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Ways of thinking: from crows to children and back again. This article reviews some of the recent work on the remarkable cognitive capacities of food-caching corvids. The focus will be on their ability to think about other minds and other times, and tool-using tests of physical problem solving. Research on developmental cognition suggests that young children do not pass similar tests until they are at least four years of age in the case of the social cognition experiments, and eight years of age in the case of the tasks that tap into physical cognition. This developmental trajectory seems surprising. Intuitively, one might have thought that the social and planning tasks required more complex forms of cognitive process, namely Mental Time Travel and Theory of Mind. Perhaps the fact that children pass these tasks earlier than the physical problem-solving tasks is a reflection of cultural influences. Future research will hope to identify these cognitive milestones by starting to develop tasks that might go some way towards understanding the mechanisms underlying these abilities in both children and corvids, to explore similarities and differences in their ways of thinking.

[Effect and mechanism of intermedin in acute rat cardiac ischemic injury]. To investigate the effect and potential mechanism of intermedin (IMD) in acute cardiac ischemic injury and to provide a new approach for exploring mechanism of sudden cardiac death. Seventy-two healthy male rats were randomly divided into 3 groups: control, ischemic and the IMD-treated group. The activity of lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) in heart blood were tested by enzyme chemistry method. The mRNA changes of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) in cardiac were measured by real-time PCR analysis. Myocardial cyclic adenosine monophosphate (cAMP) content was determined by enzyme linked immunosorbent assay (ELISA). Apoptosis related factors Bcl-2 and Bax were detected by immunohistochemistry. Comparing with the control group, LDH and MDA activity of ischemic group in heart blood increased and SOD activity decreased. The concentration of cAMP increased in ventricular muscle, Bcl-2 and Bax proteins expression ratio level decreased. The intravenation of IMD decreased the level of increased activity of LDH and MDA, and lessened the level of decreased activity of SOD. The mRNA expression of CRLR and RAMPs obviously increased in ventricular muscle. The protective effect of IMD against myocardial ischemic injury could be caused by decreasing the oxidative stress of ischemia and inhibiting the myocardial apoptosis.

Replication of mitochondrial DNA occurs throughout the mitochondria of cultured human cells. Replication of mitochondrial DNA (mtDNA) is dependent on nuclear-encoded factors. It has been proposed that this reliance may exert spatial restrictions on the sites of mtDNA replication within the cytoplasm, as a previous study only detected mtDNA synthesis in perinuclear mitochondria. We have studied mtDNA replication in situ in a variety of human cell cultures labeled with 5-bromo-2'-deoxyuridine. In contrast to what has been reported, mtDNA synthesis was detected at multiple sites throughout the mitochondrial network following short pulses with bromodeoxyuridine. Although no bromodeoxyuridine incorporation was observed in anuclear platelets, incorporation into mtDNA of fibroblasts that had been enucleated 2 h prior to labeling was readily detectable. Blotting experiments indicated that the bromodeoxyuridine incorporation into mtDNA observed in situ represents replication of the entire mtDNA molecule. The studies also showed that replication of mtDNA occurred at any stage of the cell cycle in proliferating cells and continued in postmitotic cells, although at a lower level. These results demonstrate that mtDNA replication is not restricted to mitochondria in the proximity of the nucleus and imply that all components of the replication machinery are available at sufficient levels throughout the mitochondrial network to permit mtDNA replication throughout the cytoplasm.

Recent cancer trends in the United States. Cancer incidence rates have been reported to be increasing in the United States, although trends vary according to form of cancer. We identify the cancers accounting for the rising incidence, quantify the changes that have occurred from the mid-1970s to the early 1990s, and contrast incidence and mortality trends to provide clues to the determinants of the temporal patterns. Sex-, race-, and age-specific and age-adjusted incidence rates for the 5-year periods 1987-1991 versus 1975-1979 were calculated for 28 cancers among men and 30 cancers among women using data from the Surveillance, Epidemiology, and End Results (SEER) Program of cancer registration covering about 10% of the U.S. population. Similar rates were computed using national mortality data. Cancers were ranked according to the change in incidence rates over the two periods. Age-adjusted incidence rates for all cancers combined increased by 18.6% among males and 12.4% among females from 1975-1979 to 1987-1991, due largely to rising rates for prostate cancer among men and for breast and lung cancers among women. National mortality rates for all cancers combined rose less steeply, 3% and 6% among men and women, respectively, driven mostly by continuing increases in lung cancer mortality, while death rates for the majority of the cancers were steady or declining. Total cancer incidence rose at all ages, but with different tumors responsible for the increases at different ages: leukemia and brain/nervous system cancer among children; testicular cancer, nonmelanoma skin cancer (largely Kaposi's sarcoma), non-Hodgkin's lymphoma, and melanoma among young and middle-aged adults; and prostate, breast, and lung cancers among older individuals. In contrast, mortality rates for all cancers combined declined among both males and females under age 55 years, increasing only among older persons. Trends in cancer incidence and mortality differ. For most cancers, incidence rates are rising, while mortality rates are generally stable or declining. Much of the recent increase in cancer incidence can be explained by known factors. Improved detection appears to account for most of the increases in breast cancer among women and prostate cancer among men. On the other hand, cigarette smoking is the major determinant of the rise in lung cancer among women, acquired immunodeficiency syndrome has led to increases in non-Hodgkin's lymphoma and Kaposi's sarcoma among young and middle-aged men, and sunlight exposure patterns have affected the trends in melanoma. Some trends remain unexplained, however, and may reflect changing exposures to carcinogens yet to be identified and clarified.

Ideal CdSe/CdS Core/Shell Nanocrystals Enabled by Entropic Ligands and Their Core Size-, Shell Thickness-, and Ligand-Dependent Photoluminescence Properties. This work explored possibilities to obtain colloidal quantum dots (QDs) with ideal photoluminescence (PL) properties, i.e., monoexponential PL decay dynamics, unity PL quantum yield, ensemble PL spectrum identical to that at the single-dot level, single-dot PL nonblinking, and antibleaching. Using CdSe/CdS core/shell QDs as the model system, shell-epitaxy, ligand exchange, and shape conversion of the core/shell QDs were studied systematically to establish a strategy for reproducibly synthesizing QDs with the targeted properties. The key synthetic parameter during epitaxy was application of entropic ligands, i.e., mixed carboxylate ligands with different hydrocarbon chain length and/or structure. Well-controlled epitaxial shells with certain thickness (∼3-8 monolayers of the CdS shells) were found to be necessary to reach ideal photoluminescence properties, and the size of the core QDs was found to play a critical role in determining both photophysical and photochemical properties of the core/shell QDs. Effects of shape of the core QDs were unnoticeable, and shape of the core/shell QDs only affected photophysical properties quantitatively. Surface ligands, amines versus carboxylates, were important for photochemical properties (antiblinking and antibleaching) but barely affected photophysical properties as long as entropic ligands (mixed carboxylate ligands with distinguishable hydrocarbon chain lengths) were applied during epitaxy. Chemical environment (in polymer or in air), coupled with surface ligands, determined photochemical properties of the core/shell QDs with a given core size and shell thickness.

Oral administration of lyophilized Dunaliella salina, a carotenoid-rich marine alga, reduces tumor progression in mammary cancer induced rats. Dunaliella salina is a photosynthetic cell factory used for the commercial production of food additives, cattle stock feed and cosmetics as well as active ingredients for pharmaceutical industries. The investigation of the in vivo antitumor activity of D. salina lyophilized powder (DSLP) against 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinogenesis in female Wistar rats indicated a dose-dependent effect of DSLP. We studied the effect of DSLP at two different dosages of 500 and 1000 mg per kg bw on DMBA induced mammary cancer in rats by measuring the status of antioxidant enzymes, phase I and phase II detoxification enzymes, lipid peroxidation, and glycoconjugated proteins and by investigating the expression pattern of cell proliferation (Ki-67), hormonal receptor (ER, PR and HER2) status by immunohistochemical analysis, and apoptotic (caspase-3 and -9) and pro-inflammatory (COX-2) markers by colorimetric analysis. After 16 weeks of the study, we observed 100% tumor formation (including high tumor incidence and tumor volume) and a significant increase in the level of hormonal receptors, cell proliferation, and pro-inflammatory and apoptosis markers in tumor-bearing animals compared to the control. The oral administration of DSLP (1000 mg per kg bw) to the DMBA treated animals showed up to 83.4% reduction of tumors and effectively restored the levels of biochemical markers in the mammary tissues in addition to the downregulation of the expression of molecular markers. In conclusion, DSLP was found to show a chemopreventive effect against breast cancer induced in rats through the suppression of cell proliferation and the induction of apoptosis.

Variation in the aerobic demand of running among trained and untrained subjects. Variation in the aerobic demand (VO2) of submaximal running was quantified among trained and untrained subjects stratified by performance capability. Based on a retrospective analysis of seven published studies, maximal aerobic power (VO2max), and submaximal VO2 values were analyzed in three groups of trained distance runners (Category 1 (C1) (elite runners; N = 22), Category 2 (C2) (sub-elite runners; N = 41), and Category 3 (C3) (good runners; N = 16), and one group (N = 10) of untrained subjects (Category 4; C4). Results indicated that VO2max differed significantly (P < 0.05) across groups, such that C1 > C2 > C3 > C4. Analysis of submaximal VO2 data also revealed that C4 was more uneconomical than C1, C2, and C3 and that C2 and C3 were less economical than C1. Average within-group variability in submaximal VO2 was similar across categories and a marked overlap of minimum, mean and maximal economy values existed across categories. These data suggest that 1) trained subjects are more economical than untrained subjects, 2) elite runners display better economy compared to less-talented counterparts, and 3) economical and uneconomical runners can be found in all performance categories.

Effect of intrarectal povidone-iodine in the incidence of infectious complications after transrectal prostatic biopsy. To assess the incidence of genitourinary infections associated with transrectal ultrasound-guided prostate biopsy (TRUS-BX) using endorectal povidone-iodine gel as a bactericidal agent. We prospectively studied a total of 530 patients who were given 30g of 10% povidone-iodine intrarectally before TRUS-BX. Each patient received antibiotic prophylaxis with ciprofloxacin, starting the previous day (1g/day x 3 days), as well as cleansing enemas. One patient (0.20%) presented with an E. coli acute bacterial epididymitis after biopsy. In our study, the intrarectal use of 10% povidone-iodine gel in TRUS-BX is associated with a much lower rate of infectious complications compared to those described in recent literature.

Isoflurane-induced dilation of porcine coronary microvessels is endothelium dependent and inhibited by glibenclamide. Isoflurane has been reported to cause dose-dependent constriction in isolated coronary microvessels. However, these results are inconsistent with data from in situ and in vivo heart preparations which show that isoflurane dilates the coronary vasculature. To clarify the direct effects of isoflurane on coronary tone, we measured the response of isolated porcine resistance arterioles (ID, 75 +/- 4.0 microm; range, 41-108 microm) to isoflurane in the presence and absence of adenosine triphosphate-sensitive and Ca2+-activated potassium channel blockers and also after endothelial removal. Subepicardial arterioles were isolated, cannulated, and pressurized to 45 mmHg without flow in a 37 degrees C vessel chamber filled with MOPS buffer (pH = 7.4). After all vessels developed spontaneous (intrinsic) tone, dose-dependent (0.17-0.84 mm; approximately 0.5-2.5 minimum alveolar concentration) isoflurane-mediated effects on vessel ID were studied in the presence and absence of extraluminal glibenclamide (1 microm; an adenosine triphosphate-sensitive channel blocker) or iberiotoxin (100 nm; a Ca2+-activated potassium channel blocker) or before and after endothelial denudation using the nonionic detergent CHAPS (0.4%). Vessel ID was measured using an inverted microscope and videomicrometer, and vasomotor responses were analyzed by normalizing changes in arteriole ID to the dilation observed after exposure to 10-4 m sodium nitroprusside, which causes maximal dilation. Isoflurane caused dose-dependent dilation of all coronary arterioles. This vasodilation was 6.0 +/- 0.7 microm at an isoflurane concentration of 0.16 mm (approximately 0.5 minimum alveolar concentration) and 25.3 +/- 2.1 microm at 0.75 mm (approximately 2.5 minimum alveolar concentration). These values represent 18.1 +/- 1.7% and 74.1 +/- 3.3%, respectively, of that observed with 10-4 sodium nitroprusside (34 +/- 3 microm). Glibenclamide, but not iberiotoxin, exposure affected arteriolar dilation in response to isoflurane. Glibenclamide caused a downward displacement of the isoflurane dose-response curve, reducing isoflurane-mediated dilation by an average of 36%. Denuded arterioles showed a marked (approximately 70%) reduction in their ability to dilate in response to isoflurane. The authors conclude that isoflurane dilates coronary resistance arterioles in a dose-dependent manner, and that this dilation is partially mediated by adenosine triphosphate-sensitive channels and is highly dependent on the presence of a functioning endothelium.

Endonasal dacryocystorhinostomy in children: Our experience. Epiphora affects approximately 20% neonates, but most resolve spontaneously. Dacryocystorhinostomy (DCR) is indicated only when conservative management fails. To observe clinical presentation, treatment modalities and effectiveness of endoscopic DCR in paediatric population. It is a prospective study of 21 children done at our tertiary care hospital from 2011 to 2016. All were initially subjected to a trial of conservative management. Those that responded and didn't require surgery were excluded. The age group ranged from 40 days to 11.5 years. 19 underwent unilateral & 2 underwent bilateral endoscopic DCR. After a 6 month follow-up, 20 children were benefitted by surgery, 2 had an incomplete resolution and 1 required revision surgery. The overall success rate was 95.23% and failed cases were mainly due to post-traumatic distortion of the anatomy. No major complications were noted. Endoscopic DCR is safe and effective in children presenting with persistent epiphora.

