A novel association between RASA1 mutations and spinal arteriovenous anomalies.
CM-AVM is a recently recognized autosomal dominant disorder associated with mutations in RASA1. Arteriovenous lesions have been reported in the brain, limbs, and the face in 18.5% of patients. We report a novel association between RASA1 mutations and spinal arteriovenous anomalies. In a collaborative study, 5 index patients (2 females, 3 males) with spinal AVMs or AVFs and cutaneous multifocal capillary lesions were investigated for the RASA1 gene mutation. All 5 patients were found to have RASA1 mutation (2 de novo, 3 familial), and all had multifocal capillary malformations at birth. Neurologic deficits developed at ages ranging from infancy to early adulthood. All spinal anomalies (2 AVMs at the conus, 1 AVM at the lumbosacral junction, and 1 cervical and 1 cervicothoracic AVF) were complex, extensive, and fast-flow lesions. All patients required treatment based on the clinical and/or radiologic appearance of the lesions. To our knowledge, an association of RASA1 mutation and spinal AVM/AVF has not been described. MR imaging screening of patients with characteristic CMs and neurologic symptoms presenting at a young age may be useful in detecting the presence of fast-flow intracranial or intraspinal arteriovenous anomalies before potentially significant neurologic insult has occurred.


Hippocampal angiotensin II receptors play an important role in mediating the effect of voluntary exercise on learning and memory in rat.
The beneficial effects of physical activity and exercise on brain functions such as improvement in learning and memory are well documented. The aim of this study was to examine the possible role of hippocampal angiotensin II receptors in voluntary exercise-induced enhancement of learning and memory in rat. In order to block the hippocampal angiotension II receptors, the animals received a single injection of latex microbeads for delivery of [Sar1 Thr8]-Angiotensin II into the hippocampus. The animals were exposed to five consecutive nights of exercise and then their learning and memory were tested on the Morris water maze (MWM) task using a two-trial-per-day for five consecutive days. A probe trial was performed 2 days after the last training day. Our results showed that hippocampal angiotensin II receptor blockade reversed the exercise-induced improvement in learning and memory in rat.


CD30 (Ki-1)-positive malignant lymphomas: clinical, immunophenotypic, histologic, and genetic characteristics and differences with Hodgkin's disease.
This study compares the histologic and immunophenotypic features of 71 cases of primary CD30+ diffuse large-cell lymphomas (DLCL) and 128 cases of Hodgkin's disease (HD) and discusses the clinical features of 52 patients with CD30+ DLCL. It includes analysis of sites of involvement, staging, response to treatment, sites and treatment of recurrences, and disease-free and overall survival. Diagnostic immunophenotypic differences were found between CD30+ DLCL and HD. All cases of CD30+ DLCL were positive for one or more common or lineage-specific lymphocyte antigens or for EMA. In contrast, 96.9% of HD cases were negative for CD45, CD45-RO, CD43, and CD20. The four exceptions are discussed. All cases of HD were negative for EMA. In patients with CD30+ DLCL, a T-cell phenotype was found in 60%, a null-cell type in 22%, and a B-cell type in 18% of the cases. The median age of patients with T- and null-cell phenotype was 22 years (range, 4 to 72). Fifty-two percent of them had high-stage (III and IV) disease and 61% had extranodal involvement at presentation, including 25% with skin lesions. Lymph nodes draining the skin lesions became involved in seven of 11 patients. No patient had initial bone marrow involvement. Most patients were treated with chemotherapy, and 83% had a complete remission. Fifty-four percent remain free of disease with a median follow-up of 47 months. Thirteen patients (29%) had one or more recurrences and five of them remain free of disease after salvage therapy, with a median follow-up period of 79 months. The clinical stage did not affect survival, probably as a result of different therapy. The t(2;5) translocation was found in five of 15 patients who had cytogenetic abnormalities. Of the other 10 cases, the translocation was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in four of five cases studied. All nine cases were of T- or null-cell phenotype. The cases of B-cell CD30+ DLCL had a characteristic immunophenotype. All were negative for EMA. These patients were older and had frequent bone marrow involvement but no skin infiltration by lymphoma. All three patients who were human immunodeficiency virus-positive (HIV+) had lymphomas of B-cell lineage. Detection of the t(2;5) translocation by molecular genetics is a useful and highly specific marker in the differential diagnosis between HD and CD30+ DLCL.


Isolation and characterization of human antioxidized LDL autoantibodies.
Autoantibodies to oxidized LDL have been reported in normal subjects and in patients with arteriosclerosis, but their possible pathogenic role is not yet well defined. One important problem is the existence of contradictory data reported by different groups concerning the associations between antioxidized LDL autoantibodies and the presence or progression of arteriosclerotic lesions. Such contradictions led us to decide to isolate and characterize antioxidized LDL antibodies by affinity chromatography with the use of oxidized LDL cross-linked to Sepharose. Antioxidized LDL antibodies were isolated from selected serum samples obtained from eight subjects. Seven of them (six patients and one control subject) had high levels of antioxidized LDL antibody during screening. The other subject, a healthy volunteer, had a low level of antibody. All purified antibodies contained IgG (of subclasses 1 and 3) as the predominant isotype and were primarily specific for oxidized LDL but showed some cross-reactivity with malondialdehyde-modified LDL and native LDL. Two of the purified antibodies cross-reacted with cardiolipin. We determined average dissociation constants for the antioxidized LDL antibodies purified from five individuals, which varied between 2.4 x 10(-7) and 7.5 x 10(-7) mol/L, whereas the average dissociation constant of rabbit hyperimmune anti-LDL antibody was determined to be 2.7 x 10(-8) mol/L. In conclusion, we have purified human autoantibodies reactive with oxidized LDL that appear to be predominantly of moderate-to-low affinity and of variable cross-reactivity. The predominance of IgG1 and IgG3 antibodies is significant from the standpoint of potential pathogenicity, since these two subclasses activate the classic complement pathway system and have the highest binding affinities for Fc gamma receptors on phagocytic cells.


Reductive activation of mitomycin C by NADH:cytochrome b5 reductase.
Mitomycin C requires bioreduction in order to exert its cytotoxic action. Activation of mitomycin C to an electrophile was equally supported by NADPH and NADH in EMT6 tumor cell sonicates under hypoxia. No alkylation was observed under aerobic conditions. Purified NADH:cytochrome b5 reductase catalyzed the reduction of mitomycin C with a Km of 23 microM at pH 6.6. At pH 7.6, the rate of enzymatic reduction of mitomycin C was 61% of that at pH 6.6. NADH:cytochrome b5 reductase catalyzed the activation of mitomycin C to alkylating metabolites under both hypoxic and aerobic conditions, with alkylation being 1.5 times greater in hypoxia. Dicumarol at 100 microM inhibited the NADH:cytochrome b5 reductase-catalyzed reduction of mitomycin C by 24% and by 57% at 300 microM. The degree of inhibition of the enzyme by dicumarol was the same at both pH 6.6 and 7.6. NADH:cytochrome b5 reductase exhibited a small but measurable NADH-oxidase activity, which was unaffected by 300 microM dicumarol. These findings demonstrate that (a) NADH:cytochrome b5 reductase can metabolically activate mitomycin C and (b) dicumarol is capable of inhibiting this enzymatic activity.


Prevalence, awareness, treatment and control of hypertension in a Canarian population. Relationship with glucose tolerance categories. The Guía Study.
To estimate the prevalence, awareness, treatment and control of hypertension in a Canarian population; and their relationship with the glucose tolerance categories. From a population of 6355 subjects over 29 years old, 690 were chosen in a random sampling. Blood pressure measurements, a standard oral glucose tolerance test (excluding known diabetic patients), and a questionnaire on diabetes and hypertension history and medication use was performed. The total prevalence of hypertension was 50.3%; 62.0% of the hypertensive subjects were aware of their condition; 60.6% had their diastolic and 11.0% their systolic blood pressure controlled and 8.6% had both. For diabetic, glucose intolerant and normoglycemic subjects, the respective prevalences of hypertension were 79.4, 60.2 and 43.1% (higher in diabetic subjects, P < 0.001); the awareness of hypertension was 66.7, 61.8 and 59.5% (differences not significant); systolic blood pressure control was 4.8, 14.7 and 13.7% (lower in diabetic subjects, P = 0.017 versus glucose intolerant and P = 0.011 versus normoglycemic subjects); diastolic blood pressure control was 50.4, 72.1 and 63.2% (lower in diabetic subjects, P = 0.004 versus glucose intolerant and P = 0.025 versus normoglycemic subjects). There were no differences in the number and type of antihypertensive drugs among the different glucose tolerance categories. Blood pressure was comparable in our population and in other European populations. The prevalence of hypertension was higher, the awareness was similar, and control was worse in diabetic than in non-diabetic subjects; the drug treatment pattern was not different.


Tuning Diradical Properties of Boron-Containing π-Systems by Structural Isomerism.
Tuning diradical character is an important topic for organic diradicaloids. Herein, we report the precise borylation enabling structural isomerism as an effective strategy to modulate diradical character and thereby properties of organic diradicaloids. We synthesized a new B-containing polycyclic hydrocarbon that has the indeno[1,2-b]fluorene π-skeleton with the β-carbons bonding to two boron atoms. Detailed theoretical and experimental results show that this bonding pattern leads to its distinctive electronic structures and properties in comparison to that of its isomeric molecule. This molecule has the efficient conjugation between boron atoms and π-skeleton, resulting in downshifted LUMO and HOMO levels. Moreover, it exhibits smaller diradical character and thereby inhibited diradical properties, such as significantly blue-shifted light absorption, larger energy bandgap and weak para-magnetic resonance. Notably, this B-containing polycyclic hydrocarbon possesses much stronger Lewis acidity and its Lewis acid-base adducts display enhanced diradical character, demonstrating the positive effects of Lewis coordination on modulating diradical performance.


