves after the stage of spinal shock in 12 patients with a traumatic paraplegia above t10 level , and attributed the early absence of f waves to reduced excitability of motor neurons at the stage of spinal shock . in our patient , the mechanism of injury was ischemia ( rather than trauma ) and the injury level was at the conus ( lumbosacral spinal cord segments ) with involvement of the motor nerve roots that showed enhancement on the follow - up mri . recovery of left tibial f waves on day 18 coincided with development of hyperreflexia in the same leg .
in contrast , at the time of reappearance of right tibial f waves on day 56 , right ankle reflex was absent .
thus , we hypothesize that the absent f - waves in the acute stages of conus medullaris infarct might have been due to temporarily unexcitable ahc as a result of spinal shock , spinal cord edema , and possibly oligemia ( figure 1 ) .
we would not expect f waves to be recordable in the setting of a diffuse infarction of all ahc in the spinal cord segments subserving the tested nerve .
we are not aware of any reports describing f wave as a prognostic indicator of conus medullaris infarct .
we postulate that persistently absent f waves , beyond the stage of spinal shock ( 2 - 4 weeks ) , in conus medullaris infarct indicates severe damage to ahc in the lumbosacral region and poor chance for renervation through collateral sprouting .
all f waves had reappeared by day 56 , at least 8 weeks before he regained walking .
the area of infarct involved the ventral part of the spinal cord supplied by the anterior spinal artery .
we suspect the mechanism of infarct was secondary to a hyperextension injury similar to the non - traumatic spinal cord infarct described in novice surfers ( surfers myelopathy ) . in such cases , the postulated mechanisms of ischemia include transient arterial compression during a prolonged back hyperextension in the setting of poor collaterals , vasospasm or thrombosis of the artery of adamkiewicz , and avulsion of perforating blood vessels.4,5 the prognosis of surfers myelopathy varies from complete recovery to persistent paraparesis.4,5 a normal mri in the first few days does not rule out spinal cord infarct . in reported case series ,
the earliest changes ( bright t2-weighted signals ) appeared after 1 - 2 days , followed by enhancement appeared within the first week and peaked at 14 -21 days.6,7 cauda
equina enhancement post spinal cord infarct has been described in a few case reports and attributed to a possible disruption of blood - nerve barrier.2,8,9 in conclusion , further studies are required to test our hypothesis that reappearance of tibial and peroneal f waves has a prognostic value in predicting walking in patients with conus medullaris infarct . | absent f wave in the stage of spinal shock has been described in cases of traumatic spinal cord injury .
the role of f wave in predicting prognosis after conus medullaris infarct has not been described .
we describe herein a middle aged - man with a conus medullaris infarct .
both tibial and peroneal f waves were absent on day 4 .
the left tibial f wave reappeared in the following study on day 18 .
all f waves reappeared on day 56 at which time the patient was still wheelchair bound .
he regained walking on day 105 .
we hypothesize that reappearance of initially absent f waves post conus medullaris infarct is a good prognostic sign for the return of ambulation .
the applicability of this observation requires further research .
we also discuss clinical and diagnostic caveats in this case . | [
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west nile encephalitis is a mosquito - borne disease endemic to africa , asia , australia , and europe and the west nile virus is a single - stranded rna virus which belongs to the japanese encephalitis serogroup of flaviviruses ( 1 ) .
it could be accompanied with various neurologic symptoms and signs including headache , mental confusion , optic neuritis , and muscle weakness ( 2 , 3 , 4 ) .
after the first two cases of west nile encephalitis were diagnosed in 1999 in new york ( 5 ) , many neurological abnormalities were noted in patients of west nile encephalitis , and the flaccid muscle weakness is a distinctive feature of this disease ( 2 , 3 , 6 ) . until now
, west nile encephalitis was never diagnosed in korea , and it is the first report of west nile encephalitis in korea .
a 58-yr - old man was admitted with headache for 2 months in june 2012 .
the patient had been on a business trip in guinea , west africa since 7 months ago .
he denied other symptoms such as nausea , vomiting , neck stiffness , and dizziness .
the headache and cognitive impairment had been worsening and accompanied general weakness and weight loss 10 kg for 2 months .
he had no hypertension , cardiac diseases , chronic renal disease , and liver disease .
he had a 20 pack - year history of smoking and no recent alcohol intake .
the patient denied using any medications except for antimalarial drug ( sulfadoxine 500 mg , pyrimethamine 25 mg , artemether 80mg / ml ) and analgesics in africa . at admission to our hospital , he was afebrile ( 36.4 ) and his vital signs were blood pressure 121/78 mmhg , heart rate 97/min , and respiratory rate 20/min with normal findings of physical examinations .
findings on initial neurologic examinations were normal except minimental state examination ( mmse ) with score 20 .
admission complete blood count revealed hemoglobin of 12.7 g / dl , leukocyte count of 16.2 10/l with 79% neutrophils , and a platelet count of 388 10/l . the patient 's calcium level , chemistries , and liver function tests were normal and crp was slightly increased .