[Formation of virulent antigen-modified mutants (Fra-, Fra-Tox-) of plague bacteria resistant to rifampicin and quinolones]. Experiments were performed with two strains of plague bacteria--231 (isolated from marmot) and 358 (isolated from human) and their isogenic variants with Fra- and Fra-Tox- phenotype. Mutants resistant to rifampicin (Rifr) and nalidixic acid (Nalr) appeared independently of pathogen phenotype and genotype with frequency n.10(-8)-n.10(-9), subsequently. Rifr mutation influenced on virulence manifestation at albino mice and antigendeficient variants with Fra- and Fra-Tox- phenotype. In every group of strains highly virulent subcultures were registered. Resistance to nalidixic acid mainly was not associated with virulence loss. Nalr mutants of parent and antigenmodified mutants were cross resistant to fluoroqinolones (ciprofloxacin, ofloxacin, pefloxacin, lomefloxacin). LD50 for untreated albino mice did not differ from LD50, for mice treated with rifampicin (when mice were infected with strain resistant to rifampicin) or with nalidixic acid and fluoroquinolones (when animals were infected with Nalr mutants). Antigenmodified strains of plague bacteria and their Rifr, Nalr mutants were able to overcome specific immune reaction. The drugs should be used in synergic combinations (with aminoglycosides or cephalosporines of III generation) to prevent appearance of virulent strains resistant to rifampicin and fluroquinolones.

Readability and Suitability of Spanish Language Hypertension and Diabetes Patient Education Materials. Hispanics who speak Spanish are at risk for low health literacy. We evaluated Spanish language hypertension (HTN) and diabetes mellitus (DM) patient education materials from U.S. federal agency public sector sources using the Suitability of Assessment (SAM) instrument. Mean readability for HTN materials was grade 7.9 and for DM materials was grade 6.6. Mean SAM score for HTN materials was 43.9 and for DM materials was 63.2. SAM scores were significantly better for DM than for HTN materials in overall score, content, graphics, layout, stimulation/motivation, and cultural appropriateness (p < .05). Clinicians should evaluate suitability of Spanish language HTN and DM materials that they use in patient teaching.

Amitriptyline treatment of chronic pain in patients with temporomandibular disorders. Randomized clinical trials of amitriptyline will require data from pilot studies to be used for sample size estimates, but such data are lacking. This study investigated the 6-week and 1-year effectiveness of low dose amitriptyline (10-30 mg) for the treatment of patients with chronic temporomandibular disorder (TMD) pain. Based on clinical examination, patients were divided into two groups: myofascial and mixed (myofascial and temporomandibular joint disorders). Baseline pain was assessed by a Visual Analogue Scale (VAS) for pain intensity and by the McGill Pain Questionnaire (MPQ). Depression was assessed by the Beck Depression Inventory (BDI) short form. Patient assessment of global treatment effectiveness was obtained after 6 weeks and 1 year of treatment by using a five-point ordinal scale: (1) worse, (2) unchanged, (3) minimally improved, (4) moderately improved, (5) markedly improved. The results showed a significant reduction for all pain scores after 6 weeks and 1 year post-treatment. The depression scores changed in depressed but not in non-depressed patients. Global treatment effectiveness showed significant improvement 6 weeks and 1 year post-treatment. However, pain and global treatment effectiveness were less improved at 1 year than at 6 weeks.

Nitric oxide metabolites and arginase I levels in β-thalassemic patients: an Egyptian study. Stored red blood cells become deficient in nitric oxide that limits their ability to transfer oxygen to tissues that need it. The aims of this study are to assess the endogenous nitric oxide metabolites (NOx) and arginase I levels in transfusion-dependent β-thalassemic patients; to compare these levels in patients transfused with fresh RBCs with patients transfused with old RBCs, β-thalassemic minor patients, and normal control; and to correlate these levels with some clinical variables. Group I was composed of 23 patients with homozygous β-thalassemia on hypertransfusion regimen. They were adequately transfused with fresh RBC. Group II was composed of 17 patients with homozygous β-thalassemia on hypertransfusion regimen. They were adequately transfused with old RBCs. Group III was composed of 30 patients with homozygous β-thalassemia. They were adequately transfused with fresh RBCs. Group IV was composed of 18 patients with homozygous β-thalassemia. They were adequately transfused with old RBCs. Both group III and group IV were supposed to be on hypertransfusion regimen, but they did not follow the regimen. Group V was composed of 21 patients of β-thalassemia minor. Nineteen apparently healthy individuals (HbAA) served as a control group (group VI). In addition to routine laboratory investigations, plasma levels of NOx and serum levels of arginase I were assessed in all subjects. The mean values of plasma NOx were significantly decreased in groups III and IV compared to the other groups. Also, the levels of NOx were significantly decreased in patients who received old RBCs compared to the other groups. There were high serum levels of arginase I in groups III and IV compared to the other groups. There were significant negative correlations between plasma NOx and some hemolytic biochemical markers in groups III and IV. There were significant positive correlations between serum arginase I and some hemolytic biochemical markers in groups III and IV. Also, there was a significant negative correlation between plasma NOx and serum arginase I levels in groups III and IV. In non-adequately transfused patients with β-thalassemia major, inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate, arginine, during the process of hemolysis. New treatments aimed at improving arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, oral arginine supplementation, predonation testing, and transfusion of fresh RBCs or use of NO donors represent potential therapeutic strategies for this common hemolytic disorder.

Animal evolution: the enigmatic phylum placozoa revisited. A recent report of high levels of genetic variation between strains of Trichoplax adhaerens challenges the traditional view that the phylum Placozoa comprises only one species. At the morphological level, placozoans are amongst the simplest extant animals, but molecular evidence suggests that they may have more complex origins.

Microfluidic flow fractionation device for label-free isolation of circulating tumor cells (CTCs) from breast cancer patients. Circulating tumor cells (CTCs) are dissociated from primary tumor and circulate in peripheral blood. They are regarded as the genesis of metastasis. Isolation and enumeration of CTCs serve as valuable tools for cancer prognosis and diagnosis. However, the rarity and heterogeneity of CTCs in blood makes it difficult to separate intact CTCs without loss. In this paper, we introduce a parallel multi-orifice flow fractionation (p-MOFF) device in which a series of contraction/expansion microchannels are placed parallel on a chip forming four identical channels. CTCs were continuously isolated from the whole blood of breast cancer patients by hydrodynamic forces and cell size differences. Blood samples from 24 breast cancer patients were analyzed (half were from metastatic breast cancer patients and the rest were from adjuvant breast cancer patients). The number of isolated CTCs varied from 0 to 21 in 7.5 ml of blood. Because our devices do not require any labeling processes (e.g., EpCAM antibody), heterogeneous CTCs can be isolated regardless of EpCAM expression.

Obstructive jaundice in small cell lung carcinoma. Small cell lung carcinoma (SCLC) commonly metastasizes to distant organs. However, metastasis to the pancreas is not a common event. Moreover, obstructive jaundice as a first clinical presentation of SCLC is extremely unusual. This case reports a 51-year-old male with SCLC, manifesting with obstructive jaundice as the initial clinical presentation. Endoscopic retrograde cholangiopancreatograghy (ERCP) and abdominal computed tomography (CT) scan showed a mass at the head of the pancreas. The patient underwent pancreatoduodenectomy (Whipple procedure). Histopathology revealed a chromogranin- A-positive poorly-differentiated neuroendocrine carcinoma of the pancreas. No imaging study of the lung was performed before surgery. A few months later, a follow-up CT revealed unilateral lung nodules with ipsilateral hilar nodes. A lung biopsy was done and histopathology reported a TTF- 1-positive, chromogranin A-positive, small cell carcinoma of the lung. On review, the pancreatic tumour was also TTF-1-positive. He was then treated with combination chemotherapy (cisplatin, etoposide). These findings highlight that presentation of a mass at the head of pancreas could be a manifestation of a metastatic tumour from elsewhere such as the lung, and thorough investigations should be performed before metastases can be ruled out.

[Polyarthritis revealing hairy cell leukemia]. A female patient simultaneously developed hematologic evidence of hairy cell leukemia and marked but short-lived inflammatory involvement of a number of joints. Both these groups of symptoms resolved simultaneously and rapidly under alpha-2 interferon therapy. This course suggests that the arthritis was a rheumatologic manifestation of the hematologic disease. The concomitant occurrence in this patient of arthritis, splenomegaly and leukopenia was suggestive of Felty syndrome: these two conditions need to be differentiated.

Multi-substituted 8-aminoimidazo[1,2-a]pyrazines by Groebke-Blackburn-Bienaymé reaction and their Hsp90 inhibitory activity. Using a 2,3-diamino pyrazine substrate and yttrium triflate catalyst, various 2-alkyl and aryl substituted 3,8-diaminoimidazo[1,2-a]pyrazines were efficiently prepared through Groebke-Blackburn-Bienaymé MCR. In particular, a novel 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazine structure was prepared exclusively with this new method and was found to have moderate Hsp90 inhibitory activity. A crystalline complex with N-terminus ATP domain of Hsp90 and one of the new Hsp90 inhibitors was also obtained to elucidate the origin of activity of 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazines.

Sequence variation in the src gene product affects metastasis formation: the central, but not exclusive, role of the tumor immune response. Sequence variation in the src gene product could, in principle, influence metastasis formation through either of 2 effects: an alteration in tumor antigenicity or a non-immune-mediated change in one or more src-associated functions. Our present results establish that both mechanisms underlie the difference in relative levels of metastasis formation induced by the v-src vs. the c-src(527) oncogene. A point that emerges from this analysis is the segregation, within a chicken line genotypically uniform at the major histocompatibility (B) complex (MHC), of a phenotype defined by strong resistance to secondary v-src-induced tumor challenge. The pattern of segregation is consonant with the possibility that a gene unlinked to the MHC governs immune response levels to v-src-encoded tumor antigen.

Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats. In this study, we determined the neuroprotective effect of aucubin on diabetes and diabetic encephalopathy. With the exception of the control group, all rats received intraperitoneal injections of streptozotocin (STZ; 60 mg/kg) to induce type 1 diabetes mellitus (DM). Aucubin (1, 5, 10 mg/kg ip) was used after induction of DM (immediately) and diabetic encephalopathy (65 days after the induction of diabetes). The diabetic encephalopathy treatment groups were divided into short-term and long-term treatment groups. Treatment responses to all parameters were examined (body weight, plasma glucose, Y-maze error rates and proportion of apoptotic cells). In diabetic rats, aucubin controlled blood glucose levels effectively, prevented complications, and improved the quality of life of diabetic rats. In diabetic encephalopathy, aucubin significantly rescued neurons in the hippocampal CA1 subfield and reduced working errors during behavioral testing. The significant neuroprotective effect of aucubin could be seen not only in the short term (15 days) but also in the long term (45 days), which was a highly encouraging finding. These data suggest that aucubin may be a potential neuroprotective agent.

Successful prevention of tunneled, central catheter infection by antibiotic lock therapy using vancomycin and gentamycin. Tunneled, cuffed central vein catheters (TCC) are widely used for delivering hemodialysis (HD). Among the complications associated with central vein catheters in HD patients, infection is the principal cause of morbidity and mortality. The optimal strategy for management of TCC infections is unclear. This prospective study was aimed at assessing the efficacy of antibiotic-lock therapy using vancomycin and gentamycin in preventing catheter-related blood stream bacterial infection in patients on HD. A total of 63 HD patients with 81 TCC were enrolled at the time of catheter insertion. Patients were randomized into two groups: Group I (33 patients, 37 insertions) included TCC with antibiotic lock therapy and Group II (30 patients, 44 insertions) with routine TCC management. Infection-free catheter survival of both groups was evaluated and compared at the end of the 12-month study period. A total of 57 TCC infections were encountered with an incidence rate of 8.95 infections per 1000 dialysis sessions (DS). The rate of infection was significantly lower in Group I (4.54 per 1000 DS) as compared to Group II (13.11 per 1000 DS), p 0.05). Our study suggests that antibiotic-lock therapy using a combination of vancomycin and gentamycin is useful in preventing catheter-related blood stream infection in patients on HD.

Endoscopic lung volume reduction. Chronic obstructive pulmonary disease (COPD) is a category of diseases characterized by chronic airflow obstruction and hyperinflation. The GOLD committee and the American Thoracic Society/European Respiratory Society have published detailed, evidence-based reviews of management approaches, providing stepped-care algorithms for pharmacologic and nonpharmacologic therapy. Over the past several decades, much effort was spent in designing additional nonpharmacologic approaches to ameliorate symptoms in these patients. Three endoscopic lung volume reduction principles have shown promise and reached later-stage clinical trials in patients with heterogeneous emphysematous diseases. These include so-called blocking devices (valves), nonblocking devices (coils) and irreversible nonblocking techniques (bronchoscopic thermal vapor ablation, polymeric lung volume reduction) designed to collapse and remodel hyperinflated lung. For homogeneous diseases the formation of airway bypass tracts designed to facilitate emptying of damaged lung regions with long expiratory times is being investigated.