[Summary of the Dutch College of General Practitioners' practice guideline, "Examination of the neonate"].
The routine examination of the neonate by the general practitioner directly after birth provides a first impression of the state and vitality of the newborn, gives base values that may be relevant for later occurring illnesses or problems, and is a first orientation on the presence of congenital malformations. Inspection of the newborn is the most important. Four possible malformations receive special attention: congenital malformations of the heart and eye, developmental hip dysplasia, and undescended testes. If the first examination was properly performed, a second routine examination by the general practitioner during the maternity visit has no proven added value. A specific physical examination should take place if indicated. It is recommended that all involved parties (health centre physicians, obstetricians, general practitioners, paediatricians and midwives) reach agreement as to the content and reporting of the first examination.


Parallelized traveling cluster approximation to study numerically spin-fermion models on large lattices.
Lattice spin-fermion models are important to study correlated systems where quantum dynamics allows for a separation between slow and fast degrees of freedom. The fast degrees of freedom are treated quantum mechanically while the slow variables, generically referred to as the "spins," are treated classically. At present, exact diagonalization coupled with classical Monte Carlo (ED + MC) is extensively used to solve numerically a general class of lattice spin-fermion problems. In this common setup, the classical variables (spins) are treated via the standard MC method while the fermion problem is solved by exact diagonalization. The "traveling cluster approximation" (TCA) is a real space variant of the ED + MC method that allows to solve spin-fermion problems on lattice sizes with up to 10(3) sites. In this publication, we present a novel reorganization of the TCA algorithm in a manner that can be efficiently parallelized. This allows us to solve generic spin-fermion models easily on 10(4) lattice sites and with some effort on 10(5) lattice sites, representing the record lattice sizes studied for this family of models.


Vestibular evaluation following cochlear implantation in patients with inner-ear anomalies.
This cross-sectional study investigated vestibular function outcomes after cochlear implantation in patients with inner-ear anomalies. Twenty-two patients with bilateral symmetric inner-ear anomalies and 28 patients with normal inner ears were included. All were congenitally or progressively deaf persons implanted unilaterally during the previous 15 years. Vestibular system function was assessed by vestibular-evoked myogenic potential and bithermal caloric tests. The vestibular-evoked myogenic potential abnormality rate in implanted ears with an inner-ear anomaly was 81.8 per cent, compared with 39.3 per cent in implanted ears with normal anatomy. In the non-implanted sides, the rate was 45.5 per cent (10 out of 22 cases) in the inner-ear anomaly patients compared with 17.9 per cent in patients with normal inner-ear structure. The respective abnormal caloric test rates in inner-ear anomaly versus normal anatomy patients were 81.8 per cent and 17.9 per cent (implanted ears), 77.3 per cent and 14.3 per cent (non-implanted sides). Inner-ear anomaly and implantation were both associated with more vestibular-evoked myogenic potential abnormalities; when occurring together, these factors showed a synergistic effect. Caloric test abnormality is mainly dependent on the presence of an inner-ear anomaly, but implantation is not associated with caloric abnormality.


Salmonella typhimurium transcytoses flagellin via an SPI2-mediated vesicular transport pathway.
Apical colonization of polarized epithelia by Salmonella typhimurium results in translocation of flagellin to the basolateral membrane domain, thus enabling activation of toll-like receptor 5 (TLR5)-mediated pro-inflammatory gene expression. Such flagellin transcytosis occurred without a change in epithelial permeability to 40 kDa FITC dextran, did not require bacterial motility and was independent of transepithelial movement of intact bacteria. Flagellin transcytosis was blocked at 20 degrees C, suggesting dependence on vesicular transport consistent with results from confocal microscopy that showed flagellin independent of bacteria inside epithelial cells. Furthermore, vesicles isolated from S. typhimurium-infected epithelia were highly enriched in flagellin. Flagellin transcytosis was dependent upon genes of Salmonella pathogenicity island (SPI)-2, which alter vesicular trafficking, but independent of SPI-1 that mediates bacterial invasion. Furthermore, such SPI-2 mutants were unable to mediate the localization of flagellin into intracellular vesicles consistent with flagellin transcytosis mediated by a S. typhimurium take-over of host vesicle trafficking pathways. As a result of their inability to transcytose flagellin, apical colonization by SPI-2 mutants induced substantially less epithelial IL-8 secretion than wild-type strains suggesting that such SPI-2 mediated transcytosis of flagellin plays a role in the pathogenesis of the mucosal inflammation characteristic of human Salmonellosis.


High angle and ligand-induced low angle DNA bends incited by OccR lie in the same plane with OccR bound to the interior angle.
The OccR protein of Agrobacterium tumefaciens activates transcription of the occQ operon in response to octopine. Octopine shortens the DNase I footprint of OccR and relaxes an OccR-incited DNA bend. In this study, we used hydroxyl radical footprinting to show that OccR contacts only one face of the operator. This contact spans 50 nucleotide pairs in the absence of octopine, and 39 nucleotide pairs in the presence of octopine. Octopine enhanced protection of the central region of the footprint. OccR blocked intercalation by methidiumpropyl EDTA along most of the operator, but did not block intercalation at the bend center. OccR protected DNA against both reagents far more completely at the promoter-distal half of the operator than at the promoter-proximal half. Experiments to alter the phasing between the operator bend and an adjacent sequence-directed bend indicated that the high angle DNA bend in the absence of octopine, and the low angle bend in the presence of octopine, lie in the same plane. Operator DNA was bent toward the helical face that OccR protected from hydroxyl radicals, indicating that OccR occupies the interior angle of this bend.


[nm23-H1 protein expression and its clinical significance in human laryngeal carcinoma].
The Objective of the study on the expression of nm23-H1 protein in human laryngeal carcinoma, was to explore the role of nm23 gene in lymph node metastasis and invasion. The expression of nm23-H1 protein was immunohistochemically examined in 86 resected human laryngeal carcinomas. Anti-nm23-H1 monoclonal antibody was used. The results showed that 66.3%(57/86) of the cases were positive for nm23-H1 protein expression in the primary lesions. The positive staining rate (90.5%, 38/42) of the patients without regional lymph node metastasis, was significantly higher than that of patients with nodal involvement (43.2%, 19/44). Inverse relationship were found between the nm23-H1 protein expression in the primary lesions and the depth of tumor invasion or the advance of clinical stage. Expression of nm23-H1 protein was positively associated with the ascending histological grade of the lesion, and the relationship was significant. The above data suggest that nm23 gene plays an important role in the control of lymph node metastasis and invasion in laryngeal carcinomas.


Interpersonal style and anxiety.
Agoraphobic anxiety has been linked to traditional feminine sex role attitudes and related dyadic interactions. This research correlated measures of panic experience and agoraphobic anxiety with interpersonal style in a college student population. Significant positive correlations were observed between anxiety scores and the following interpersonal styles: submissive/deferent, self-effacing/obedient, mistrusting/cold, submissive, inhibited, and unassured. Results lend support to clinical reports that some individuals may develop agoraphobic symptoms as a result of the interaction of interpersonal style with relationship patterns.


Three years follow-up results of ranibizumab treatment for choroidal neovascularization secondary to pathologic myopia.
Choroidal neovascularization (CNV) secondary to pathological myopia (PM) is one of the main causes of severe visual impairment in patients younger than 50 years. In this analysis we want to demonstrate the long-term results of Ranibizumab treating CNV secondary to PM. We retrospectively analysed 15 treatment naive eyes of 13 patients (10 women, 3 men, mean age: 61.5, SD 11.6, range: 41-80) with visual impairment due to CNV secondary to PM, which were treated with ranibizumab. Criteria for re-treatment were reduction of visual acuity and/or activity in OCT or fluorescence angiography. We applied a mean of 3 injections (standard deviation [SD] 2.5, range: 1-8) ranibizumab during a mean period of 39.6 months (SD 5.3, range: 31-52). The spherical equivalent was -12.4 diopters ± 4.1 (range -7.5 to -20.5 diopters). Before the first injection mean visual acuity (logMAR) was 0.69 ± 0.26. After one month visual acuity improved to 0.39 ± 0.23 (p = 0.002), after 3 months to 0.30 ± 0.22 (p = 0.002) and after 6 months up to 0.30 ± 0.22 (p = 0.002). After 12 months visual acuity was 0.30 ± 0.22 (p = 0.001) and after 24 months 0.30 ± SD 0.24 (p = 0.001). 11 patients reached a follow-up of at least 36 months and visual acuity was 0.30 ± 0.13 (p = 0.001). Treating CNV secondary to PM with ranibizumab during a follow-up of 36 months, we found considerable improvement of visual acuity. Compared to treatment of CNV secondary to exudative age-related macular degeneration, CNVs secondary to PM seem to respond faster to ranibizumab treatment and less injections are neccessary to reach stabilization.


Effective treatment improves the body composition of patients with esophageal motility disorders.
Although treatment for esophageal motility disorder improves dysphagia and increases body weight, the effect of the treatment on body composition is unclear. This study aimed to assess the change in body composition between before and after treatment, the preoperative predictors of muscle increase, and the association between muscle increase and quality of life. Sixty-one patients (achalasia, n = 55; spastic esophageal disorder n = 6) who underwent per-oral endoscopic myotomy were analyzed in a single-arm prospective observational study. Appendicular skeletal muscle mass was measured with dual X-ray absorptiometry before and 3 months after per-oral endoscopic myotomy. For subgroup analysis, patients with postoperative appendicular skeletal muscle mass increase were defined as the muscle-increase group and the rest as the non-muscle-increase group. Preoperative factors related to the muscle-increase group were clarified via multivariate analysis. Further, the improvement after per-oral endoscopic myotomy in health-related quality-of-life score (Short Form-36) was compared between the muscle-increase and non-muscle-increase groups. Appendicular skeletal muscle mass increased significantly 3 months after per-oral endoscopic myotomy (P = 0.0002). The patients who underwent effective treatment (postoperative Eckardt score < 3) showed a significant improvement in appendicular skeletal muscle mass compared to those who did not (P = 0.04). In the stepwise logistic regression analysis, the preoperative Eckardt score (odds ratio: 1.95, 95% confidence interval 1.30-3.26, P = 0.0005) and preoperative serum prealbumin (odds ratio: 0.83, 95% confidence interval 0.70-0.97, P = 0.02) were identified as independent factors related to postoperative muscle increase. The improvements in the Short Form-36 domains of General Health (P = 0.0007) and Vitality (P = 0.003) were significantly higher in the muscle-increase group. The findings show that effective treatment improved the body composition of patients with esophageal motility disorder and that the Eckardt score and serum prealbumin may aid the prediction of increased appendicular skeletal muscle mass after treatment, resulting in a better quality of life.