analysis of cerebrospinal fluid ( csf ) demonstrated 0 rbc/l , 214 wbcs/l ( with 80% lymphocytes and 12% neutrophils ) , a protein level of 161.9 mg / dl , a glucose level of 93 mg / dl and ada level of 4.8 .
a brain magnetic resonance imaging ( mri ) revealed multifocal patchy t2 high signal lesions in both temporal lobes , basal ganglia , internal capsule posterior limb , and corona radiata , which suggested encephalitis .
electroencephalogram showed frequent semirrhythmic medium amplitude delta slowing on both hemispheres , with frontal dominancy . on hospital day 1 , his body temperature was 38.0 and malaria test was negative .
follow up csf tapping was done on hospital day 3 and 6 rbc/l , 340 wbcs/l ( with 67% neutrophils and 28% lymphocytes ) , a protein level of 164.6 mg / dl , a glucose level of 70 mg / dl and ada level of 6.0 .
the patient complained of both leg weakness and the motor strength of bilateral lower extremity was 4+/4 + .
he also complained of both leg pain and paresthesia , deep tendon reflex on both lower extremities were areflexia .
there was no remarkable finding on nerve conduction study ( ncs ) and needle electromyogram ( emg ) , but arachnoiditis and myelitis were observed on lumbar spine mri ( fig .
polymerase chain reactions ( pcr ) for hsv , vzv , ebv , cmv , enterovirus , tuberculosis , and mycoplasma pneumonia were negative in csf .
serological test for brucellosis , lyme disease , leptospirosis , hantann virus and tsutsugamuchi disease were negative at admission
an additional serological study for specific antibody for west nile virus was done , the total antibody titer of west nile virus was 1:337 , and follow up titer after 2 weeks was 1:1,632 in serum by plaque reduction neutralization test .
treatment with interferon- 3mu was started and maintained for 2 weeks . follow up csf tapping was done after one month later and 9 rbc/l , 9 wbcs/l ( with 16% neutrophils and 67% lymphocytes ) , a protein level of 99.9 mg / dl and a glucose level of 66 mg / dl .
encephalitis with severe muscle weakness is a common symptom and may provide a diagnostic clue . to confirm a diagnosis , it needs identification of west nile virus in serum or csf .
igm antibody is usually detectable only during a few days of illness ( 7 ) .
another method is the identification of a change by a factor of four or more in the antibody titer or virus - neutralization tests ( 7 ) , the case was positive for the virus - neutralization tests .
serological test and pcr for other infectious agents were all negative and autoimmune encephalitis such as nmda receptor encephalitis was excluded by clinical symptoms ( 8) .
many studies indicated that the weakness was probably caused by infection and inflammation in the anterior horn cells of the spinal cord and brainstem like poliomyelitis ( 6 , 9 , 10 ) .
electrophysiologic studies showed reduced compound muscle action potentials , and normal sensory nerve action potentials , which is distinguished from guillain - barre syndrome ( 3 , 6 , 9 , 10 ) .
a few autopsy studies demonstrated that the inflammatory changes with severe leukocytic inflammation of the anterior horns with striking loss of motor neurons ( 4 , 11 ) . but this case did not present any abnormalities in the electrophysiologic study .
he complained about severe sensory symptoms with leg pain and arachnoiditis was observed in lumbar mri .
only a few reports noted a caudal equine enhancement ( 4 ) and weakness due to acute radiculitis ( 12 ) .
it 's hard to say that his weakness was caused by only radiculopathy , because paralysis of the west nile encephalitis generally results from anterior horn cell damage .
but in this case , radiculopathy also contributes the motor weakness of the west nile encephalitis . at present
there is no established treatment for west nile encephalitis and basic treatment is a supportive care .
but because it 's a fatal disease , sometimes it was treated with plasmapheresis or administration of iv immunoglobulin ( 5 ) .
interferon- has been reported to inhibit west nile virus replication , and some successful cases were reported using of interferon- to treat west nile encephalitis ( 13 ) .
korea is not an endemic area of west nile virus , but an increasing overseas trip poses a risk of the influx of overseas diseases and may contribute to the global spread of infectious diseases . | west nile encephalitis was first identified in 1937 , but until now , it was never diagnosed in korea .
a 58-yr - old korean man was admitted with headache and cognitive dysfunction .
the patient had been on a business trip in guinea .
cerebrospinal fluid ( csf ) showed pleocytosis .
the patient complained of both leg weakness , and arachnoiditis and myelitis were observed on lumbar magnetic resonance imaging ( mri ) .
a specific neutralizing antibody for west nile virus was positive in serum .
after a treatment with interferon- 3mu , follow up csf findings recovered completely after 3 months later .
the first case of west nile encephalitis in korea was imported from guinea , and was cured successfully.graphical abstract | [
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This repository contains model predictions generated by AutoTrain for the following task and dataset:
- Task: Summarization
- Model: google/bigbird-pegasus-large-arxiv
- Dataset: scientific_papers
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