Psychodrama: group psychotherapy through role playing. The theory and the therapeutic procedure of classical psychodrama are described along with brief illustrations. Classical psychodrama and sociodrama stemmed from role theory, enactments, "tele," the reciprocity of choices, and the theory of spontaneity-robopathy and creativity. The discussion focuses on key concepts such as the therapeutic team, the structure of the session, transference and reality, countertransference, the here-and-now and the encounter, the group-as-a-whole, resistance and difficult clients, and affect and cognition. Also described are the neoclassical approaches of psychodrama, action methods, and clinical role playing, and the significance of the concept of behavioral simulation in group psychotherapy.

Alzheimer's and Parkinson's Diseases: Expected Economic Impact on Europe-A Call for a Uniform European Strategy. The purpose of this study is to analyze the economic burden of persons with Alzheimer's disease (AD) and Parkinson's disease (PD) in Europe. On the basis of available data about the number of persons with dementia, their prevalence, and treatment and care costs, a mean cost burden is estimated for the year of 2030 and for the year of 2050 in Europe. The method of retrospective analysis of available sources was used; furthermore, analysis of database data such as WHO and Eurostat, which provide information about the number of older people and people with dementia; and specification of direct and indirect medical and nonmedical costs of patients with AD and PD from current studies was also used. The findings of this study confirm that the number of patients affected with AD and PD, as well as annual costs of the treatment and care of these patients, in the selected European countries are rapidly growing. The cost burden of both AD and PD in the selected European countries rises year by year, and by 2050, the cost burden of both diseases in fact will be almost two times higher in comparison with the year of 2010. In 2050, the overall mean cost burden is estimated to reach 357 billion Euros. The European Union calls for a joint initiative in the development of a uniformed strategic plan in the fight against dementia.

Overview of the pharmacokinetics of fleroxacin. The pharmacokinetic properties of fleroxacin in relation to other quinolones are presented. Fleroxacin, like all quinolones, is well absorbed, reaching peak concentrations within 2 hours. Interactions with Ca2+ and Al3+ are minimal and possibly of little clinical importance. The drug is eliminated via filtration in the kidney. It is therefore sensitive to changes in renal function. Accumulation of drug in the body is minimal, and change from intravenous to oral dosing results in nearly identical serum concentrations. Aside from the modest effect of metals on its absorption, fleroxacin does not interact/compete with substances oxidized in the liver, such as theophylline, and drug interactions are minimal. Its long serum half-life (8-12 hours) allows once-a-day dosing. This feature, along with its modest drug interactions, makes fleroxacin an attractive quinolone, at least with respect to its pharmacokinetics.

Synthesis and characterization of nano-HA/PA66 composites. Based on the bioactivity and biocompatibility of hydroxyapatite (HA) and the excellent mechanical performance of polyamide 66 (PA66), a composite of nanograde HA with PA66 was designed and fabricated to mimic the structure of biological bone which exhibits a composite of nanograde apatite crystals and natural polymer. The HA/PA66 composite combines the bioactivity of HA and the mechanical property of PA66. This study focused on the preparation method of HA/PA66 composite and the influence of HA crystals on the characterization of the composite. HA slurry was used directly to prepare HA/PA66 composite by a solution method, in which HA is able to form hydrogen bond, i.e. chemical bonding with PA66. The nano-HA needle-like crystals treated by hydrothermal method are better in the particle size distribution and the particle dispersion. The morphology, crystal structure and crystallinity as well as crystal size of these needle-like crystals are similar to bone apatite. The nano-HA needle-like crystals dispersed uniformly in PA66 matrix with reinforcement effect and can prevent the micro-crackle spreading into cleft and fracture during the deformation process. The mechanical testing shows that the nano-HA/PA66 composite has a good mechanical property, and may be a promising bone replacement material.

SOC1 translocated to the nucleus by interaction with AGL24 directly regulates leafy. Suppressor of overexpression of constans1 (SOC1) is one of the flowering pathway integrators and regulates the expression of LEAFY (LFY), which links floral induction and floral development. However, the mechanism by which SOC1, a MADS box protein, regulates LFY has proved elusive. Here, we show that SOC1 directly binds to the distal and proximal region of the LFY promoter where critical cis-elements are located. Intragenic suppressor mutant analysis shows that a missense mutation in the MADS box of SOC1 causes loss of binding to the LFY promoter as well as suppression of the flowering promotion function. The full-length SOC1 protein locates in the cytoplasm if expressed alone in protoplast transient expression assay, but relocates to the nucleus if expressed with AGAMOUS-LIKE 24 (AGL24), another flowering pathway integrator and a MADS box protein. The domain analysis shows that co-localization of SOC1 and AGL24 is mediated by the MADS box and the intervening region of SOC1. Finally, we show that LFY is expressed only in those tissues where SOC1 and AGL24 expressions overlap. Thus, we propose that heterodimerization of SOC1 and AGL24 is a key mechanism in activating LFY expression.

Mouse cyp2g1 gene: promoter structure and tissue-specific expression of a cyp2g1-lacz fusion gene in transgenic mice. The structure of the mouse Cyp2g1 gene was determined to identify regulatory regions important for its olfactory mucosa-specific expression. Two Cyp2g1 genomic clones were isolated and characterized. A 3.6-kilobase 5'-flanking sequence was used to prepare a Cyp2g1--LacZ fusion gene for transgenic mice production. Transgene expression, as determined by beta-galactosidase activity in tissue extracts, was detected in the olfactory mucosa, but not in any other tissues examined, in five different transgenic lines. Thus, the 3.6-kilobase fragment contained regulatory elements sufficient for olfactory mucosa-specific and proper developmental expression of the reporter gene. However, histological and immunohistochemical studies indicated that the expression of the transgene in the olfactory mucosa was patchy and the cellular expression patterns of the transgene did not exactly match that of the endogenous gene. These results implicate the presence of additional regulatory sequences that are necessary for the correct cell type-selectivity within the olfactory mucosa.

[Systemic chemotherapy for advanced colorectal cancer with liver metastasis]. We report the progress of systemic chemotherapy for advanced colorectal cancer with liver metastasis. It must be noted that the purpose of this treatment is to prolong the symptom-free period. Review of hepatic arterial infusion (HAI) compared with systemic chemotherapy for the treatment of unresectable liver metastases from colorectal cancer showed that was attained with HAI a much higher response rate and survival benefit than systemic chemotherapy. However, systemic chemotherapy has shown progress since that time. Regarding administration methods, continuous injection is better than bolus injection for 5-FU. New modulators of 5-FU have also became available, such as leucovorin, CPT-11, and I-OHP. Futhermore, many studies of 5-FU-based combination therapy have shown that the mean survival time (MST) and response rate (RR) are now close to those of HAI. Finally, the combination with HAI with systemic chemotherapy using CPT-11 resulted in the highest RR of 74%. Further trials of such combination therapy will be performed in the future.

Comparative carcinogenicity in F344 rats of the tobacco-specific nitrosamines, N'-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone. The tobacco-specific carcinogens, N'-nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were tested for carcinogenicity in F344 rats. Each nitrosamine in trioctanoin was administered by s.c. injection to 12 male and 12 female rats over a period of 20 weeks. The total dose of each nitrosamine was 3.4 mmol. The experiment was terminated after 12 months. NNK induced nasal cavity tumors in 83% of the males and in 83% of the females, liver tumors in 83% of the males and in 100% of the females, and lung tumors in 67% of the males and in 67% of the females. NNN induced nasal cavity tumors in 92% of the males and in 75% of the females. Only one liver tumor and no lung tumors were observed in the NNN-treated rats. These results indicate that, in the F344 rat, NNK is a more powerful carcinogen than is NNN.

Initiation and reinitiation of anticoagulation therapy. A thorough understanding of the pharmacology, pharmacokinetics, and pharmacodynamics of the most commonly prescribed anticoagulants is necessary to ensure optimal therapeutic outcomes and patient safety. Evidence is available to guide some, but not all aspects of anticoagulation therapy initiation. Issues related to the initiation of anticoagulation therapy, including the resumption of therapy following interruption of anticoagulation for invasive procedures, are reviewed. Initiating unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux is challenging for patients with renal dysfunction and obesity. UFH is preferred in patients with severe renal dysfunction. Morbidly obese patients may require higher than usual prophylactic doses of LMWH. Therapeutic doses of LMWH should be based on actual body weight, even in obese patients. Currently available evidence does not demonstrate the superiority of one initial warfarin dose over another. All anticoagulants increase the risk of bleeding and should therefore only be initiated in appropriately selected patients with sufficiently low underlying bleeding risk.

Effect of 1DMe, a neuropeptide FF analog, on acetylcholine release from myenteric plexus of guinea pig ileum. Since neuropeptide FF (NPFF) is a putative neurotransmitter to exert anti-opioid activity, we examined the effects of [D-Tyr', (NMe)Phe3]neuropeptide FF (IDMe), a stable NPFF analog, on acetylcholine (ACh) release from a longitudinal muscle-myenteric plexus (LMMP) preparation of guinea pig ileum in which opioids were known to inhibit ACh release when muscarinic autoinhibition was not fully activated. In the presence of atropine, 1DMe increased spontaneous and electrical field stimulation (EFS)-evoked ACh release in a concentration-dependent manner. Naloxone also increased ACh release. The stimulatory effects of 1DMe and naloxone were not additive. In the absence of atropine, 1DMe did not affect ACh release. Morphine decreased spontaneous and EFS-evoked ACh release in the presence of 1 microM atropine. 1DMe as well as naloxone counteracted the inhibitory effects of morphine on EFS-evoked ACh release. The combination of 1DMe and naloxone was not more inhibitory than either drug alone. 1DMe had no appreciable effect on norepinephrine-induced inhibition of spontaneous and EFS-evoked ACh release. These results first demonstrated the effects of a NPFF analog on neurotransmitter release: 1DMe had a stimulatory effect on spontaneous and EFS-induced ACh release from the LMMP preparation of guinea pig ileum, probably by counteracting the inhibitory effect of endogenous opioids on ACh release.

Pathogenesis of parathyroid dysfunction in end-stage renal disease. The parathyroid functions to maintain normal calcium and phosphate homeostasis and is central to normal bone physiology. In end-stage renal disease (ESRD), there is a failure of these normal homeostatic mechanisms with the frequent development of secondary hyperparathyroidism, which contributes to the pathogenesis of renal bone disease. The phosphate retention of ESRD, together with the reduced serum calcium and 1,25-dihydroxycholecalciferol vitamin D(3) (1,25[OH](2)D(3)) concentrations are the known factors that determine the progression to secondary hyperparathyroidism. 1,25(OH)(2)D(3) markedly decreases parathyroid hormone (PTH) gene transcription, whereas the effects of calcium and phosphate are on PTH mRNA stability, PTH secretion, and parathyroid cell proliferation. The mechanisms of these effects are discussed in this review.

Synthesis and cytotoxicity evaluation of biaryl-based chalcones and their potential in TNFα-induced nuclear factor-κB activation inhibition. A series of biaryl-based chalcones were designed as a combination of the natural chalcone and biphenyl moieties, and synthesized by two step chemistry involving Knoevenagel reaction and microwave assistant Suzuki coupling. Sulforhodamine B (SRB) assay was performed to evaluate the cell viability inhibitory abilities of these compounds against five cancer cell lines (A549, CNE2, SW480, MCF-7, and HepG2) from different tissues. Their Nuclear Factor-κB (NF-κB) nuclear translocation inhibitory activities were further investigated by High Content Analysis (HCA) based assay. Most of the compounds showed moderate to strong anticancer and NF-κB nuclear translocation inhibition activities and potent compounds were found.

[Different steps in construct validation of the Basel Drug and Alcohol Questionnaire (BDA)]. In a first study we developed a test (BDA) for measuring the degree of dependence on alcohol, medicaments and drugs in alcoholics as well as drug addicts. The present study analysed this test according to the principles of construct validity. The aim was to create a test with those items that optimally fulfil some of the following criteria. This was achieved with 22 out of the original 59 items of the test. The shortened test contains those items that optimally differentiate both externally (the addicted population from the rest of the sample: depressives, neurotics and normals) and internally (the degree of dependence). The score obtained with 22 items was more efficacious in differentiating the addicts from the rest of the sample than the total score of 59 items. 86% of the 22 items are sufficiently sensitive to measure changes during hospitalisation in a psychiatric clinic. However only 33% of the 22 items can effectively discriminate between alcohol-, medicaments- und drug-dependence. Intercorrelation and factor analyses with other variables that were also measured indicate that a large part of the variance arises from unspecific "general psychopathology" and only a small part is specific for drug-dependence. The test is sufficiently reliable (rtt = .89), unifactoral, and with clear mean test-item correlation (rit = .54), to justify further investigation. We recommend this 22 items test for scientific research into dependence, in spite of the questions that still remain open. The English version of the 22 items is given in the appendix.

Origin of Disagreements in Tandem Mass Spectra Interpretation by Search Engines. Several proteomic database search engines that interpret LC-MS/MS data do not identify the same set of peptides. These disagreements occur even when the scores of the peptide-to-spectrum matches suggest good confidence in the interpretation. Our study shows that these disagreements observed for the interpretations of a given spectrum are almost exclusively due to the variation of what we call the "peptide space", i.e., the set of peptides that are actually compared to the experimental spectra. We discuss the potential difficulties of precisely defining the "peptide space." Indeed, although several parameters that are generally reported in publications can easily be set to the same values, many additional parameters-with much less straightforward user access-might impact the "peptide space" used by each program. Moreover, in a configuration where each search engine identifies the same candidates for each spectrum, the inference of the proteins may remain quite different depending on the false discovery rate selected.