Fetal calf serum-free generation of functionally active murine dendritic cells suitable for in vivo therapeutic approaches.
Standard protocols to generate mouse dendritic cells (DC) generally use culture medium supplemented with fetal calf serum; however, reinjection in vivo of DC cultured in fetal calf serum results in priming to xenogeneic proteins that clearly limits the use of such DC. We therefore established a fetal calf serum-free culture system for the generation of murine DC from bone marrow precursors. DC can be generated fetal calf serum-free using RPMI supplemented with 1.5% syngeneic mouse serum. Although the yield of DC grown under fetal calf serum-free conditions was somewhat lower than that of the standard culture, large numbers of DC could be generated without the exposure to xenogeneic proteins. The yield of fetal calf serum-free cultured DC was further enhanced by addition of the proinflammatory cytokines TNF-alpha and IL-1beta with the combination resulting in up to 10% more DC. Phenotypically, CD11c + DC cultured fetal calf serum-free homogenously coexpressed the DC-specific molecule DEC-205 as well as the costimulatory molecules CD40, CD80, and CD86. In contrast, only a subpopulation of the CD11c + DC cultured in fetal calf serum-containing medium coexpressed these molecules. Functionally, fetal calf serum-free DC showed strong stimulatory capacity for naïve allogeneic CD4 + and CD8 + T cells. Importantly, fetal calf serum-free DC showed spontaneous in vivo migratory activity. Moreover, 5 x 105 subcutaneously injected TNBS-conjugated fetal calf serum-free DC were able to mediate contact sensitivity. Furthermore, the intravenous or subcutaneous injection of a single dose of 5 x 105 OVA-pulsed fetal calf serum-free DC resulted in the induction of an OVA-specific immune response in naïve TCR transgenic animals. Thus DC cultured under fetal calf serum-free conditions are suitable instruments for in vivo therapeutic approaches, especially in autoimmune models. DC vaccines/dendritic cell development/fetal calf serum-free culture conditions for DC/in vivo therapeutic DC approaches.


Evaluation of NanoDot Optically Stimulated Luminescence Dosimeter for Cone-shaped Small-field Dosimetry of Cyberknife Stereotactic Radiosurgery Unit: A Monte Carlo Simulation and Dosimetric Verification Study.
The aim of this study was to investigate the adequacy of nanoDot optically stimulated luminescence (OSL) dosimeter for small field dosimetry before its in vivo applications in CyberKnife SRS unit. A PTW 60018 SRS Diode, 60019 microDiamond, and Gafchromic EBT3 films were used along with a nanoDot carbon-doped aluminum oxide OSL dosimeter to collect and compare beam data. In addition, the EGSnrc/BEAMnrc code was employed to simulate 6-MV photon beams of CyberKnife SRS system. All detectors showed good consistency with each other in output factor measurements for cone sizes of 15 mm or more. The differences were maintained within 3% for these cones. However, OSL output factors showed higher discrepancies compared to those of other detectors for smaller cones wherein the difference reached nearly 40% for cone size of 5 mm. Depending on the performance of OSL dosimeter in terms of output factors, percentage depth doses (PDDs) were only measured for cones equal to or larger than 15 mm. The differences in PDD measurements were within 5% for depths in the range of 5-200 mm. Its low reliable readings for cones smaller than 15 mm should be considered before its in vivo applications of Cyberknife system.


Phenotypic drift in human tenocyte culture.
Tendon ruptures are increasingly common, repair can be difficult, and healing is poorly understood. Tissue engineering approaches often require expansion of cell numbers to populate a construct, and maintenance of cell phenotype is essential for tissue regeneration. Here, we characterize the phenotype of human Achilles tenocytes and assess how this is affected by passaging. Tenocytes, isolated from tendon samples from 6 patients receiving surgery for rupture of the Achilles tendon, were passaged 8 times. Proliferation rates and cell morphology were recorded at passages 1, 4, and 8. Total collagen, the ratio of collagen types I and III, and decorin were used as indicators of matrix formation, and expression of the integrin beta1 subunit as a marker of cell-matrix interactions. With increasing passage number, cells became more rounded, were more widely spaced at confluence, and confluent cell density declined from 18,700/cm2 to 16,100/cm2 ( p = 0.009). No change to total cell layer collagen was observed but the ratio of type III to type I collagen increased from 0.60 at passage 1 to 0.89 at passage 8 ( p < 0.001). Decorin expression significantly decreased with passage number, from 22.9 +/- 3.1 ng/ng of DNA at passage 1, to 9.1 +/- 1.8 ng/ng of DNA at passage 8 ( p < 0.001). Integrin expression did not change. We conclude that the phenotype of tenocytes in culture rapidly drifts with progressive passage.


Dopamine neuronal responses in monkeys performing visually cued reward schedules.
Dopamine neurons are important for reward-related behaviours. They have been recorded during classical conditioning and operant tasks with stochastic reward delivery. However, daily behaviour, although frequently complex in the number of steps, is often very predictable. We studied the responses of 75 dopamine neurons during schedules of trials in which the events and related reward contingencies could be well-predicted, within and across trials. In this visually cued reward schedule task, a visual cue tells the monkeys exactly how many trials, 1, 2, 3, or 4, must be performed to obtain a reward. The number of errors became larger as the number of trials remaining before the reward increased. Dopamine neurons frequently responded to the cues at the beginning and end of the schedules. Approximately 75% of the first-cue responsive neurons did not distinguish among the schedules that were beginning even though the cues were different. Approximately half of the last-cue responsive neurons depended on which schedule was ending, even though the cue signalling the last trial was the same in all schedules. Thus, the responses were related to what the monkey knew about the relation between the cues and the schedules, not the identity of the cues. These neurons also frequently responded to the go signal and/or to the OK signal indicating the end of a correctly performed trial whether a reward was forthcoming or not, and to the reward itself. Thus, dopamine neurons seem to respond to behaviourally important, i.e. salient, events even when the events have been well-predicted.


A comparison of day treatment and outpatient treatment for children with disruptive behaviour problems.
The authors explored the relative merits of outpatient and day treatment for 30 children with severe behaviour problems. The effectiveness of treatment on behaviour, self-perception, and social and family functioning was assessed. Day treatment was found to be more effective in reducing behaviour problems, alleviating depressive symptoms, increasing social skills and improving family functioning.


Regulation of progesterone receptor messenger ribonucleic acid in the rat medial preoptic nucleus by estrogenic and antiestrogenic compounds: an in situ hybridization study.
Progesterone receptor (PR) messenger RNA (mRNA) is concentrated in neurons of the preoptic area and other regions of the rat hypothalamus where it is colocalized with the estrogen receptor and regulated by changes in the steroid hormonal milieu. To date, little is known about the regulation of PR mRNA by estrogens and whether antiestrogenic compounds are capable of modulating its expression. The present studies used in situ hybridization to ascertain the time course of PR mRNA regulation in the medial preoptic nucleus by 17beta-estradiol, determine the effective dose required to elicit a response, and compare the efficacy of 17beta-estradiol with a variety of estrogenic or antiestrogenic compounds. The first series of studies revealed that the treatment of ovariectomized rats with 17beta-estradiol resulted in an increase in PR expression within 2 h, after which it remained elevated until 10 h postinjection and then returned to baseline levels. When ovariectomized rats were injected with 25-1000 ng/kg of 17beta-estradiol and euthanized 6 h later, a dose-dependent increase in the level of PR mRNA was observed, with a maximal response at 1000 ng/kg and an EC50 of 93.5 ng/kg. Subsequent studies evaluated the efficacy of a variety of estrogenic and antiestrogenic compounds in the rat preoptic nucleus. 17Beta-estradiol, diethylstilbestrol, and 17alpha-estradiol all significantly increased the level of PR mRNA, although the degree of induction varied with each compound. The injection of tamoxifen, raloxifene, toremifene, droloxifene, clomiphene, GW 5638, or ICI 182,780 had no significant estrogenic effect on PR gene expression at the dose evaluated. In contrast, when tamoxifen or raloxifene, but not ICI 182,780, was administered in the antagonist mode, a significant dose-related decrease in the estradiol-induced level of PR mRNA was seen in the preoptic area. The results of these studies clearly demonstrate that PR mRNA expression in the rat preoptic area is rapidly stimulated by a small dose of 17beta-estradiol. Moreover, the present report has also shown that the estrogenic nature of compounds such as tamoxifen, raloxifene, toremifene, droloxifene, clomiphene, and GW 5638 cannot be predicted by their activity in peripheral tissues. Together, the results of these studies provide important information about the central activity of estrogens and provide evidence for their tissue-specifc actions in the rat.


Recording and quantifying fetal magnetocardiography signals using a flexible array of optically-pumped magnetometers.
Fetal magnetocardiography (fMCG) is a non-invasive biomagnetic technique that provides detailed beat-to-beat fetal heart rate analysis, both in normal rhythm as well as in fetal arrhythmias. New cryogenic-free sensors called optically pumped magnetometers (OPMs) have emerged as a less expensive and more geometrically flexible alternative to traditional Superconducting Quantum Interference Device (SQUID) technology for performing fMCG. The objective of the study was to show the ability of OPMs to record fMCG using flexible geometry while seeking to preserve signal quality, and to quantify fetal heart rate variability (FHRV). Biomagnetic measurements were performed with OPMs in 24 healthy pregnant women with uncomplicated singleton pregnancies between 28 and 38 weeks gestation (GA). A total of 96 recordings were analyzed from OPM data that was collected using sensors placed in two different maternal configurations over the abdomen. The fMCG signals were extracted and the quality of the recordings were quantified by peak amplitudes and signal-to-noise ratio (SNR). R peaks were used to perform both time and frequency domain FHRV analysis. FHRV measures obtained from OPMs were compared descriptively to the same measures obtained from GA-matched existing SQUID data. The fMCG derived from OPMs were observed in 21 of the 24 participants. Higher detection rates (85%) of fMCG signals were observed in the data sets recorded at GA >32 weeks. Peak amplitudes and SNR values were similar between two maternal configurations, but peak amplitudes were significantly higher (p = 0.013) in late GA compared to early GA. FHRV indicators were successfully extracted and their values overlapped substantially with those obtained from SQUID recordings. Taking advantage of the geometric flexibility of the OPMs, we have demonstrated their ability to record and quantify fMCG in different maternal positions as opposed to rigid SQUID configurations.


Correlation between cosmic rays and ozone depletion.
This Letter reports reliable satellite data in the period of 1980-2007 covering two full 11-yr cosmic ray (CR) cycles, clearly showing the correlation between CRs and ozone depletion, especially the polar ozone loss (hole) over Antarctica. The results provide strong evidence of the physical mechanism that the CR-driven electron-induced reaction of halogenated molecules plays the dominant role in causing the ozone hole. Moreover, this mechanism predicts one of the severest ozone losses in 2008-2009 and probably another large hole around 2019-2020, according to the 11-yr CR cycle.


Staged intraperitoneal brachytherapy and hyperthermic intraperitoneal chemotherapy in an adolescent: novel anesthetic challenges for pediatric anesthetists.
Newer techniques that have found a place in cancer management in adults are offered far less commonly in pediatric patients. We present a case of a patient with recurrent Wilms' tumor managed with a novel combination of cytoreductive surgery, intraperitoneal brachytherapy, and subsequent hyperthermic intraperitoneal chemotherapy. Each stage presents challenges that the pediatric anesthetist is unlikely to have faced before. Such cases require flexibility and thorough planning to manage the combination of major surgery, remote anesthesia with brachytherapy and hyperthermic chemotherapy with its potential for metabolic derangement, significant fluid shifts, analgesic care, and potential exposure of staff to cytotoxic agents. Comprehensive care can be offered in pediatric centers.


Benzannulation from alkyne without metallic catalysts at room temperature to 100 degrees C.
An efficient, novel metal-catalyst-free aminobenzannulation of 2-(prop-2-ynyl)(oxo)benzenes 1 with various dialkylamines 2 afforded a variety of 2-aminonaphthalenes 3 in good to excellent yields under mild reaction conditions at room temperature to 100 degrees C (at most).


Developing library bioinformatics services in context: the Purdue University Libraries bioinformationist program.
Purdue University is a major agricultural, engineering, biomedical, and applied life science research institution with an increasing focus on bioinformatics research that spans multiple disciplines and campus academic units. The Purdue University Libraries (PUL) hired a molecular biosciences specialist to discover, engage, and support bioinformatics needs across the campus. After an extended period of information needs assessment and environmental scanning, the specialist developed a week of focused bioinformatics instruction (Bioinformatics Week) to launch system-wide, library-based bioinformatics services. The specialist employed a two-tiered approach to assess user information requirements and expectations. The first phase involved careful observation and collection of information needs in-context throughout the campus, attending laboratory meetings, interviewing department chairs and individual researchers, and engaging in strategic planning efforts. Based on the information gathered during the integration phase, several survey instruments were developed to facilitate more critical user assessment and the recovery of quantifiable data prior to planning. Given information gathered while working with clients and through formal needs assessments, as well as the success of instructional approaches used in Bioinformatics Week, the specialist is developing bioinformatics support services for the Purdue community. The specialist is also engaged in training PUL faculty librarians in bioinformatics to provide a sustaining culture of library-based bioinformatics support and understanding of Purdue's bioinformatics-related decision and policy making.


Blind deconvolution of a noisy degraded image.
We develop a unified algorithm for performing blind deconvolution of a noisy degraded image. By incorporating a low-pass filter into the asymmetric multiplicative iterative algorithm and extending it to multiframe blind deconvolution, this algorithm accomplishes the blind deconvolution and noise removal concurrently. We report numerical experiments of applying the algorithm to the restoration of short-exposure atmosphere turbulence degraded images. These experiments evidently demonstrate that the unified algorithm has both good blind deconvolution performance and high-resolution image restoration.


Platelet abnormalities in renal transplantation.
Forty-six transplant patients had lower platelet serotonin and higher plasma beta-thromboglobulin (beta-TG) than normal controls. These abnormalities were more pronounced in acute rejection (AR) than in chronic rejection (CR), but were also present in normally functioning transplants (FT). Patients also showed lower serum levels of thromboxane B2 (TxB2) than controls. Plasma fibrinopeptide A (FPA) was higher in AR, but not in CR and in FT, than in controls. Therefore, in renal transplant recipients, platelets continue to circulate after in vivo activation, the abnormalities being roughly proportional to the extent of graft injury. Granule-bound substances secreted into the circulation might produce ischaemia and platelet aggregates, damaging the graft and aggravating the rejection lesions.


Treatment of complete acromioclavicular dislocation: present indications and surgical technique with biodegradable cords.
We report a retrospective study of 48 patients with complete acromioclavicular dislocation (Tossy III). All patients (38 male; 10 female) with an average age of 33.4 years underwent surgery including PDS-augmentation. More than half of the injuries were caused by sport accidents. There were no complications during surgery. 87% of the patients were free of complaints and subjectively very satisfied with the surgical results. By radiological examination we diagnosed a subluxation of the clavicula in 25% of the cases and arthrosis in 17% of the cases. Assessment of subjective complaints, the clinical examination, and the radiological diagnostic according to the Taft Score (0-12 points) resulted in an average value of 10.2 points. The surgical intervention using PDS-cord augmentation in cases of complete acromioclavicular separation is a safe and economic method with a low complication rate. Advantages are possible early-functional treatment, no risk of movement of implants, and avoidance of metal removal.


Plasma studies of the permanent magnet electron cyclotron resonance ion source at Peking University.
At Peking University (PKU) we have developed several 2.45 GHz Permanent Magnet Electron Cyclotron Resonance ion sources for PKUNIFTY, SFRFQ, Coupled RFQ&SFRFQ, and Dielectric-Wall Accelerator (DWA) projects (respectively, 50 mA of D(+), 10 mA of O(+), 10 mA of He(+), and 50 mA of H(+)). In order to improve performance of these ion sources, it is necessary to better understand the principal factors that influence the plasma density and the atomic ion fraction. Theoretical analysis about microwave transmission and cut-off inside the discharge chamber were carried out to study the influence of the discharge chamber diameters. As a consequence, experimental studies on plasma density and ion fraction with different discharge chamber sizes have been carried out. Due to the difficulties in measuring plasma density inside the discharge chamber, the output beam current was measured to reflect the plasma density. Experimental results show that the plasma density increases to the maximum and then decreases significantly as the diameter changed from 64 mm to 30 mm, and the atomic ion fraction has the same tendency. The maximum beam intensity was obtained with the diameter of 35 mm, but the maximum atomic ion fraction with a diameter of 40 mm. The experimental results are basically accordant with the theoretical calculation. Details are presented in this paper.


Direct and Indirect Genotoxicity of Graphene Family Nanomaterials on DNA-A Review.
Graphene family nanomaterials (GFNs), including graphene, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots (GQDs), have manifold potential applications, leading to the possibility of their release into environments and the exposure to humans and other organisms. However, the genotoxicity of GFNs on DNA remains largely unknown. In this review, we highlight the interactions between DNA and GFNs and summarize the mechanisms of genotoxicity induced by GFNs. Generally, the genotoxicity can be sub-classified into direct genotoxicity and indirect genotoxicity. The direct genotoxicity (e.g., direct physical nucleus and DNA damage) and indirect genotoxicity mechanisms (e.g., physical destruction, oxidative stress, epigenetic toxicity, and DNA replication) of GFNs were summarized in the manuscript, respectively. Moreover, the influences factors, such as physicochemical properties, exposure dose, and time, on the genotoxicity of GFNs are also briefly discussed. Given the important role of genotoxicity in GFNs exposure risk assessment, future research should be conducted on the following: (1) developing reliable testing methods; (2) elucidating the response mechanisms associated with genotoxicity in depth; and (3) enriching the evaluation database regarding the type of GFNs, applied dosages, and exposure times.


Complete transition from open surgery to laparoscopy: 8-year experience with more than 500 laparoscopic living donor hepatectomies.
This study was designed to review laparoscopic living donor liver transplantations (LDLTs) at a single center that achieved complete transition from open surgery to laparoscopy. LDLTs performed from January 2013 to July 2021 were reviewed. Comparisons between open and laparoscopic surgeries were performed according to periods divided into initial, transition, and complete transition periods. A total of 775 LDLTs, 506 laparoscopic and 269 open cases, were performed. Complete transition was achieved in 2020. Bile duct variations were significantly abundant in the open group both in the initial period (30.2% vs. 8.1%; p < 0.001) and transition period (48.1% vs. 24.3%; p < 0.001). Portal vein variation was more abundant in the open group only in the initial period (13.0% vs. 4.1%; p = 0.03). Although the donor reoperation rate (0.0% vs. 4.1%; p = 0.02) and Grade III or higher complication rate (5.6% vs. 13.5%; p = 0.03) were significantly higher in the laparoscopy group in the initial period, there were no differences during the transition period as well as in overall cases. Median number of opioids required by the donor (three times [interquartile range, IQR, 1-6] vs. 1 time [IQR, 0-3]; p < 0.001) was lower, and the median hospital stay (10 days [IQR, 8-12] vs. 8 days [IQR, 7-9]; p < 0.001) was shorter in the laparoscopy group. Overall recipient bile leakage rate (23.8% vs. 12.8%; p < 0.001) and overall Grade III or higher complication rate (44.6% vs. 37.2%; p = 0.009) were significantly lower in the laparoscopy group. Complete transition to laparoscopic living donor hepatectomy was possible after accumulating a significant amount of experience. Because donor morbidity can be higher in the initial period, donor selection for favorable anatomy is required for both the donor and recipient.