Malignant mesothelioma in Israel, 1961-1992. The authors monitored time trends in the incidences and distributions of malignant mesotheliomas during 1961-92 in 223 Israeli persons, including 21 men from a cohort of 3,057 asbestos-cement workers (83,122 person-years). The annual incidence rates of malignant mesotheliomas in Jewish men ranged between 2.5 per million in 1961-82 and 4.6 per million in 1985-92. The male-to-female incidence ratio rose from 1.2 in the 1960s to 2.9 during 1985-92, as a result of increases in risk among Israeli-born males. Females accounted for 37.6% of all cases, after exclusion of the cohort of asbestos workers. Of the 223 cases, 202 (91%) had no indication of direct occupational exposure to asbestos. In Jewish females, the incidence of malignant mesotheliomas did not increase after 1961. The mean age at diagnosis in all cases was lowest in the Israeli-born (53.0 years). High levels of asbestos exposure in the 1970s and the relatively early age of onset of the disease indicate that exposure began at a younger age in Israel than in European countries. Asbestos manufacture and use peaked in Israel during the mid-1970s, so the maximum impact of these trends has yet to be seen.

Technology evaluation: BL22, NCI. BL22 (RFB4(dsFv)-PE38) is a recombinant Pseudomonas exotoxin-based immunotoxin under development by the National Cancer Institute for the treatment of B-cell malignancies. It is composed of the disulfide-stabilized Fv portion of the anti-CD22 antibody RFB4 genetically fused to a truncated form of Pseudomonas exotoxin A. It has entered phase I trials for the treatment of B-cell lymphoma.

Perioral Ruler in Routine Esthetic Surgery: Convenient and Exact. Lip and perioral surgery, like any other esthetic surgery, requires an exact and convenient measurement tool to ensure reliable and reproducible outcomes. Although three-dimensional measuring equipment has proven its effectiveness in measuring facial parameters over the past two decades, it has some drawbacks, including high cost, long scanning times, and non-portability. Thus, digital photography remains the standard tool of measurement in esthetic surgery to date. Many authors have presented evaluation and measurement methods using digital photography in combination with different tools. However, there are no specific tools for the perioral region. Therefore, we devised a specific ruler for perioral measurements. The ruler has differently colored lines for length and angle measurements and a reference point for correct positioning. It can be used in preoperative consultation, intraoperative orientation, and postoperative evaluation.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Reliability and reproducibility of a clinical application of a simple technique for repeated circumferential leg measurements. The aim of this study is to determine the reliability and reproducibility of repeated tape measurements to assess the leg circumference during a long period. A tape measure is a simple instrument that is applicable in the presence of oedema. Measurements were performed by four observers on 11 volunteers. Four measurements were done in the first week (short term), a fifth measurement at two weeks (medium term) and a sixth measurement was done at 12 weeks (long term). The short-, medium- and long-term intra-class correlation coefficients for repeated measurements were 0.90, 0.89 and 0.78, respectively. The short-term and long-term reproducibility indices equalled 4.4% and 6.5%. If only a single observer would be involved, the short-term intra-class correlation coefficients would improve to 0.94 (reproducibility index 3.3%). Tape measurements have been proved to be a reliable and reproducible method to asses the lower limb circumference.

Novel method for estimation of chlorinated pesticide residues in milk. A new, simple, and rapid procedure for determining chlorinated pesticide residues in milk is described. The entire acetonitrile extract from milk is passed through a 0.5 g activated charcoal chromatographic column. Chlorinated pesticides adsorbed on the charcoal are eluted with 100 mL acetone-hexane (1 + 1). The eluate is washed with water and 1% sodium carbonate solution, and chlorinated pesticides are extracted with hexane. The extract is concentrated and measured by electron capture gas chromatography. Recoveries from 50 mL milk samples fortified with 0.04-1.6 micrograms of different BHC isomers, 0.05-2 micrograms DDT and its metabolites, and 0.05-0.5 micrograms dieldrin ranged from 86.9 to 103.2%.

Lymph node biopsy does not impair survival after therapeutic dissection for palpable melanoma metastases. To determine the effects of disrupting a nodal basin in patients with American Joint Committee on Cancer stage III melanoma with clinically palpable lymph nodes, we studied patients who underwent therapeutic lymph node dissection after excisional lymph node biopsy, after fine-needle aspiration (FNA) biopsy, or without a preoperative biopsy. We performed a retrospective review of our patients with American Joint Committee on Cancer stage III melanoma who were treated between January 1972 and June 1995, using data acquired from our 8200-patient database. The study group included 670 patients with melanoma, with known primary tumors, who underwent therapeutic lymph node dissection for palpable nodal metastases diagnosed by open biopsy (227 patients), by FNA (66 patients), or by clinical observation without biopsy (377 patients). Regional node recurrence, 5-year disease-free survival, and overall survival rates were calculated. The same-basin regional node recurrence rates were similar for the three groups (open biopsy, 4.6%; FNA, 3.2%; no biopsy, 4.6%; P = .14). The 5-year disease-free survival rates were 36.8% for the open-biopsy group, 29.6% for the FNA group, and 28.9% for the no-biopsy group (P = .08); corresponding 5-year overall survival rates were 40.6%, 43.9%, and 36.1%, respectively (P = .18). Multivariate analysis failed to identify preoperative biopsy as a significant risk factor. Matched-pair analysis using age, gender, primary tumor site, Breslow thickness, and tumor burden showed no differences in the 5-year disease-free survival rates (33% for the open-biopsy group vs. 27% for the FNA and no-biopsy groups, P = .42) and the 5-year overall survival rates (41% vs. 35%, P = .32). For patients with melanoma with palpable regional adenopathy, histological confirmation of clinical suspicion with either FNA or excisional lymph node biopsy does not adversely affect survival or recurrence rates.

Identification of salivary basic proline-rich proteins as receptors for Candida albicans adhesion. The adherence of Candida albicans cells to oral surfaces is believed to be an important step in the development of oral candidosis. Electrophoretically separated parotid salivary proteins were transferred to nitrocellulose membranes and incubated with [35S]methionine-radiolabelled C. albicans cells in a cell overlay adherence assay. A subset of four proteins with apparent molecular masses of 17, 20, 24 and 27 kDa (designated bands A-D) acted as receptors for cells of C. albicans ATCC 10261 and four clinical C. albicans isolates, in overlay assays. The N-terminal amino acid sequence of bands A-D indicated that these proteins were members of the basic proline-rich protein (bPRP) family. Digestion of protein A with endoproteinase Glu-C resulted in a single band (designated Ap) detected by Coomassie blue staining after SDS-PAGE. This band was not bound by C. albicans cells in overlay assays and comprised two fragments, designated ApN and ApC. These fragments had N-terminal sequences corresponding to the N-terminal and post endoproteinase Glu-C cleavage site sequences of bPRP IB-6 and had molecular masses of 6189 and 4261 Da as determined by mass spectrometry. Thus intact bPRP IB-6, and other bPRPs, may act as receptors for C. albicans adhesion.

Two novel mutations of the vasopressin gene associated with familial diabetes insipidus and identification of an asymptomatic carrier infant. Familial diabetes insipidus (FDI) is a syndrome of central vasopressin deficiency that is inherited in an autosomal dominant manner and that typically becomes clinically apparent in the first decade of life. Two novel mutations of the vasopressin gene have been identified in two previously unstudied kindreds with FDI. In each kindred, the inheritance of the FDI phenotype was consistent with an autosomal dominant mode of inheritance. In each proband, the diagnosis of central diabetes insipidus had been confirmed previously with a water deprivation protocol. After extraction of genomic DNA from each individual, the three exons of the vasopressin gene were separately amplified by PCR and directly sequenced using an automated dye termination method. In the proband and two other carriers of one kindred, a heterozygous C to T mutation was identified at nucleotide 1857. This is predicted to produce a serine to phenylalanine substitution at residue 56 of the vasopressin-related neurophysin peptide encoded by the mutated allele. The mutation also abolished an MspI site in the vasopressin sequence, and analysis of genomic DNA from eight members of the kindred (five with FDI) confirmed segregation of the mutation with the FDI phenotype. Another member of the kindred, a 13-month-old infant, also has the heterozygous C to T mutation, but a formal water balance study showed no evidence of diabetes insipidus. In the proband of the other kindred, a heterozygous G to A mutation was identified at nucleotide 1873. This mutation would be predicted to cause a cysteine to tyrosine substitution at residue 61 of the neurophysin encoded by the mutated allele. This heterozygous mutation was confirmed by the presence of an RsaI restriction site in one vasopressin allele in two members of the kindred. Therefore, two novel heterozygous mutations of the vasopressin gene have been identified in FDI kindreds. In one kindred, an asymptomatic carrier infant was identified and will require continued observation to determine whether she will develop clinical diabetes insipidus. The presence of these two novel mutations in a region of the vasopressin gene where other FDI mutations have been reported suggests that the part of the neurophysin peptide encoded by these sequences may be critically important in the appropriate expression of vasopressin.

Romidepsin in relapsed/refractory T-cell lymphomas: Italian experience and results of a named patient program. Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients.

Solution structure of BmP01 from the venom of scorpion Buthus martensii Karsch. From the venom of scorpion Buthus martensii Karsch,a short peptide (BmP01, 29 amino acid residues) was isolated and characterized as previously reported (Lebren, R. R., et al. (1997) Eur. J. Biochem. 245, 457-464). It was shown to reduce 33% outward K(+) channel (hippocampal neurons) currents at 10 microM. The solution structure of BmP01 was determined by 2D (1)H NMR spectroscopy. The NOEs, coupling constants, and H-D exchange obtained from NMR spectroscopy were used in structural calculations. The conformation of BmP01 is composed of a short alpha-helix (Cys 3-Thr 12) and a two-stranded antiparallel beta-sheet (Ala 15-Asp 20 and Lys 23-Pro 28). There are three disulfide bridges (Cys 3-Cys 19, Cys 6-Cys 24 and Cys 10-Cys 26) connecting the alpha-helix and beta-sheet. Asp 20 to Lys 23 form a type II turn linking the two strands. Structural and electrostatic potential comparison between BmP01 and its analogues are also presented.

Coronary artery bifurcation narrowing treated by Axxess stent implantation: The CARINAX registry. To compare the safety and efficacy of the Axxess™ biolimus-eluting stent with the second-generation drug-eluting stent (DES) in the treatment of bifurcation lesions. The Axxess™ is a dedicated bifurcation stent, designed to cover the lesion at the carina level. Between April 2012 and August 2014, 165 patients with de novo bifurcation lesions were treated with the Axxess™ stent (Axxess group). A propensity-score matched group of 165 patients treated with DES in the same period was selected (Control group). The primary objectives were (1) the procedural complication rate, including side branch (SB) occlusion and trouble in SB access after main vessel stenting; and (2) the device, the angiographic, and the procedural success rate. Procedural complications occurred in 1 patient (0.6%) in the Axxess group and in 20 patients (12%) in the Control group (OR = 0.03; 95% confidence interval 0.005-0.27; P < 0.001). Device success was obtained in 164 (99.5%) patients in the Axxess group and in all in the Control group (P = 1.00). Angiographic success was obtained in all patients. Inaccurate Axxess™ stent position occurred in 21 (13%) patients, and was more often associated with moderate-to-severe calcifications and distal lesion site. Procedural success was obtained in 91.5% patients in the Axxess group and in 90% patients in the Control group (P = 0.72). The present registry suggests that the Axxess™ stent (1) may represent a valid alternative approach for the treatment of bifurcation lesions and (2) should be avoided in moderate-to-severe calcifications and/or in distal lesions. © 2016 Wiley Periodicals, Inc.

DFB fiber laser hydrophone with band-pass response. A distributed-feedback fiber laser hydrophone with band-pass response is presented. The design of the hydrophone aims to equalize static pressure and eliminate signal aliasing of high-frequency acoustic components. Theoretical analysis is presented based on electro-acoustic theory. The experimental results agree well with the theory. The measured underwater responses show that the hydrophone has a pressure sensitivity of -170 dB re:pm/μPa over a bandwidth between 100 Hz and 500 Hz. A sensitivity reduction exceeding -35 dB is observed at 2500 Hz. The tested static pressure sensitivity of the hydrophone is -226 dB. The proposed fiber laser hydrophone of this kind is expected to have important application in deep water fiber-optic sonar systems with anti-aliasing, and the understanding gained through this work can be extended to a guide of hydrophone design for required filtering bandwidth.