Relationship between serum cytokines profiles and hepatic fibrosis in schistosomiasis mansoni: an experimental study.
Forty of eighty mice (10 each group) were infected with S. mansoni cercariae and sacrificed at 3 weeks (G-A), 6 weeks (G-B), 12 weeks (G-C) and 16 weeks (G-D) post infection (P.I). The other forty mice were used as control groups of ten mice each. There were highly significant difference between egg counts after 12 weeks & 16 weeks of infection compared to 6 weeks P.I. The maximum egg count and mature eggs were in 6th week P.I while dead eggs reached the peak at 16th weeks P.I. Liver egg counts showed maximum followed by intestinal and then, stool egg counts. A highly significant differences in hydroxyproline, TGF-Bland IL-4 of infected than in controls and their peak at 16 weeks P.I. A significant difference in the IFN-gamma in the infected than in controls with peak occurred at 6 weeks P.I. and declined after that reaching a low level at 16 weeks P.I. A highly significant positive correlation was between TGF-Bland IL4 and significant negative correlation between IFN-gamma and both IL4 & TGF-B1. A highly significant and significant negative correlation between TGF-B1 and egg count at 12 & 16 weeks P.I respectively. Negative correlation was between IL-4 and egg count at 16 weeks P.I. But, significant positive correlation was between IFN-gamma with the egg count at 16 weeks P.I. A significant negative correlation was between TGF-B1 and oogram at 6 & 16 weeks P.I, but highly significant positivity was between IFN-gamma and oogram at 16 weeks P.I. A significant negative correlation was between IL-4 and oogram at 16 weeks P.I. A significant positive correlation was between levels of hydroxyproline and TGF-B1 at 12 & 16 weeks P.I. Highly significant negative correlation between hydroxyproline and IFN-gamma was at 12 weeks P.I with significant and highly significant positive correlation between hydroxyproline and IL4 at 12 & 16 weeks P.I.


Nano vaccines for T. gondii Ribosomal P2 Protein With Nanomaterials as a Promising DNA Vaccine Against Toxoplasmosis.
Caused by Toxoplasma gondii, toxoplasmosis has aroused great threats to public health around the world. So far, no effective vaccine or drug is commercially available, and the demands for a safe and effective therapeutic strategy have become more and more urgent. In the current study, we constructed a DNA vaccine encoding T. gondii ribosomal P2 protein (TgP2) and denoted as TgP2-pVAX1 plasmid. To improve the immunoprotection, nanomaterial poly-lactic-co-glycolic acid (PLGA) and chitosan were used as the delivery vehicle to construct TgP2-pVAX1/PLGA and TgP2-pVAX1/CS nanospheres. Before vaccinations in BALB/c mice, TgP2-pVAX1 plasmids were transiently transfected into Human Embryonic Kidney (HEK) 293-T cells, and the expression of the eukaryotic plasmids was detected by laser confocal microscopy and Western blotting. Then the immunoprotection of naked DNA plasmids and their two nano-encapsulations were evaluated in the laboratory animal model. According to the investigations of antibody, cytokine, dendritic cell (DC) maturation, molecule expression, splenocyte proliferation, and T lymphocyte proportion, TgP2-pVAX1 plasmid delivered by two types of nanospheres could elicit a mixed Th1/Th2 immune response and Th1 immunity as the dominant. In addition, TgP2-pVAX1/PLGA and TgP2-pVAX1/CS nanospheres have great advantages in enhancing immunity against a lethal dose of T. gondii RH strain challenge. All these results suggested that TgP2-pVAX1 plasmids delivered by PLGA or chitosan nanomaterial could be promising vaccines in resisting toxoplasmosis and deserve further investigations and applications.


Vascular Ehlers-Danlos syndrome, an often unrecognized clinical entity: a case report of a novel mutation in the COL3A1 gene.
Due to life-threatening complications, vascular Ehlers-Danlos syndrome (vEDS) is the most severe form of EDS. Because the syndrome is associated with a shortened life expectancy and variable clinical presentation, diagnosis confirmed by genetic testing is crucial to determining appropriate treatment. Despite some distinguishing features, this rare disease often goes unrecognized. Apart from surgical or endovascular treatment of serious vascular complications, medical treatment based on celiprolol helps reduce arterial complications. We report on a case of vEDS in a young man who suffered several episodes of severe vascular complications. The diagnosis of vEDS was established based on clinical manifestations and confirmed by genetic testing. A novel heterozygous pathogenic variant in the COL3A1 gene was found. To our knowledge, this is the first case of vEDS caused by this variant.


Do health educator telephone calls reduce at-risk drinking among older adults in primary care?
Alcohol screening and brief intervention for unhealthy alcohol use has not been consistently delivered in primary care as part of preventive healthcare. To explore whether telephone-based intervention delivered by a health educator is efficacious in reducing at-risk drinking among older adults in primary care settings. Secondary analyses of data from a randomized controlled trial. Subjects randomized to the intervention arm of the trial (n = 310). Personalized risk reports, advice from physicians, booklet about alcohol and aging, and up to three telephone calls from a health educator. All interventions were completed before the three-month follow-up. Risk outcomes (at-risk or not at-risk) at 3 and 12 months after enrollment. In univariate analyses, compared to those who remained at risk, those who achieved not at-risk outcome at 3 months were more likely to be women, Hispanic or non-white, have lower levels of education, consume less alcohol, drink less frequently, and have lower baseline number of risks. In mixed-effects logistic regression models, completing all three health educator calls increased the odds of achieving not at-risk outcome compared to not completing any calls at 3 months (OR 5.31; 95% CI 1.92-14.7; p = 0.001), but not at 12 months (OR 2.01; 95% CI 0.71-5.67; p = 0.18). Telephone-based intervention delivered by a health educator was moderately efficacious in reducing at-risk drinking at 3 months after enrollment among older adults receiving a multi-faceted intervention in primary care settings; however, the effect was not sustained at 12 months.


Is the psychological composition of the therapeutic group associated with individual outcomes in group cognitive behavioural therapy for chronic pain?
This study explored whether the psychological composition of a group, with respect to mood, catastrophising, fear of movement and pain self-efficacy characteristics at baseline, is associated with individuals' treatment outcomes following group cognitive behavioural therapy (CBT)-based programmes for chronic pain. Retrospective analyses of outcomes from two independently run CBT-based pain management programmes (Programme A: N = 317 and Programme B: N = 693) were conducted. Mixed modelling analyses did not consistently support the presence of associations between group median scores of depression, catastrophising or fear avoidance with outcomes for individuals in either programme. These results suggest that the psychological profiles of groups are not robust predictors of individual outcomes in CBT groups for chronic pain. By implication, efforts made to consider group composition with respect to psychological attributes may be unnecessary.


Driving problems in patients with rheumatoid arthritis.
To assess driving problems experienced by patients with rheumatoid arthritis (RA) and to examine the relationship between functional status and driving difficulty. Using the South Eastern Ontario Medical Organization (SEAMO) database, we identified 721 patients with RA from both urban and rural backgrounds. They completed a cross-sectional, self-administered mail survey that included the Health Assessment Questionnaire (HAQ-DI) and a co-morbidity questionnaire. We assessed the proportion of drivers versus non-drivers and patients who reported difficulty driving and who used vehicle adaptations. Survey response rate was 74% and 92.2% of the subjects were current drivers. Fifty percent of the current drivers reported a little difficulty, 6.8% reported quite a bit of difficulty, and 1.5% a great deal of difficulty driving. Major reasons given for why RA limited their driving were stiffness and pain. Frequent use of mobility aids (adjusted odds ratio, OR: 5.85), HAQ-DI > or = 1 (adjusted OR: 3.40), and older age (adjusted OR: 1.04) were significant predictors of an individual with RA discontinuing driving. Higher levels of disability (HAQ-DI) were associated with a greater number of problems reported with driving and with curtailment of driving. A multivariate logistic regression determined that having a HAQ-DI > or = 1 (adjusted OR: 4.3) and difficulties sitting in the vehicle (adjusted OR: 2.9) were associated with RA limiting driving. Over 50% of respondents reported some degree of difficulty driving due to their RA. Scores on HAQ-DI > or = 1 were associated with difficulty driving. Further validation of our findings needs to be performed.


Dose- and Time-Dependent Cellular Effects of Cold Atmospheric Pressure Plasma Evaluated in 3D Skin Models.
Application of cold atmospheric pressure plasmas (CAPs) in or on the human body was termed 'plasma medicine'. So far, plasmas were utilized for sterilization of implants, other heat-sensitive products, or employed for chemical surface modifications. By now, CAPs are further used effectively for wound treatment. The present study analyses the effect of a plasma jet with air or nitrogen as process gas, previously evaluated for antimicrobial efficacy, on human cells using a 3D skin model. CAP treatment of 3D skin models consisting of a keratinocyte-containing epidermal layer and a fibroblast/collagen dermal matrix was performed using the Tigres plasma MEF technology. To evaluate the effects on the 3D skin models, the following plasma parameters were varied: process gas, input power, and treatment time. Low CAP doses exhibited good cell compatibility. Increasing input power or elongating treatment intervals led to detrimental effects on 3D skin model morphology as well as to release of inflammatory cytokines. It was further observed that air as process gas was more damaging compared to nitrogen. Treatment of 3D skin models with the plasma MEF nozzle using air or nitrogen is reported. A clearly dose- and time-dependent effect of CAPs could be observed in which the CAP based on nitrogen exhibited higher cell compatibility than the CAP generated from air. These settings might be recommended for medical in vivo applications such as wound decontamination.