Alterations in vascular gene expression in invasive breast carcinoma. The molecular signature that defines tumor microvasculature will likely provide clues as to how vascular-dependent tumor proliferation is regulated. Using purified endothelial cells, we generated a database of gene expression changes accompanying vascular proliferation in invasive breast cancer. In contrast to normal mammary vasculature, invasive breast cancer vasculature expresses extracellular matrix and surface proteins characteristic of proliferating and migrating endothelial cells. We define and validate the up-regulated expression of VE-cadherin and osteonectin in breast tumor vasculature. In contrast to other tumor types, invasive breast cancer vasculature induced a high expression level of specific transcription factors, including SNAIL1 and HEYL, that may drive gene expression changes necessary for breast tumor neovascularization. We demonstrate the expression of HEYL in tumor endothelial cells and additionally establish the ability of HEYL to both induce proliferation and attenuate programmed cell death of primary endothelial cells in vitro. We also establish that an additional intracellular protein and previously defined metastasis-associated gene, PRL3, appears to be expressed predominately in the vasculature of invasive breast cancers and is able to enhance the migration of endothelial cells in vitro. Together, our results provide unique insights into vascular regulation in breast tumors and suggest specific roles for genes in driving tumor angiogenesis.

[Strict additivity of the antispasmodic effects of papaverine and tiemonium: an example of sequential blockage]. The interaction of papaverine and tiemonium alone or combined, with BaCL2 and histamine on guinea pig ileum and with acetylcholine on rat jejunum have been studied with the help of molecular pharmacology techniques. The competitive antagonist effects of tiemonium and the non competitive antagonist effects of papaverine are evidenced and shown to be strictly additive when the two drugs are combined. This reflects a sequential blockage of the effects of acetylcholine, histamine and barium ions at the smooth muscle level. No such antagonism has been previously described in the case of the interaction with barium chloride with any other combination of two spasmolytic drugs.

A task analysis of the shift from teacher instructions to self-instructions in performing an in-common task. Three preschool children repeatedly did four kinds of sorts with a deck of stimulus cards: a difficult, untaught target sort and three other sorts considered analytic of self-instructing the target performance. The untaught target sort was to find in a deck of cards those matching what two sample cards had in common. Most preschool children must be taught to mediate this problem. The three other kinds of sorts taught skills involved in the target performance or its mediation. As correct self-instructive talk emerged in the target sorts, it was confirmed. The untaught target sorts were interspersed infrequently among the three alternating directly taught skill sorts, to see if accurate target sorts, and accurate self-instructive talk about the target sorts, would emerge as the three skill sorts were mastered. As all the sorts progressed, increasing accuracy was seen first in the skill sorts and then in the untaught target sorts. All three subjects showed subsequent generalization to new target sorts involving other stimulus sets. Correct spontaneous self-instructions about the target sorts increased from near zero at the beginning of the experiment to consistency at its end. Thus the three skill sorts appeared sufficient for the emergence of a self-instructed solution to the previously insoluble target performance.

Pediatric kidney transplantation. Kidney transplantation in pediatric patients has become a routinely successful procedure, with 1- and 5-year patient survival rates of 98% and 94%, and 1- and 5-year graft survival rates of 93% to 95% and 77% to 85% (the range takes into account differences between living and deceased donors). These good outcomes represent the cumulative effect of improvements in pre- and posttransplant patient care, operative techniques, immunosuppression, and infection prophylaxis, diagnosis, and treatment. This article provides a brief historical overview, discusses the indications for transplantation, describes the evaluation process for the recipient and the potential donor, outlines the operative details, reviews the various causes of and risk factors for graft dysfunction, and analyzes outcomes.

Identification and characterization of human ZNF274 cDNA, which encodes a novel kruppel-type zinc-finger protein having nucleolar targeting ability. A human cDNA encoding a novel zinc-finger protein, ZNF274, was identified by the "nuclear transportation trap" method (Ueki, N., Oda, T., Kondo, M., Yano, K., Noguchi, T., and Muramatsu, M., 1998, Nat. Biotechnol. 16: 1338-1342). Based on sequence analysis of the full-length cDNA, this novel gene has two alternative splicing forms, ZNF274a and ZNF274b, which encode putative proteins of 621 and 584 amino acids, respectively. ZNF274a contains five C2H2-type zinc-finger motifs, two KRAB-A (Kruppel-associated box) domains, and one leucine-rich domain. ZNF274b lacks the first KRAB-A domain at the N-terminus. ZNF274 mRNA is detected in various human tissues by Northern analysis. The ZNF274 gene is mapped distal to marker RP S28 1 in the human chromosome 19qter region, by RH mapping. The KRAB domains of ZNF274 exhibited transcription repressor activity when tested in GAL4 fusion protein assays. EGFP-ZNF274 fusion protein expressed in COS7 cells predominantly localized to the nucleoli. A series of deletion constructs revealed that a minimal domain consisting of the third and fourth zinc-fingers possesses nucleolar targeting ability. These results suggest that ZNF274 is a ubiquitous transcription repressor that plays a role in the nucleoli.

DAB389EGF fusion protein therapy of refractory glioblastoma multiforme. Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and chemoradioresistance. Novel therapies are needed. One class of therapeutics is fusion proteins consisting of peptide toxins fused to brain tumor selective ligands. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). DAB389EGF is selectively toxic to EGF receptor (EGFR) overexpressing cells. Close to half of all high-grade primary brain tumors have EGFR gene amplification and EGFR overexpression. With the use of convection-enhanced delivery (CED), DAB389EGF may be delivered locally at high concentrations to the brain tumor. CED would avoid many of the pharmacologic and toxicologic barriers which have limited effective use of this agent including rapid clearance from the circulation, high anti-diphtheria toxin antibody titers in the blood and toxicities to the liver and kidney. Both cell lines and animal models are available to assess the potential of this agent for brain tumor therapy. Since significant amounts of clinical grade DAB389EGF are available, some careful additional preclinical efficacy work should lead to testing of this agent in patients within the next few years.

Magnetic resonance imaging techniques for monitoring changes in tumor oxygenation and blood flow. The application of functional magnetic resonance (MR) imaging techniques to the measurement of oxygenation and blood flow in tumors is described. Gradient recalled echo MR imaging (GRE-MRI) offers a real-time noninvasive method for monitoring tumor response to vasomodulators such as carbogen (95% O2/5% CO2) breathing in attempts to overcome tumor hypoxia and improve treatment efficacy. Although the response is tumor-type dependent, increases in signal intensity of up to 100% have been observed in several animal tumor types. Responses are also seen in human tumors. The observed increases in GRE-MRI signal intensity are due to a combination of a reduction of deoxyhemoglobin in the blood causing changes in the MR imaging relaxation time T2* and changes in blood flow and may also reflect the capillary density. Thus, the magnitude of the GRE image intensity change gives an indication of the potential response of an individual tumor to treatments that aim to improve tissue oxygenation and therefore how the tumor may respond to therapy. In addition, carbogen breathing by the host has been shown to increase the uptake and efficacy of chemotherapeutic agents in animal tumors.

Management of tumor adherent to the vertebral column. Twelve patients with non-small cell lung cancer had tumors that were adherent to the vertebral column and clinically suspected of invading the bone. All were free of mediastinal node involvement as assessed by pretreatment mediastinoscopy. All received 3000 rads of preoperative radiation followed by en bloc resection of the lung and a tangential portion of the involved vertebral bodies. A complete mediastinal lymphadenectomy was also performed. Three patients had true Pancoast's syndrome and in the remaining nine the tumor was located above T6 with the majority in the apex of the chest. Resectability was based on the absence of tumor extension into the costotransverse foramen and the extent of vertebral body involvement. Detailed studies of the decalcified surgical specimen show that the tumor extended into the cortex in two patients, periosteum in six, parietal in three, and up to the visceral pleura in one. Six patients are alive after 1 to 11 years (four beyond 5 years) without evidence of recurrent tumor and arthritic pain. The overall 5- and 10-year survival rate (Kaplan-Meier method) was 42%. In patients with tumors adherent to the vertebral body and no evidence of roentgenographic erosion, the en bloc removal of the lung and the involved portion of the vertebral body is required for complete excision and is associated with long-term survival without sequelae.

Milestones or furlongstones? A study was carried out over five years of 15000 children aged between one day and three months. It was observed that many infants passed their important 'milestones' much earlier than is suggested in present textbooks. A plea is made for discarding the traditional ages for the various landmarks in the development of a child. The changes of mental development are very important in the first three months and during the three to six months period the baby seems to be merely consolidating more methodically what he was doing less conveniently during the first three months.

Evaluation of the cytotoxicity, genotoxicity and mucus permeation capacity of several surface modified poly(anhydride) nanoparticles designed for oral drug delivery. The main concerns with drugs designed for oral administration are their inactivation or degradation in the harsh conditions of the gastrointestinal tract, their poor solubility through the gastrointestinal mucus gel layer, the poor intestinal epithelium permeability that limits their absorption, and their toxicity. In this context, poly(anhydride) nanoparticles are capable of protecting the drug from the harsh environment, reduce the drug's toxicity and, by virtue of surface modification, to enhance or reduce their mucus permeability and the bioadhesion to specific target cells. The copolymer between methyl vinyl ether and maleic anhydride (commercialized as Gantrez® AN 119) are part of the poly(anhydride) nanoparticles. These biocompatible and biodegradable nanoparticles (NPs) can be modified by using different ligands. Their usefulness as drug carriers and their bioadhesion with components of the intestinal mucosa have been described. However, their toxicity, genotoxicity and mucus permeation capacity has not been thoroughly studied. The aim of this work was to evaluate and compare the in vitro toxicity, cell viability and in vitro genotoxicity of the bioadhesive empty Gantrez® AN 119 NPs modified with dextran, aminodextran, 2-hydroxypropyl-β-cyclodextrin, mannosamine and poly-ethylene glycol of different molecular weights. Results showed that, in general, coated NPs exhibit better mucus permeability than the bare ones, those coated with mannosamine being the most permeable ones. The NPs studied did not affect cell metabolism, membrane integrity or viability of Caco-2 cells at the different conditions tested. Moreover, they did not induce a relevant level of DNA strand breaks and FPG-sensitive sites (as detected with the comet assay).

Diabetes does not influence oral oncogenesis through fibroblast growth factor receptors. Increased expression of fibroblast growth factors and their receptors (FGFRs) has recently been described in oral squamous cell carcinoma. In addition, we have previously described a molecular basis for an association between oral cancer and diabetes. The expression of FGFR-2 and FGFR-3 investigated in an experimental model of chemically induced carcinogenesis in normal and diabetic (type I) rats. Tissue sections ranging from normal mucosa to moderately-differentiated oral squamous cell carcinoma were studied using monoclonal antibodies against FGFR-2 and FGFR-3 proteins. A similar pattern of elevated FGFR-2 and FGFR-3 expression was observed in the initial stages of oncogenesis for both diabetic and non-diabetic animals. In the last stages of oral oncogenesis, the expression of both proteins remained relatively stable. It seems that diabetes does not affect the FGFR-2 and FGFR-3 pattern of expression throughout the various stages of oral oncogenesis.

Expression of antigens on haemopoietic progenitor cells in bovine bone marrow. We analysed the surface phenotype of bovine bone marrow erythroid and myeloid progenitor cells with monoclonal antibodies (mAbs) from the Second Workshop. For the antibodies tested, no difference could be observed in burst-forming unit (erythroid) and colony-forming unit (erythroid) both are positive for BoCD44, BoWC9, MHC Class I, transferrin receptor and the p150/158 antigen detected by BT3/8.12, but neither express BoCD11a, BoCD45, BoWC5 or the antigen recognized by mAb Bo116. The myeloid progenitor cells, colony-forming unit (granulocyte/macrophage), can be discriminated from the erythroid progenitors by the absence of a transferrin receptor and the expression of BoCD11a and BoWC5 antigens. By selecting the right panel of mAbs, it should now be possible to enrich bone marrow cells for erythroid and/or myeloid progenitor cells.

Characterization of the binding of radioiodinated hybrid recombinant IFN-alpha A/D to murine and human lymphoid cell lines. The hybrid recombinant human interferon (IFN) rIFN-alpha A/D was radioiodinated. Specific binding of [125I]rIFN-alpha A/D was observed with both human and murine cell lines. The binding of [125I]rIFN-alpha A/D to human Daudi cells had similar characteristics to the previously described binding of [125I]rIFN-alpha A or -alpha 2. The following lines of evidence demonstrated that [125I]rIFN-alpha A/D bound with high affinity to the same receptor on murine cells as murine IFN-alpha and -beta: (i) the binding of [125I]rIFN-alpha A/D to murine LBRM cells was inhibited to a similar extent by natural murine IFN-alpha, natural murine IFN-beta, and rIFN-A/D; (ii) the Kd (approximately 2 X 10(-10) M) obtained from both competition experiments and saturation binding experiments with [125I]rIFN-alpha A/D was comparable to the previously reported Kd for the binding of natural murine IFN-alpha and -beta to other murine cell lines; (iii) the size of the cross-linked [125I]rIFN-alpha A/D receptor complex formed on murine LBRM cells was similar to the previously reported cross-linked complex formed after binding radioiodinated natural murine IFN-beta to other murine cell lines. Due to the current lack of readily available recombinant murine IFN-alpha or -beta for radiolabeling and the previously demonstrated biological activity of rIFN-alpha A/D on murine cells, [125I]rIFN-alpha A/D should prove to be a useful reagent for further studies of murine IFN receptors.

Evaluation of internal standardization for the determination of semivolatile analytes in difficult matrices by simultaneous multielement atomic absorption spectrometry. The aim of the present work is to investigate the use of the internal standardization technique combined with permanent chemical modification for the determination of two semivolatile analytes, such as As and Se, in difficult matrices by electrothermal atomic absorption spectrometry. Bismuth and tellurium have been evaluated as internal standards to minimize matrix effects on the direct determination of selenium and arsenic in sediments, by simultaneous electrothermal atomic absorption spectrometry using graphite tubes with integrated platform, pre-treated with different masses of Zr and Ir as permanent modifier. A Perkin-Elmer SIMAA 6000 simultaneous multielement spectrometer was used to study the correlation between two integrated absorbance signals. Matrix effects were evaluated by calculating the slope ratio between the analytical curve obtained from reference solutions prepared in 1.0% (v/v) HNO3 and analytical curve obtained from IS additions in matrix solutions. The results showed that Te was the optimal internal standard and 200 μg Zr and 20 μg Ir was the optimal permanent chemical modifier for both analytes. The instrumental limits of detection for As and Se were 1.48 and 1.96 μg L(-1) without the use of an internal standard and 0.59 and 0.35 μg L(-1) when Te was used as an internal standard, respectively. Relative standard deviations for a sample with matrix effect containing 100 μg L(-1) As and 200 μg L(-1) Se were 1.3% and 2.3% (n=20) using 100 μg L(-1) Te, respectively, and for a standard solution sample containing 100 μg L(-1) As and 200 μg L(-1) Se were 3.0% and 1.2% (n=20) using 100μgL(-1) Te, respectively. The accuracy of the proposed method was evaluated by an addition-recovery experiment and by the analysis of different certified reference materials. The recovered values were in the 95-100% range for both analytes.

Followup of psychoanalysis five to ten years after termination: III. The relation between the resolution of the transference and the patient-analyst match. As part of a long-term followup study of the outcome of psychoanalysis, we examined the relation between the extent of resolution of the transference at termination and the characteristics of the patient-analyst match. For twelve of the seventeen patients interviewed five to ten years after termination of psychoanalysis, the researchers found that the patient-analyst match played a role in the outcome of the analysis. Illustrations of the influence of the match in cases where the transference was resolved and those where it was not are presented.

Evidence for two distinct lysophospholipase activities that degrade lysophosphatidylcholine and lysophosphatidic acid in neuronal nuclei of cerebral cortex. Neuronal nuclei were isolated from immature rabbit cerebral cortex and nuclear lysophospholipase activities studied using two different 1-acyl lysophospholipids: lysophosphatidylcholine (lysoPC) and lysophosphatidic acid (lysoPA). Our interest in these two lysolipids arose from the observation that lysoPA could promote the acetylation of lysoPC by substantially inhibiting a very active nuclear lysoPC lysophospholipase activity, in a competitive manner (R.R. Baker, H. -y. Chang, Mol. Cell. Biochem. (1999) in press). As there was also evidence for nuclear lysoPA deacylation, it was of interest to see whether one activity could possibly utilize both lysolipid substrates. We now have evidence for two separate lysophospholipase activities in neuronal nuclei. The lysoPC lysophospholipase activity was the more active, more highly enriched in the neuronal nuclei, and showed optimal activity at pH 8.4-9, while the lysoPA lysophospholipase activity was maintained over a much broader pH range. The lysoPC activity was substantially inhibited by free fatty acid, and showed considerable stimulation by serum albumin, while the activity utilizing lysoPA was much less affected by these agents. When lysoPC was added to incubations containing radioactive lysoPA, there was no significant inhibition found in rates of release of radioactive fatty acid, indicating that the lysoPA lysophospholipase activity did not utilize the lysoPC substrate. In incubations with lysoPC, MgATP and CoA brought about a sizable formation of phosphatidylcholine whose radioactivity was equally distributed between the sn-1 and sn-2 positions suggesting labelling both directly from the lysoPC substrate and from fatty acid produced by the lysophospholipase activity. By comparison, with the radioactive lysoPA substrate, MgATP and CoA promoted relatively lower levels of phosphatidic acid formation whose principal labelling came directly from the radioactive lysoPA. Largely because of the high activity of the nuclear lysoPC lysophospholipase, there is considerable potential in the neuronal nucleus to limit the use of lysoPC in other reactions, such as the formation of acylPAF (1-acyl analogue of platelet activating factor). It is of interest that conditions associated with brain ischaemia such as increased free fatty acid levels, falling pH and declines in MgATP may allow a preservation of neuronal nuclear lysoPC levels for acetylation. The existence of a separate lysophospholipase activity for lysoPA allows an independent control of lysoPA which can serve as an important regulator of the nuclear lysoPC lysophospholipase.

[Demonstration of the presence during acute inflammatory reactions of a serum factor mitogenic macrophages (author's transl)]. 1. The authors have searched for the existence of mitogenic factor for macrophages in the serums of rats having undergone diverse immune and non-immune inflammatory reactions. 2. The evolution of the mitogenic activity of the inflammatory serums have been studied over a 48 hour period. This study underlined that the appearance of the mitogenic factor is very rapid since it can be found as early as 30 minutes after the injection of the irritant. 3. In most cases the evolution of the mitogenic activity of serums reveals a biphasic aspect: a strong activity is observed 1 to 2 hours after the injection of the irritant followed by a decrease of this activity which becomes weak or even null towards the sixth hour. It then increases to attain, after about 24 hours, values almost equal to those seen for the first peak.

Will gene therapy trump factor treatment in hemophilia? Hemophilia treatment is entering a new phase, with the exciting possibility of gene therapy promising a cure. Novel gene transfer strategies are being considered for patients with inhibitors.Improvement of factor-replacement therapy is being aggressively pursued with long-acting factor concentrates, many of which are in clinical trials. Whether gene therapy will be safe and cost effective to eventually supersede factor-replacement therapy is yet to be determined. It is hoped that with the profusion of clinical trial programs in hemophilia care, it will eventually provide affordable treatment to many patients who currently cannot access adequate treatment in the developing countries.

Inter- and intraindividual correlations of background abundances of (2)H, (18)O and (17)O in human urine and implications for DLW measurements. The method of choice for measuring total energy expenditure in free-living individuals is the doubly labeled water (DLW) method. This experiment examined the behavior of natural background isotope abundance fluctuations within and between individuals over time to assess possible methods of accounting for variations in the background isotope abundances to potentially improve the precision of the DLW measurement. In this work, we measured natural background variations in (2)H, (18)O and (17)O in water from urine samples collected from 40 human subjects who resided in the same geographical area. Each subject provided a urine sample for 30 consecutive days. Isotopic abundances in the samples were measured using Off-Axis Integrated Cavity Output Spectroscopy. Autocorrelation analyses demonstrated that the background isotopes in a given individual were not temporally correlated over the time scales of typical DLW studies. Using samples obtained from different individuals on the same calendar day, cross-correlation analyses demonstrated that the background variations of different individuals were not correlated in time. However, the measured ratios of the three isotopes (2)H, (18)O and (17)O were highly correlated (R(2)=0.89-0.96). Although neither specific timing of DLW water studies nor intraindividual comparisons were found to be avenues for reducing the impact of background isotope abundance fluctuations on DLW studies, strong inter-isotope correlations within an individual confirm that use of a dosing ratio of 8‰:1‰ (0.6 p.p.m.: p.p.m.) optimizes DLW precision. Theoretical implications for the possible use of (17)O measurements within a DLW study require further study.

Piracetam in elderly motorists. 101 elderly motorists with reduced reaction capacity were examined under real traffic conditions with regard to their driving ability. They were given a daily dose of 4.8 g piracetam or placebo over a six-week period in a randomised double-blind study. The percentage of correctly solved sign-observance items, which reflects orientation and perception in real traffic conditions, increased in the placebo-treated test-group from 79.86% in the pretest to 80.07% in the retest, whereas the test subjects of the piracetam-treated group improved their performance from 77.08% to 84.16%. After being treated with piracetam for 6 weeks, the drivers showed a significantly better performance than the placebo-group. Of particular interest is the finding that the test-subjects who had scored less than 80% in the pretest improved without exception in the retest after treatment with piracetam.

Client beliefs about a multicouple group service for intimate partner violence: a narrative analysis. Despite the ongoing debate about intervention best practices for intimate partner violence (IPV), few researchers have elicited the perspectives of clients themselves about what interventions most effectively decrease violence and increase safety. Using qualitative narrative analysis methodology, the researchers conducted 48 client participant interviews and 5 staff interviews to better understand couples' perspectives of a multicouple conjoint treatment program for IPV. Several recurring themes included (a) group purpose and general service characteristics, (b) motivation for participation, (c) comparison with other services, (d) benefits of, (e) disadvantages of, and (f) suggestions for Couples Achieving Relationship Enrichment. Important research implications for community intervention are discussed.

Migrating lumbar facet joint cysts. The majority of lumbar facet joint cysts (LFJCs) are located in the spinal canal, on the medial aspect of the facet joint with characteristic diagnostic features. When they migrate away from the joint of origin, they cause diagnostic problems. In a 7-year period we examined by computed tomography (CT) and magnetic resonance (MR) imaging five unusual cases of facet joint cysts which migrated from the facet joint of origin. Three LFJCs were identified in the right S1 foramen, one in the right L5-S1 neural foramen and one in the left erector spinae and multifidus muscles between the levels of L2-L4 spinous process. Awareness that spinal lesions identified at MRI and CT could be due to migrating facet joint cyst requires a high level of suspicion. The identification of the appositional contact of the cyst and the facet joint needs to be actively sought in the presence of degenerative facet joints.

Motoring along the hyphae: molecular motors and the fungal cytoskeleton. This review discusses molecular motors that use the microfilament and microtubule cytoskeletal systems in filamentous fungi. There has been an explosion in our knowledge of kinesins over the past year, because of the integration of genetic and biochemical data. The recognition of possible interactions between septation genes and cytokinesis has also advanced our understanding of microfilament-based cytoskeletal systems. We review recent findings on microfilament motors, including conventional and unconventional myosins, and the microtubule motors of the kinesin family and cytoplasmic dynein. The roles that these molecules play in hyphal morphogenesis and organelle transport provide an insight into cytoskeletal-based transport systems.

Aerosol addiction. A case of dependency on prescribed pressurised aerosols in a patient with asthma and mild mental handicap is reported. The majority of reported cases involve young asthmatics, abuse being reported mainly using salbutamol inhalers although other inhalers have also given cause for concern. The agent of addition is uncertain although it may be the fluorinated hydrocarbons used as propellants, rather than the active substance itself.

Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem. A five-stage reactor was developed to simulate the gastro-intestinal microbial ecosystem of humans. The small intestine was simulated by a two-step "fill and draw" system, the large intestine by a three-step reactor. A representative supply medium was developed to support a microbial community resembling that of the human gastro-intestinal tract. The entire system was validated by monitoring fermentation fluxes and products, i.e. indicator bacterial groups, volatile fatty acids, enzymatic activities and headspace gases. The simulator was operated with varying concentrations and combinations of arabinogalactan, xylan, pectin, dextrins and starch. The resulting patterns of microbial diversity and activity were analysed and compared with data for in-vivo gastro-intestinal microbial communities as described in the literature and found to be representative.

Cholinergic regulation of striatal Nova mRNAs. Alternative splicing is an important mechanism for expanding proteome diversity from a limited number of genes, especially in higher vertebrates. Brain-specific splicing factors play an important role in establishing specific patterns of alternative splicing in the brain and thereby contribute to its complex architecture and function. Nova proteins are splicing factors that are expressed specifically in the central nervous system, where they regulate a large number of pre-mRNAs encoding synaptic proteins that are important for the balance of neuronal excitation and inhibition. Since this balance is interrupted in epileptic seizures, we explored whether LiCl/pilocarpine- or kainate-induced epileptic seizures would induce changes in the levels of Nova mRNAs in the rat brain. We found that the muscarinic agonist, pilocarpine, but not the glutamatergic agonist, kainate, induced a significant downregulation of Nova2 mRNA and upregulation of all three Nova1 mRNA isoforms in the striatum. Treatment with the muscarinic antagonist, scopolamine, at the onset of pilocarpine-induced seizures inhibited the seizures and the changes in Nova mRNA levels. Therefore it seems likely that pilocarpine stimulation of muscarinic acetylcholine receptors was a prerequisite for the observed changes, while the contribution of other striatal neurotransmitter systems activated by seizures could not be excluded. We propose that the LiCl/pilocarpine seizure model could serve as a valuable tool for studying mechanisms of Nova-regulated alternative splicing in rat striatum.

Zoonotic potential of infection with Fasciola spp. by consumption of freshly prepared raw liver containing immature flukes. Mice were successfully infected with metacercariae of the Japanese Fasciola sp., resulting in the recovery of a mean number of 110 live immature flukes per mouse 4-5 days after inoculation. Twenty-four mice were then inoculated orally, each with a mean number of 68 freshly recovered immature flukes. The livers of 7 of the 24 recipient mice showed migratory lesions of capsular and subcapsular granulomatous infiltration and 2 of those mice also had haemorrhagic lesions. The lesions were typical of those caused by active migration of early immature flukes. However, no flukes were found in the livers of the recipient mice at necropsy when the flukes were aged 14 weeks. In another experiment, 10 piglets were given fresh livers of mice harbouring approximately 2000 live immature flukes aged 3-7 days. Two additional piglets were inoculated with 2000 metacercariae of Fasciola. All pigs were killed when the flukes were 14 days old. Granulomatous lesions were present in all pigs, except in those that were given livers containing flukes aged 7 days. The lesions were localized, forming well-defined foci, different from the typical migratory lesions normally observed in mouse or sheep liver at the early stage of fluke migration. From the 10 pigs given livers, 65 live flukes were recovered at necropsy, 0.29% of the estimated number of immature flukes given. From the 2 pigs which received 2000 metacercariae each, a total of 198 flukes were recovered (5%). The results of the experiments suggest that humans consuming raw liver dishes prepared from fresh livers infected with immature Fasciola spp. could become infected with liver fluke.