Bottom-up nanotechnology: the human nephron filter.
Over one million patients worldwide have end-stage renal disease and require dialysis or kidney transplantation. Despite the availability of these forms of renal replacement therapy for nearly four decades, mortality and morbidity are high and patients often have a poor quality of life. We have developed a human nephron filter (HNF) utilizing bottom-up nanotechnology that would eventually make feasible a continuously functioning, wearable or implantable artificial kidney. The device consists of two membranes operating in series within one device cartridge. The first membrane mimics the function of the glomerulus, using convective transport to generate a plasma ultra filtrate, which contains all solutes approaching the molecular weight of albumin. The second membrane mimics the function of the renal tubules, selectively reclaiming designated solutes to maintain body homeostasis. No dialysis solution is used in this device. The HNF has been computer modeled, and operating 12 hour per day, 7 days per week the HNF provides the equivalent of 30 ml/min glomerular filtration rate (compared to half that amount for conventional thrice-weekly hemodialysis). The HNF system, by eliminating dialysate and utilizing a novel membrane system created through applied nanotechnology, represents a breakthrough in renal replacement therapy based on the functioning of native kidneys. The enhanced solute removal and wearable design should substantially improve patient outcomes and quality of life.


Lanthanide (Eu3+, Tb3+) centered hybrid materials using modified functional bridge chemical bonded with silica: molecular design, physical characterization, and photophysical properties.
1,3-Bis(2-formylphenoxy)-2-propanol (BFPP) was first synthesized and then grafted to 3-(triethoxysilyl)propyl isocyanate (TESPIC) to achieve a molecular precursor BFPP-Si through the hydrogen-transfer nucleophilic addition reaction between the hydroxyl group of BFPP and the isocyanate group of TESPIC. Then, a chemically bonded lanthanide/inorganic/organic hybrid material (BFPP-Si-Ln) was constructed using BFPP-Si as a bridge molecule that can both coordinate to lanthanide ions (Eu3+ or Tb3+) and form an inorganic Si-O network with tetraethoxysilane (TEOS) after cohydrolysis and copolycondensation processes. Furthermore, two types of ternary rare-earth/inorganic/organic hybrids (BFPP-Si-Dipy-Ln and BFPP-Si-Phen-Ln) were assembled by the introduction of the second ligands (4,4'-bipyridyl and 1,10-phenanthroline) into the above system. All of these hybrid materials exhibit homogeneous microstructures and morphologies, suggesting the occurrence of self-assembly of the inorganic network and organic chain. Measurements of the photoluminescent properties of these materials show that the ternary rare-earth/inorganic/organic hybrids present stronger luminescent intensities, longer lifetimes, and higher luminescent quantum efficiencies than the binary hybrids, indicating that the introduction of the second ligands can sensitize the luminescence emission of the lanthanide ions in the ternary hybrid systems.


Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies.
In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2), which is preferentially induced by carcinogenic heterocyclic amines. Enhancement of the activities of their phase II counterparts, such as glutathione S-transferase might have also played a critical role in post-initiation suppression in a study of tongue carcinogenesis. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis.


Neonatal hypothyroidism: treatment and outcome.
Systematic neonatal screening for congenital hypothyroidism (CH), which was progressively implemented in industrialized countries over the past 15 to 25 years, has been extremely successful in eradicating severe mental deficiency resulting from CH. However, in the first generation of children diagnosed by screening, the concept that CH has a threshold effect on intelligence was confirmed. In spite of earlier diagnosis through screening, children with severe CH (i.e., those with a marked retardation of bone age and/or a low circulating thyroxine [T4] before treatment) still had clinically significant intellectual sequelae, amounting to a loss of 6 to 19 IQ points. Recent studies suggest that this developmental gap may be closed by treating more rapidly after birth (2 weeks instead of 4-5 weeks in the early years of the screening era) and by using a higher initial dose of levothyroxine (10-15 instead of 5-8 microg/kg per day). This regimen induces transient hyperthyroxinemia, but no clinical signs or symptoms of hyperthyroidism. Longer term follow-up of larger numbers of patients remains necessary to confirm the normalization of intellectual development and the absence of untowards effects of the treatment regimen in children with severe CH.


Enumeration-screening method for the design of simple polygonal tensegrities.
Tensegrities, consisting of axially pre-compressed bars and pre-stretched strings, hold broad applications in the design of, for instance, architectures, soft robotics and metamaterials. In this paper, we propose an enumeration-screening method to design planar tensegrities of simple polygonal shapes. In such a polygonal tensegrity, the strings are joined pair-wise to form a simple polygon (a planar shape consisting of straight, non-intersecting line segments) and only one bar is added at each node. The total number of simple polygonal tensegrities designed by this scheme increases exponentially with the number of bars. Moreover, we demonstrate that each of these designed topologies can produce a self-equilibrated and stable tensegrity configuration. This work helps understand the topological features of simple polygonal tensegrities, which can be used as elementary cells to design some novel two- and three-dimensional tensegrity structures.


Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes.
The ezrin-radixin-moesin (ERM) family of proteins crosslink actin filaments and integral membrane proteins. Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice and is concentrated at bile canalicular membranes (BCMs). Here we show that Rdx(-/-) mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile. In the BCMs of Rdx(-/-) mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26) and P-glycoproteins. In vitro binding studies show that radixin associates directly with the carboxy-terminal cytoplasmic domain of human MRP2. These findings indicate that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.


UHPLC-MS/MS Determination, Pharmacokinetic, and Bioavailability Study of Taxifolin in Rat Plasma after Oral Administration of its Nanodispersion.
A rapid and sensitive LC-MS/MS method based on the Triple Quad system has been developed and validated for the determination and pharmacokinetics of taxifolin and its nanodispersion in rat plasma. Taxifolin plasma samples along with butylparaben (internal standard) were pre-treated by liquid-liquid extraction with ethyl acetate, and then separated on a SB-C18 RRHD column (150 mm × 2.1 mm × 1.8 μm) using isocratic elution with a run time of 3.0 min. The mobile phase was acetonitrile-water (90:10, v/v) containing 5 mM ammonium acetate at a flow rate of 0.4 mL/min. Quantification of taxifolin was performed by the electrospray ionization tandem mass spectrometry in the multiple reaction monitoring (MRM) mode with negative atmospheric ionization at m/z 303.0→285.0 for taxifolin and 193.1→92.0 for I.S., respectively. The calibration curve of taxifolin showed good linearity over a concentration range of 5.0-4280 ng/mL with a correlation coefficient of 0.9995. The limit of quantification (LLOQ) was 5.0 ng/mL. Intra-day, inter-day precision and accuracy (percent relative to standard deviation) were all within 8% at three concentration levels. A total recovery of taxifolin and I.S. was beyond 75%. The present LC-MS/MS method was successfully applied to pharmacokinetic studies of taxifolin after intravenous administration of taxifolin, oral administration of its physical mixture and nanodispersion. The absolute bioavailability of taxifolin was calculated as 0.75% for taxifolin nanodispersion and 0.49% for taxifolin, respectively.


Triggering Receptor Expressed on Myeloid cells-1: a new player in platelet aggregation.
Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is an immunoreceptor initially known to be expressed on neutrophils and monocytes/macrophages. TREM-1 acts as an amplifier of the inflammatory response during both infectious and aseptic inflammatory diseases. Another member of the TREM family, The Triggering receptor expressed on myeloid cells Like Transcript-1 (TLT-1) is exclusively expressed in platelets and promotes platelet aggregation. As the gene that encodes for TLT-1 is located in the TREM-1 gene cluster, this prompted us to investigate the expression of TREM-1 on platelets. Here we show that TREM-1 is constitutively expressed in α-granules and mobilised at the membrane upon platelet activation. Pharmacologic inhibition of TREM-1 reduces platelet activation as well as platelet aggregation induced by collagen, ADP, and thrombin in human platelets. Aggregation is similarly impaired in platelets from Trem-1-/- mice. In vivo, TREM-1 inhibition decreases thrombus formation in a carotid artery model of thrombosis and protects mice during pulmonary embolism without excessive bleeding. These findings suggest that TREM-1 inhibition could be useful adducts in antiplatelet therapies.


Overexpression of nuclear receptor SHP in adipose tissues affects diet-induced obesity and adaptive thermogenesis.
The orphan nuclear receptor small heterodimer partner (SHP) regulates metabolic pathways involved in hepatic bile acid production and both lipid and glucose homeostasis via the transcriptional repression of other nuclear receptors. In the present study, we generated fat-specific SHP-overexpressed transgenic (TG) mice and determined the potential role of SHP activation, specifically in adipocytes, in the regulation of adipose tissue function in response to stressors. We determined in 2 mo-old SHP TG mice body weight, fat mass index, adipose tissues morphology, thermogenic and metabolic gene expression, metabolic rates at baseline and in response to beta adrenergic receptor agonists, and brown fat ultrastructural changes in response to cold exposure (6-48 h). Mice were fed a 10-wk high-fat diet (HFD; 42% fat). Weight gain, fat mass index, adipose tissues morphology, glucose tolerance, and metabolic rates were determined at the end of the feeding. Young TG mice had increased body weight and adiposity; however, their energy metabolism was increased and brown fat function was enhanced in response to cold exposure through the activation of thermogenic genes and mitochondrial biogenesis. SHP overexpression exacerbated the diet-induced obesity phenotype as evidence by marked weight gain over time, increased adiposity, and severe glucose intolerance compared with wild-type mice fed a HFD. In addition, SHP-TG mice fed HFD had decreased diet-induced adaptive thermogenesis, increased food intake, and decreased physical activity. In conclusion, SHP activation in adipocytes strongly affects weight gain and diet-induced obesity. Developing a synthetic compound to antagonize the effect of SHP may prove to be useful in treating obesity.


[An infant without nails].
A 2-week-old boy, born after an uncomplicated pregnancy of consanguineous parents, was seen with congenital absence of all nails on fingers and toes. After 6 weeks marginal nail growth was seen. Because there were no other congenital abnormalities, this was considered to be anonychia congenita; probably caused by a recessive defect of the R-spondin 4-coding gene.