Current and historical involvement of dentistry in child protection and a glimpse of the future. Dental teams have been involved with child protection for over 40 years. This brief review summarises their involvement in the detection of various types of child abuse and goes on to discuss the gap between the proportions of dental professionals who suspect child abuse or neglect in their paediatric patients and those who refer such cases on. Potential reasons for this discrepancy are discussed, and a glimpse of the future is given as to where further research may be necessary to tackle this existing gap.

Learned discrimination of pattern orientation in walking flies. To determine the pattern-orientation discrimination ability of blowflies, Phaenicia sericata, a learning/memory assay was developed in which sucrose served as the reward stimulus and was paired with one of two visual gratings of different orientations. Individual, freely walking flies with clipped wings were trained to discriminate between pairs of visual patterns presented in the vertical plane. During training trials, individual flies learned to search preferentially at the rewarded stimulus. In subsequent testing trials, flies continued to exhibit a learned preference for the previously rewarded stimulus, demonstrating an ability to discriminate between the two visual cues. Flies learned to discriminate between horizontal and vertical gratings, +45 degrees (relative to a 0 degrees vertical) and -45 degrees gratings, and vertical and +5 degrees gratings. Individual patterns of learning and locomotive behavior were observed in the pattern of exploration during training trials. The features of the visual cue critical for discrimination of orientation are discussed.

Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. The murine monoclonal antibody OKT3 (IgG2a) was administered prophylactically to 17 renal allograft recipients (5 mg/day, i.v.), either alone or in association with corticosteroids (0.25 mg/kg/day) and azathioprine (3 mg/kg/day). In all patients the kinetics of the IgM and IgG anti-OKT3 response was monitored by means of immunofluorescence and ELISA. All patients treated with OKT3 alone showed a rapid and strong sensitization that completely neutralized the therapeutic effectiveness of the monoclonal antibody. The anti-OKT3 sensitization was manifested by accelerated OKT3 clearance and abrupt reappearance of circulating OKT3+ cells before the end of treatment. This immune response was significantly delayed and reduced in its incidence and intensity in patients receiving low dose corticosteroids and azathioprine in association to OKT3; mainly IgM anti-OKT3 antibodies that did not accelerate OKT3 clearance were then observed. The fine specificity of the antibodies produced was studied, using patients whole sera and various mouse IgG2a-affinity chromatography-purified serum fractions. The results obtained showed that the anti-OKT3 response was remarkably restricted to two main categories of antibodies: a) anti-idiotypic antibodies that inhibited OKT3 binding to T cells and abrogated its therapeutic activity and b) anti-mouse IgG2a (anti-isotypic) antibodies that did not neutralize OKT3 immunosuppressive activity. These results suggest that OKT3-immunized patients might still be sensitive to the immunosuppressive effect of other anti-T cell monoclonals that do not share the OKT3 idiotype and possibly isotype.

Severe hypertension caused by alleles from normotensive Lewis for a quantitative trait locus on chromosome 2. Pursuing fully a suggestion from linkage analysis that there might be a quantitative trait locus (QTL) for blood pressure (BP) in a chromosome (Chr) 2 region of the Dahl salt-sensitive rat (DSS), four congenic strains were made by replacing various fragments of DSS Chr 2 with those of Lewis (LEW). Consequently, a BP QTL was localized to a segment of around 3 cM or near 3 Mb on Chr 2 by comparative congenics. The BP-augmenting alleles of this QTL originated from the LEW rat, a normotensive strain compared with DSS. The dissection of a QTL with such a paradoxical effect illustrated the power of congenics in unearthing a gene hidden in the context of the whole animal system, presumably by interactions with other genes. The locus for the angiotensin II receptor AT-1B (Agtr1b) is not supported as a candidate gene for the QTL because a congenic strain harboring it did not have an effect on BP. There are approximately 19 known and unknown genes present in the QTL interval. Among them, no standout candidate genes are reputed to affect BP. Thus the QTL will likely represent a novel gene for BP regulation.

Adipose conversion of 3T3-L1 cells in a serum-free culture system depends on epidermal growth factor, insulin-like growth factor I, corticosterone, and cyclic AMP. A culture system for 3T3-L1 preadipocytes based on a serum-free chemically defined medium containing fetuin, transferrin, and pantothenate is described. In this system, adipose conversion depends on the following conditions. 1) In the presence of high insulin concentrations (1 microM), addition of corticosterone together with 1-methyl-3-isobutylxanthine (MIX) for not more than the first 4 days after confluence to the culture medium induces maximal adipose conversion within 12-14 days. MIX may be replaced by forskolin or permeable analogues of cAMP, indicating that its effect is due to elevated cellular cAMP levels. 2) At low insulin concentrations (1 nM), adipose conversion is reduced. Growth hormone or insulin-like growth factor I together with epidermal growth factor have to be present as a medium supplement together with corticosterone and MIX to get maximal adipose conversion. 3) The induction of adipose conversion by corticosterone and MIX in the presence of either high insulin concentrations or insulin-like growth factor I together with epidermal growth factor is accompanied by post-confluent mitoses. Inhibitors of DNA replication markedly reduce adipose conversion. Fibroblast growth factor and platelet-derived growth factor, although acting as potent mitogens on 3T3-L1 cells, do not support adipose conversion induced by corticosterone and MIX.

Pd-Catalyzed Selective Remote Ring Opening of Polysubstituted Cyclopropanols. The distant functionalization of ω-ene cyclopropanols is induced by a Pd-catalyzed Heck reaction triggering a "metal-walk" and selective ring-opening of the three-membered ring. This approach provides a new class of acyclic aldehydes possessing concomitantly a stereodefined double bond and a quaternary carbon stereocenter α to the carbonyl group.

[White nevus of the oral mucosa]. A white sponge nevus of the oral mucosa is described in a 12-year-old girl and her 36-year-old mother. This anomaly, which is inherited as an autosomal dominant trait, deserves no treatment. Because of the bilateral involvement, which is found in the majority of cases, the white sponge nevus is often misdiagnosed as therapy-resistant thrush.

Enhancement of (Ca2+ + Mg2+)-ATPase activity of human erythrocyte membranes by hemolysis in isosmotic imidazole buffer. I. General properties of variously prepared membranes and the mechanism of the isosmotic imidazole effect. 1. Membranes prepared from human erythrocytes hemolyzed in isosmotic (310 imosM) imidazole buffer, pH 7.4, show enhanced and stabilized (Ca2+ + Mg2+)-ATPase activity compared with membranes prepared from erythrocytes hemolyzed in hypotonic (20 imosM) phosphate or imidazole buffer, pH 7.4. 2. Exposure of intact erythrocytes or well-washed erythrocyte membranes to isosmotic imidazole does not cause enhanced (Ca2+ + Mg2+)-ATPase activity. 3. Exposure of erythrocyte membranes, in the presence of isosmotic imidazole, to the supernatant of erythrocyte hemolysis or to a partially purified endogenous (Ca2+ + Mg2+)-ATPase activator, promotes enhanced (Ca2+ + Mg2+)-ATPase activity. Under appropriate conditions, NaCl can be shown to substitute for imidazole. The results demonstrate that imidazole does not act directly on the erythrocyte membrane but rather by promoting interaction between an endogenous (Ca2+ + Mg2+)-ATPase activator and the erythrocyte membrane.

Serum total cholesterol levels and risk of mortality from stroke and coronary heart disease in Japanese: the JACC study. The relation between serum total cholesterol and coronary heart disease is well established, but the relations with total stroke and stroke subtypes are controversial. We conducted a nested case-control study as part of the JACC study. A total of 39,242 subjects, 40-79 years of age, provided serum samples at baseline between 1988 and 1990. During the 10-year follow-up, 345 deaths from total strokes (including 76 intraparenchymal hemorrhages) and 150 deaths from coronary heart diseases were recorded. The control subjects were matched for sex, age, community, and year of serum storage, and further adjusted for systolic blood pressure, high density lipoprotein (HDL)-cholesterol, ethanol intake category, smoking status, and diabetes. Serum total cholesterol levels were measured using an enzymatic method. Cases with total stroke and more specifically intraparenchymal hemorrhage had lower mean values of serum total cholesterol levels compared with control subjects. The risk of mortality from intraparenchymal hemorrhage was significantly higher for persons with low total cholesterol levels [less than 4.14 mmol/l (160 mg/dl)] than with those with higher levels. The risk of mortality from coronary heart disease for persons with serum total cholesterol levels more than or equal to 6.72 mmol/l (260 mg/dl) was significantly higher than those with levels less than 4.14 mmol/l (160 mg/dl). Low serum total cholesterol levels are associated with high mortality from intraparenchymal hemorrhage while high levels are associated with high mortality from coronary heart disease among Japanese.

Prospective, five-year follow-up study of patients with symptomatic uncomplicated diverticular disease. The natural history of diverticular disease is largely unknown. Most studies are retrospective and treatment recommendations are derived from outdated literature. This study was a prospective, long-term assessment of the development of complications in patients with symptomatic diverticular disease. All patients with a confirmed diagnosis of symptomatic diverticular disease between August 1999 and April 2001 were followed up prospectively for an average of five years. Hospital computerized discharges were assessed for any subsequent elective or emergency admission for diverticular disease-related complications, including surgical intervention. A telephone questionnaire was conducted on all patients and/or their family physician looking specifically for symptoms, complications, and surgical intervention. A total of 163 patients (106 females) were identified (median age, 74 (interquartile range, 64-80) years). The diagnosis was confirmed through colonoscopy (n = 106), flexible sigmoidoscopy (n = 57), and barium enema (n = 31). Nineteen were lost to follow-up and a further 19 died from unrelated causes. Twenty-five were excluded. After the initial diagnosis, two patients (1.7 percent) subsequently presented with an episode of diverticulitis, which was treated conservatively. A single patient (0.8 percent) required surgery for chronic symptoms. One hundred sixteen patients (97 percent) had no or mild symptoms after a median follow-up of 66 months. In this prospective long-term study, symptomatic uncomplicated diverticular disease seems to run a long-term benign course with a very low incidence of subsequent complications. Symptomatic disease, acute diverticulitis, and complicated diverticular disease seem to constitute distinct clinical entities with little crossover between groups.

[Screening for ovarian cancer-associated genes with cDNA microarrays]. The molecular mechanism leading to the development and progression of ovarian carcinoma are not completely understood. It may be the result of a series of molecular changes in the cell caused by changes in the expression level of numerous genes of tumor. In this report the authors used cDNA microarray to identify differentially expressed genes between ovarian cancer tissue and normal ovary tissue to screen ovarian cancer-associated genes. cDNA microarrays were prepared by spotting PCR products of 512 cDNA of human oncogene and tumor suppressor gene onto specially treated glass slides with robotics. The probes were prepared by labeling normal tissue mRNA and cancer tissue mRNA with Cy3-dUTP and Cy5-dUTP separately through reverse transcription PCR. The arrays were then hybridized against the cDNA probe mixture and the fluorescent signals were scanned. The obtained data were analyzed using ImaGene 3.0 software. Thirty-eight genes showed co-expression specificity in 3 or more than 3 cases. There were 15 upregulated genes and 23 downregulated genes in ovarian cancer tissues. Utilizing cDNA microarrays, 3 ovarian cancer-associated genes have been initially screened.

Results and complications after laparoscopic sleeve gastrectomy. Laparoscopic sleeve gastrectomy (SG) has gained popularity and acceptance among bariatric surgeons, mainly due its low morbidity and mortality. The purpose of the present study was to evaluate the efficacy of SG on weight loss, and to determine the postoperative course, clinical presentation and treatment of complications after SG. Between January 2006 and October 2012, 153 consecutive patients underwent SG. All data were prospectively collected in a computerized database. This series comprised 119 females and 34 males with a median age of 46 years and a median preoperative BMI of 42.3 kg/m2. The median EWL was 53.0 % after 18.4 months of follow-up. The median postoperative BMI was 33.3 kg/m2 (range 19.7–56.1 kg/m2). Eight patients (5.2 %) required re-laparoscopy to manage postoperative hemorrhage (3.3 %) and leakage (1.9 %). Neither abdominal drains nor postoperative contrast-swallow studies were successful in diagnosing hemorrhage or leaks in our patients. SG is an effective procedure to achieve significant short-term weight loss. Clinical signs, such as tachycardia, pain, fever and hypotension, provide the best evidence of the presence of postoperative leakage or bleeding. An early diagnosis of these complications is the key to ensuring adequate treatment with immediate re-laparoscopy.