Dextromethorphan metabolic phenotyping in a Chinese population.
To establish a phenotyping of dextromethorphan (DM) oxidation polymorphism in a native Chinese population. The urine concentrations of DM and its metabolite dextrophan (DX) were assayed by HPLC and metabolic ratios (MR) were calculated in 120 unrelated native Chinese subjects after ingestion of DM 20 mg. The incidence of poor metabolizers was 0.8% (one in 120 subjects). There were distinct dimodal distributions which divided extensive metabolizers into 43 intermediate metabolizers and 76 very extensive metabolizers. The 0-8 h urinary recoveries of DM and DX were 0.4% +/- s 0.5% and 26% +/- s 13%, respectively. There was no difference in 0-8 h urinary recoveries between male and female subjects. DM metabolic phenotyping provides a new information for debrisoquine 4-hydroxylation (CYP2D6) polymorphism in native Chinese.


Revealing sources and distribution changes of dissolved organic matter (DOM) in pore water of sediment from the Yangtze estuary.
Dissolved organic matter (DOM) in sediment pore waters from Yangtze estuary of China based on abundance, UV absorbance, molecular weight distribution and fluorescence were investigated using a combination of various parameters of DOM as well as 3D fluorescence excitation emission matrix spectra (F-EEMS) with the parallel factor and principal component analysis (PARAFAC-PCA). The results indicated that DOM in pore water of Yangtze estuary was very variable which mainly composed of low aromaticity and molecular weight materials. Three humic-like substances (C1, C2, C4) and one protein-like substance (C3) were identified by PARAFAC model. C1, C2 and C4 exhibited same trends and were very similar. The separation of samples on both axes of the PCA showed the difference in DOM properties. C1, C2 and C4 concurrently showed higher positive factor 1 loadings, while C3 showed highly positive factor 2 loadings. The PCA analysis showed a combination contribution of microbial DOM signal and terrestrial DOM signal in the Yangtze estuary. Higher and more variable DOM abundance, aromaticity and molecular weight of surface sediment pore water DOM can be found in the southern nearshore than the other regions primarily due to the influence of frequent and intensive human activities and tributaries inflow in this area. The DOM abundance, aromaticity, molecular weight and fluorescence intensity in core of different depth were relative constant and increased gradually with depth. DOM in core was mainly composed of humic-like material, which was due to higher release of the sedimentary organic material into the porewater during early diagenesis.


Molecular cloning and characterization of a translational inhibitory protein that binds to coding sequences of human acid beta-glucosidase and other mRNAs.
Acid beta-glucosidase (GCase) is the enzyme deficient in Gaucher disease, a prototypical inherited metabolic error for enzyme and gene therapy. An 80-kDa cytoplasmic protein, termed TCP80, was found to inhibit GCase mRNA translation in mammalian cells by binding to RNA-coding regions. The TCP80 cDNA was cloned by screening an expression library with the GCase-coding region RNA. The cDNA sequence was nearly identical to those for M-phase phosphoprotein (MPP4; 99%) and for the IL-2 enhancer binding protein (NF90; 96%). Expression of the carboxy-terminal third, TCP30, showed it to be an RNA-binding protein that bound to a 184-nt fragment of GCase-coding sequence near the 5' end of the mature mRNA. When added to reactions, a large molar excess of TCP30 diminished the translation inhibition of GCase RNA by cytoplasmic TCP80. TCP50, expressed from the NH(2)-terminal two-thirds of TCP80, did not bind to nor inhibit the translation of GCase RNA. Reconstitution of in vitro translation inhibition of GCase RNA required intact human TCP80 heterologously expressed in insect cells. Time course analyses show that TCP80 functions at the initiation phase of GCase mRNA translation, probably by inhibiting its binding to polysomes. Seven additional RNAs were isolated by specific binding to TCP30 including those for aldolase B, complement protein 8 gamma-subunit, fibronectin receptor beta1, ABL, lactate dehydrogenase A, fibrinogen gamma-chain, and peroxisomal proliferator-activated receptor alpha. In vitro translation of their RNAs was inhibited by TCP80. These studies show that TCP80 has RNA-binding (TCP30) and inhibitory (TCP50) domains that function to modulate translation of several mRNAs. TCP80 is likely identical to MPP4 and NF90, but has previously undescribed roles in cellular function.


[Recombinant human erythropoietin: method of in vivo evaluation using normocythemic mice].
The implementation of an in vivo assay to determine the biological activity of human recombinant erythropoietin (Hu-r EPO) is essential. The purpose of this study was to perform and optimize the conditions of an easy in vivo bioassay suitable for routine testing of quality control of Hu-r EPO preparations. Normocythemic 8 weeks female mice treated with different Hu-r EPO doses were employed. The reticulocyte response was measured by flow cytometry and by visual count in a Neubauer cell count chamber, after selective red blood cell haemolysis. A unique subcutaneous injection with blood extraction 96 hours later was the schedule employed. The reticulocyte count measured by both methods was plotted against the log dose of Hu-r EPO. The dose-response curve obtained was linear between 5 and 160 UI/mouse and the doses chosen for future assays were 10, 30 and 90 UI/mouse. The use of at least 6 animals per dose and not less than 3 assays to obtain reliable limits according to international regulations is convenient. Thirty assays were performed in four different samples and were analyzed by parallel lines (3 + 3) relating the response with the log dose. The coefficient of correlation between both methods was 0.989, so they are equivalent. This method is suitable because fewer animals and bioassays are necessary to obtain fiducial limits according to international requirements. It is in agreement with the tendency to reduce the number of animals used for bioassay because ethical and economic reasons.


Secretory abnormalities in functional dyspepsia.
During the past 30 years much interest has been focused on gastric acid as a possible causative factor in functional dyspepsia. The similarities to duodenal ulcer with regard to the symptoms, previous reports of a high risk of subsequent ulcer development, and a growing number of clinical therapeutic trials showing a significant advantage for acid-reducing drugs over placebo--although challenged by many investigators--have all contributed to a common notion that the gastric acid may play an equally important pathogenic role in functional dyspepsia as in peptic ulcer disease. However, recent studies in patients with well-defined functional dyspepsia indicate quite clearly that hypersecretion of hydrochloric acid is a rare finding. Available data also contradict the hypothesis that patients with functional dyspepsia are abnormally sensitive to their gastric acid. Those dyspeptic individuals who benefit from antacids purchased over the counter usually do not have functional dyspepsia but rather organic diseases such as esophagitis or peptic ulcer. The association or pathophysiologic parallelism between functional dyspepsia and peptic ulcer implied by the results of some studies of functional dyspepsia in the past might be explained by unintended inclusion of overlooked or subclinical cases of peptic ulcer disease in those studies.


Virulence Genes Profile of Multidrug Resistant Pseudomonas aeruginosa Isolated from Iranian Children with UTIs.
Virulent and resistant strains Pseudomonas aeruginosa (P. aeruginosa) is one of the most important cause of UTIs in pediatrics. The present study was carried to investigate the frequency of virulence factors in the multi-drug resistant strains of P. aeruginosa isolated from pediatrics hospitalized due to the UTIs. One-hundred and forty three urine samples were collected from pediatric patients suffered from UTIs. Samples were cultured and those that were P. aeruginosa positive were analyzed for the presence of putative virulence genes. Seventy one out of 143 samples (49.65%) were positive for P. aeruginosa. Monthly, sex and age-dependent prevalence were seen for P. aeruginosa. Bacterial strains had the highest levels of resistance against ampicillin (95.77%), gentamicin (92.95%) and ciprofloxacin (81.69%). Of 71 P. aeruginosa isolates, 12 strains were resistant to more than 9 antibiotics (16.90%). The most commonly detected virulence factors in the cases of urethral infections were exoU and plcH while those of pyelonephritis and cystitis were were exoS and lasB. Our findings should raise awareness about antibiotic resistance in hospitalized pediatrics with UTIs in Iran. Clinicians should exercise caution in prescribing antibiotics, especially in cases of UTIs. Such information can help in identifying these virulence genes as useful diagnostic markers for clinical P. aeruginosa strains isolated from UTIs.


Diagnostic assessment.
Precision in diagnosis is the basis for treatment. The use of structured assessments of diagnosis, severity of illness, and side effects through various rating instruments likely will become of greater importance to clinicians in the next decade.


An experimental approach for systematic identification of antisense transcripts.
Extract: Natural antisense transcripts are endogenous transcripts that contain sequences that are complementary to other transcripts. Such complementary transcripts may be transcribed from opposing DNA strands at the same genomic locus (cis), or from different loci (trans), for example, pseudogenes. Notably, both types of antisense RNAs are genome-encoded and transcribed by DNA-directed RNA polymerases. A third putative source of antisense RNAs is transcription of the sense mRNA by an RNA-dependent RNA polymerase. Although only a few examples have been studied in detail, a significant number of naturally occurring antisense RNAs have been described in most eukaryotes, including mammals. Recent advances in bioinformatics have predicted as many as 2,500 mammalian cis-natural antisense transcripts. In one study, >2,600 human antisense transcripts were identified, of which >1600 were predicted to be true. 8% of the estimated 40,000 human genes were believed to have an antisense partner. Thus, it is likely that gene regulation by antisense transcription might be a common phenomenon in eukaryotic cells.