Adaptation, Evolution And Reproduction Of Gaia By The Means Of Our Species. Nowadays, the idea that life affects the development of the planetary environment, and can, in turn, affect the future evolution of itself (in a coevolutionary way) is well-accepted. However, since the proposal of the Gaia hypothesis, there has been widespread criticism. Most of it is related to teleology, the absence of natural selection at a universal scale, and the lack of planetary reproduction. Some of the problems concerning the 'internal' logic of the idea have been resolved. Nevertheless, it is not sure whether Earth can be considered a unit of selection and (therefore) Gaia can adapt according to Darwinian evolution. After Lovelock and Margulis, Gaia has been considered a symbiotic planet composed of biotic (the biosphere) and abiotic (the geosphere-atmosphere) interacting with and coevolving elements. Here I propose why and suggest how a Gaian system should be considered alive in any evolutionary sense. I take into consideration the three principal criticisms and I analyse them following a logic-inductive reasoning. I use thought experiments and analogical arguments to analyse the rationale and the mechanisms by which Gaia evolves and may reproduce. This reasoning could allow rejecting the aforementioned criticisms as outdated and insufficient to discredit the main idea. I argue that without invoking teleology - so without any foresight or planning - a Gaian planet can be considered a coevolutionary system analogous to a multicellular body: a super-unit of selection. I describe different situations according to which Gaia is able to reproduce and transfer her planetary genome to other uninhabited or inhabited planets. Then I suggest that Gaia can face exclusion- competition-coexistence states depending on the fitness of her biota compared to those of the other reproducing biospheres. This demonstrates that Gaia can reproduce and evolve in competition-cooperation with other planets. Some deep implications arise from this evidence, also in light of the recent discovery of a new solar system with Earth-like planets by NASA.

Highly efficient production of phosphorylated hepatitis B core particles in yeast Pichia pastoris. Virus-like particles (VLPs) of the recombinant hepatitis B virus (HBV) core protein (HBc) are routinely used in HBV diagnostics worldwide and are of potential interest as carriers of foreign peptides (e.g., immunological epitopes and targeting addresses, and/or as vessels for packaged diagnostic and therapeutic nanomaterials). Despite numerous reports exploiting different expression systems, a rapid and comprehensive large-scale methodology for purification of HBc VLPs from yeast is still lacking. Here, we present a convenient protocol for highly efficient production and rapid purification of endotoxin-free ayw subtype HBc VLPs from the methylotrophic yeast Pichia pastoris. The HBc gene expression cassette along with the geneticin resistance gene was transferred to the P. pastoris genome via homologous recombination. A producer clone was selected among 2000 transformants for the optimal synthesis of the target protein. Fermentation conditions were established ensuring biomass accumulation of 163g/L. A simple combination of pH/heat and salt treatment followed by a single anion-exchange chromatography step resulted in a more than 90% pure preparation of HBc VLPs, with a yield of about 3.0mg per 1g of wet cells. Purification is performed within a day and may be easily scaled up if necessary. The quality of HBc VLPs was verified by electron microscopy. Mass spectrometry analysis and direct polyacrylamide gel staining revealed phosphorylation of HBc at at least two sites. To our knowledge, this is the first report of HBc phosphorylation in yeast.

Two species of human Fc epsilon receptor II (Fc epsilon RII/CD23): tissue-specific and IL-4-specific regulation of gene expression. The Fc epsilon receptor II (Fc epsilon RII, CD23) functions in B cell growth and differentiation and in IgE-mediated immunity. The Fc epsilon RII structure expressed on various cell types has been analyzed identifying two species, Fc epsilon RIIa and Fc epsilon RIIb. Sequence analysis of the cloned cDNAs revealed that they differ only at the N-terminal cytoplasmic region, but share the same C-terminal extracellular region. These Fc epsilon RII species appear to be generated utilizing different transcriptional initiation sites and alternative RNA splicing. Fc epsilon RIIa is constitutively expressed only in normal B cells and B cell lines, whereas Fc epsilon RIIb expression is detectable in various cell types, such as monocytes and eosinophils. Normally, Fc epsilon RIIb is undetectable in B cells and monocytes, and can be induced by interleukin-4. Moreover, Fc epsilon RIIb is expressed on peripheral blood lymphocytes in atopic individuals. These findings may explain the difference in Fc epsilon RIIa and Fc epsilon RIIb function in B cells and the effector phase of IgE-mediated immunity.

Apple (Malus x domestica). Apple (Malus x domestica) is one of the most consumed fruit crops in the world. The major production areas are the temperate regions, however, because of its excellent storage capacity it is transported to distant markets covering the four corners of the earth. Transformation is a key to sustaining this demand - permitting the potential enhancement of existing cultivars as well as to investigate the development of new cultivars resistant to pest, disease, and storage problems that occur in the major production areas. In this paper we describe an efficient Agrobacterium tumefaciens-mediated transformation protocol that utilizes leaf tissues from in vitro grown plants. Shoot regeneration is selected with kanamycin using the selectable kanamycin phosphotransferase (APH(3)II) gene and the resulting transformants confirmed using the scorable uidA gene encoding the bacterial beta-glucuronidase (GUS) enzyme via histochemical staining. Transformed shoots are propagated, rooted to create transgenic plants that are then introduced into soil, acclimatized and transferred to the greenhouse from where they are taken out into the orchard for field-testing.

Expanded turn conformations: characterization and sequence-structure correspondence in alpha-turns with implications in helix folding. Like the beta-turns, which are characterized by a limiting distance between residues two positions apart (i, i+3), a distance criterion (involving residues at positions i and i+4) is used here to identify alpha-turns from a database of known protein structures. At least 15 classes of alpha-turns have been enumerated based on the location in the phi,psi space of the three central residues (i+1 to i+3)-one of the major being the class AAA, where the residues occupy the conventional helical backbone torsion angles. However, moving towards the C-terminal end of the turn, there is a shift in the phi,psi angles towards more negative phi, such that the electrostatic repulsion between two consecutive carbonyl oxygen atoms is reduced. Except for the last position (i+4), there is not much similarity in residue composition at different positions of hydrogen and non-hydrogen bonded AAA turns. The presence or absence of Pro at i+1 position of alpha- and beta-turns has a bearing on whether the turn is hydrogen-bonded or without a hydrogen bond. In the tertiary structure, alpha-turns are more likely to be found in beta-hairpin loops. The residue composition at the beginning of the hydrogen bonded AAA alpha-turn has similarity with type I beta-turn and N-terminal positions of helices, but the last position matches with the C-terminal capping position of helices, suggesting that the existence of a "helix cap signal" at i+4 position prevents alpha-turns from growing into helices. Our results also provide new insights into alpha-helix nucleation and folding.

Bone Metabolism of the Patient with a Malignant Melanoma during the Entry Examination and the Check-up of Whole-body Bone Scintigraphy. Malignant melanoma is a malignancy located predominantly in the skin and the incidence of melanoma increases. We compared the markers of bone metabolism - osteocalcin (OC), beta-carboxyterminal cross-linked telopeptide of type I collagen (β-CrossLaps, β-CTx) and tumour marker - human epididymis protein 4 (HE4) in the serum with finding during the entry examination and the check-up of whole-body bone scintigraphy of the patient with a malignant melanoma. Serum concentrations of OC, β-CTx, HE4 were determined in 1 patient (female, age 64 years) with malignant melanoma and correlated with the presence of equivocal bone metastases detected by whole-body bone scintigraphy (the entry examination and check-up after 6 months). Concentrations of bone metabolism markers decreased during six months and we observed progress in bone metastases. The change of the markers levels during the entry examination and the check-up of the whole-body bone scintigraphy with equivocal finding of bone metastases could be a sign of a possible initiating progression of malignant melanoma despite a clinically negative finding that does not prove the progression of the disease.

Generation of histo-blood group B transferase by replacing the N-acetyl-D-galactosamine recognition domain of human A transferase with the galactose-recognition domain of evolutionarily related murine alpha1,3-galactosyltransferase. The alpha1,3-galactosyl epitope (alpha1-3Gal epitope), a major xenotransplant antigen, is synthesized by alpha1,3-galactosyltransferase (alpha1-3Gal transferase), which is evolutionarily related to the histo-blood group A/B transferases. We constructed structural chimeras between the human type A and murine alpha1-3Gal transferases and examined their activity and specificity. In many instances, a total loss of transferase activity was observed. Certain areas could be exchanged, with a potential diminishing of activity. With a few constructs, changes in acceptor substrate specificity were suspected. Unexpectedly, a functional conversion from A to B transferase activity was observed after replacing the short sequence of human A transferase with the corresponding sequence from murine alpha1-3Gal transferase. Because these two paralogous enzymes differ in 16 positions of the 38 amino acid residues in the replaced region, our finding may suggest that despite separate evolution and diversified acceptors, these glycosyltransferases still share the three-dimensional domain structure that is responsible for their sugar specificity, arguing against the functional requirement of a strong purifying selection playing a role in the evolution of the ABO family of genes.

The effect of oral contraceptives on reproductive function during semichronic exposure to ethanol by the female rat. 1. Female rats were placed on water, 5% ethanol (ET), or 20% ET drinking solutions for 8 weeks. The last 2 weeks, the rats received orally either ethinyl estradiol (EE), norethindrone acetete (NED), or a combination of both. 2. Luteinizing hormone decreased due to ET drinking and was undetectable subsequent to the steroidal treatment. 3. Prolactin increased after steroid treatment and alcohol drinking in the controls. 4. Ethanol (5%) plus EE increased prolactin as did the steroidal combination, whereas ET (20%) likewise increased prolactin in conjunction with NED over water controls. 5. Hepatic alcohol dehydrogenase was inhibited due to EE when compared to water-controls in the 5% ET drinking animal, whereas aldehyde dehydrogenase was induced in combination with NED in both the 5% and 20% ET drinking rats.

Genotype and allele frequencies of C3435T polymorphism of the MDR1 gene in various Jewish populations of Israel. The human multidrug-resistant gene (MDR1) encodes for P-glycoprotein (P-gp), which is a membrane-bound efflux-transporter conferring resistance to a number of natural cytotoxic drugs and potentially toxic xenobiotics. The wobble C3435T polymorphism at exon 26 was associated with different expression levels of the MDR1 gene and substrate uptake. Differences in allele frequencies of the C3435T polymorphism have previously been demonstrated between racial groups. In this study, 500 individuals from 5 Jewish populations of Israel (Ashkenazi, Yemenite, North African, Mediterranean, Near-Eastern) were examined for C3435T polymorphism using a PCR-RFLP-based technique to calculate genotype and allele frequencies. Frequencies of the C allele were quite similar among the Ashkenazi (0.65), Yemenite (0.645), and North-African (0.615) Jewish populations. However, the frequency of this allele was slightly lower among Mediterranean Jews (0.58) and significantly lower among Near-Eastern Jews (0.445). The frequency of the C allele among Near-Eastern Jews is, therefore, significantly different from those of all other tested Jewish populations. In comparison to previously studied non-Jewish populations, the frequency of this allele among Near-Eastern Jews is different from that in West Africans (0.91) but is similar to that in whites (0.497). However, the C allele frequencies among the other 4 Jewish populations are significantly lower than that found among West Africans and significantly higher than among non-Jewish whites. These data may have important therapeutic and prognostic implication for P-gp-related drug dosage recommendation in Jewish populations.

Acute and chronic toxicity of azinphos-methyl to two estuarine species, Mysidopsis bahia and Cyprinodon variegatus. The acute and chronic toxicity of azinphos-methyl (Guthion) was evaluated for two estuarine species in the laboratory. Mysids (Mysidopsis bahia) and sheepshead minnows (Cyprinodon variegatus) were selected as the representative invertebrate and vertebrate estuarine test species, respectively. The toxicological endpoints determined for each species included the 96-h LC50, the no-observed-effect concentration (NOEC), the maximum acceptable toxicant concentration (MATC), and the acute-to-chronic ratio. The 96-h LC50 value derived for sheepshead minnows (2.0 microg/L) was seven times higher than the 96-h LC50 value (0.29 microg/L) derived for mysids. The MATCs were 0.024 microg/L and 0.24 microg/L for the mysid and the sheepshead minnow, respectively. The estimated acute-to-chronic ratios were 12 for mysids and 8.3 for sheepshead minnows.

Tissue microarray technology for high-throughput molecular profiling of cancer. Tissue microarray (TMA) technology allows rapid visualization of molecular targets in thousands of tissue specimens at a time, either at the DNA, RNA or protein level. The technique facilitates rapid translation of molecular discoveries to clinical applications. By revealing the cellular localization, prevalence and clinical significance of candidate genes, TMAs are ideally suitable for genomics-based diagnostic and drug target discovery. TMAs have a number of advantages compared with conventional techniques. The speed of molecular analyses is increased by more than 100-fold, precious tissues are not destroyed and a very large number of molecular targets can be analyzed from consecutive TMA sections. The ability to study archival tissue specimens is an important advantage as such specimens are usually not applicable in other high-throughput genomic and proteomic surveys. Construction and analysis of TMAs can be automated, increasing the throughput even further. Most of the applications of the TMA technology have come from the field of cancer research. Examples include analysis of the frequency of molecular alterations in large tumor materials, exploration of tumor progression, identification of predictive or prognostic factors and validation of newly discovered genes as diagnostic and therapeutic targets.

Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome. Ribavirin is a broad-spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom-free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration-time profiles were well fitted by a three-compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1-hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 mumol/L, respectively. The mean +/- SD plasma beta-phase half-life, terminal-phase (gamma) half-life, and volume of distribution at steady state were 2.0 +/- 1.1 hours, 35.5 +/- 14.0 hours, and 647 +/- 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 +/- 30 and 283 +/- 37 ml/min, respectively. After an oral dose of 600, 1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 mumol/L, respectively. The mean absorption half-life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drug's elimination, and drug accumulation (greater than threefold) will result with repetitive dosing at the 6- to 8-hour dosing interval currently used.