Multiple oscillators are causing parkinsonian and essential tremor.
The tremors of Parkinson's disease (PD) and essential tremor (ET) are traditionally considered to depend on a central oscillator producing rhythmic activation of the motoneurones of all extremities. To test this hypothesis, we have compared electromyographic tremor activity in different muscles of the affected limbs using cross spectral analysis, including coherence and phase. Surface electromyographic recordings from both arms, legs, and the neck were analyzed in 22 patients with PD and 28 patients with ET. Volume conduction between neighboring muscles producing artificial "coherence" has been found to be an important methodologic problem. We have developed a mathematical test to exclude data that could distort the results. According to this test, 10% or 25% of muscle combinations from the same limb had to be excluded from further analysis in PD or ET, respectively. In both, patients with PD and ET, we found a considerable number of muscle combinations oscillating at virtually the same frequency (delta frequency <0.4 Hz) without showing a significant coherence. Thus, the frequency difference between different muscles is not sufficient to measure the correlation between two muscles. Significant coherencies between muscles within the same arm or leg were found in 70% or 90% of patients with PD or ET, respectively, whereas only one patient with PD and not a single patient with ET showed significant coherencies between muscles from different limbs. The phase between coherent muscles of the same arm of patients with PD showed a preference of either a reciprocal alternating pattern for antagonistic muscles in forearm flexor and upper arm extensor as opposed to a co-contraction pattern between the hand flexors and the triceps brachii. In patients with ET such clear differences were lacking. We conclude that multiple oscillators are responsible for the tremor in different extremities of patients with PD and ET. Differences between PD and ET concerning the phase relation within the arm may either be related to the topography within the basal ganglia or to differently involved-spinal pathways.


Genetic Regulation of Development in Sorghum bicolor: V. The ma(3) Allele Results in Gibberellin Enrichment.
Sorghum bicolor genotypes, near isogenic with different alleles at the third maturity locus, were compared for development, for responsiveness to GA(3) and a GA synthesis inhibitor, and occurrence and concentrations of endogenous GAs, IAA, and ABA. At 14 days the genotype 58M (ma(3) (R)ma(3) (R)) exhibited 2.5-fold greater culm height, 1.75-fold greater total height, and 1.38-fold greater dry weight than 90M (ma(3)ma(3)) or 100M (Ma(3)Ma(3)). All three genotypes exhibited similar shoot elongation in response to GA(3), and 58M showed GA(3)-mediated hastening of floral initiation when harvested at day 18 or 21. Both 90M and 100M had exhibited hastening of floral initiation by GA(3) previously, at later application dates. Tetcyclacis reduced height, promoted tillering, and delayed flowering of 58M resulting in plants which were near phenocopies of 90M and 100M. Based on bioassay activity, HPLC retention times, cochromatography with (2)H(2)-labeled standards on capillary column GC and matching mass spectrometer fragmentation patterns (ions [m/z] and relative abundances), GA(1), GA(19), GA(20), GA(53), and GA(3) were identified in extracts of all three genotypes. In addition, based on published Kovats retention index values and correspondence in ion masses and relative abundances, GA(44) and GA(17) were detected. Quantitation was based on recovery of coinjected, (2)H(2)-labeled standards. In 14 day-old-plants, total GA-like bioactivity and GA(1) concentrations (nanograms GA/gram dry weight) were two- to six-fold higher in 58M than 90M and 100M in leaf blades, apex samples, and whole plants while concentrations in culms were similar. Similar trends occurred if data were expressed on a per plant basis. GA(1) concentrations for whole plants were about two-fold higher in 58M than 90M and 100M from day 7 to day 14. Concentrations of ABA and IAA did not vary between the genotypes. The results indicate the mutant allele ma(3) (R) causes a two- to six-fold increase in GA(1) concentrations, does not result in a GA-receptor or transduction mutation and is associated with phenotypic characteristics that can be enhanced by GA(3) and reduced by GA synthesis inhibitor. These observations support the hypothesis that the allele ma(3) (R) causes an overproduction of GAs which results in altered leaf morphology, reduced tillering, earlier flowering, and other phenotypic differences between 58M and 90M or 100M.


Gender interactions and success.
Does gender by itself, or does gender's interaction with career variables, better explain the difference between women and men's careers in healthcare management? US healthcare managers were surveyed regarding career and personal experiences. Gender was statistically interacted with explanatory variables. Multiple regression with backwards selection systematically removed non-significant variables. All gender interaction variables were non-significant. Much of the literature proposes that work and career factors impact working women differently than working men. We find that while gender alone is a significant predictor of income, it does not significantly interact with other career variables.


Efficacy and safety of traditional Chinese medicine decoction in the treatment of adolescent myopia: A protocol for systematic review and network meta-analysis.
Adolescent myopia has become a major public health problem in Asian countries and even the world. Due to its unstable prognosis and numerous complications, it has caused serious social and economic burden. As a common treatment in Asia, Chinese medicine has been shown to be effective in controlling the development of myopia, but its evidence-based medical evidence is not sufficient. Therefore, the purpose of this study is to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in the treatment of adolescent myopia through network meta-analysis, and to provide evidence for clinical and scientific research. We searched seven databases for randomized controlled trials of TCM decoction for adolescent myopia, including PubMed, the Cochrane Library, EMbase, China National Knowledge Infrastructure, China Biological Medicine, Chinese Scientific Journals Database, and wan-fang databases, from the date of the establishment of each database to January 31, 2022. The network meta-analysis will be implemented through Aggregate Data Drug Information System 1.16.8 and Stata 13.0 software. Primary outcomes include distant vision, intraocular pressure, and diopter. Mean differences or odds ratios will be used for statistical analysis. We will ensure the reliability of the results through node-split model and heterogeneity analysis. In addition, the Cochrane Collaboration's tool and Grading of Recommendations Assessment, Development and Evaluation system will be used for the methodological quality and the evidence quality. This study will provide reliable evidence for the clinical selection of TCM decoction in the treatment of adolescent myopia. The results of this study will evaluate the efficacy and safety of TCM decoction in the treatment of adolescent myopia, and provide decision-making references for future clinical and scientific research. This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal. DOI 10.17605/OSF.IO/VXQUP.


RLTPR Q575E: A novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy caused by long-term infection with human T-cell leukemia virus type-1 (HTLV-1). While ATL pathogenesis has been associated with HTLV-1-derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined. To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL. We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11-0.68). Despite being reported in cutaneous T-cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF-κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-κB activity and significantly increased IL-2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax. We identified, and functionally validated, a novel gain-of-function mutation in patients with aggressive ATL. During TCR activation by Tax or gain-of-function mutations, RLTPR Q575E selectively upregulates NF-κB signaling and may exert oncogenic effects on ATL pathogenesis.


Orthostatic blood pressure changes and arterial baroreflex sensitivity in elderly subjects.
orthostatic hypotension in elderly people is often attributed to diminished afferent baroreflex sensitivity, but this has not been demonstrated. We examined the hypothesis that postural change in blood pressure is related to baroreflex sensitivity, independent of the confounding effect of baseline blood pressure. we studied 25 active, untreated elderly subjects free of postural symptoms (mean age 70 +/- 1 years): 16 with hypertension (clinic blood pressure 194 +/- 6/98 + 3 mmHg) and nine normotensive controls (clinic blood pressure 134 + 3/77 + 3 mmHg). We assessed baroreflex sensitivity from the heart rate and blood pressure responses to the Valsalva manoeuvre and a pressor and depressor stimulus (bolus phenylephrine injection or sodium nitroprusside infusion respectively). Subjects were then passively tilted to 60 degrees and maximum changes in systolic blood pressure, heart rate, forearm blood flow and forearm vascular resistance recorded. maximum change in systolic blood pressure with head-up tilt was correlated with supine systolic blood pressure (r = 0.60, P = 0.001). Maximum change in systolic blood pressure with orthostasis was greater in the hypertensive subjects (45 +/- 4 mmHg versus 29 +/- 6, P = 0.04) and the heart rate increment was less (16 +/- 2 bpm versus 24 +/- 4, P = 0.02). The increase in forearm vascular resistance with tilt was similar in the two groups (47 +/- 11 versus 38 +/- 7 units, P = 0.52). All three methods of assessing baroreflex sensitivity showed a reduction in the hypertensive subjects (all P < or = 0.02). Lower values of baroreflex sensitivity were related to greater falls in systolic blood pressure with tilt, after adjustment for the baseline level of systolic blood pressure. we found a relationship between baroreflex sensitivity and the systolic blood pressure fall with orthostasis, even after adjustment for prevailing systolic blood pressure. Despite equivalent changes in forearm vascular resistance with tilt, greater falls in systolic blood pressure were seen in hypertensive subjects than in normotensive controls, due in part to an inadequate baroreflex-mediated heart rate response. The postural fall in blood pressure often observed in elderly hypertensive subjects may be related to the reduced baroreflex sensitivity seen in this condition.


Use of Antipsychotics Pre- and Post-Dissemination of CATIE Data.
We investigated the share of branded and generic antipsychotics before and after the publication of the CATIE results in September, 2005. According to our data, the publication of the CATIE results has had very little impact on new patient starts. To determine the impact of CATIE on use of olanzapine (Zyprexa((R))) subsequent to first line therapy, we also examined product share for switch/add patients. We found that since the publication of the CATIE results, the use of olanzapine has stabilized, following a decline subsequent to first line therapy, and may potentially be growing very slowly. An expert commentary is provided on the data.


Histamine-1 receptors do no directly modulate canine gastric acid secretion.
The role of histamine-1 receptors in modulating gastric acid secretion was evaluated in anesthetized dogs with gastric fistulas. Histamine receptor agonists were infused directly into the gastric artery supplying the fundus to avoid any systemic hemodynamic effects. Two experimental approaches were taken to try to determine whether histamine-1 receptors participate in the control of acid secretion. Firstly, we measured the effect of H1-receptor antagonist, hydroxyzine dihydrochloride, on histamine and dimaprit stimulated acid secretion. Secondly, we measured the effect of H1-receptor agonist on dimaprit stimulated gastric secretion. Although H1-receptor antagonist enhanced stimulated gastric acid secretion to histamine, the antagonist also enhanced stimulated gastric acid secretion to dimaprit (H2-agonist), suggesting that the enhanced gastric acid secretion after administration of H1-receptor antagonist is not because of the inhibition of histamine receptor at the gastric fundus. In addition, two doses of H1-receptor agonist infused into the gastric fundus had no effect on dimaprit stimulated gastric acid secretion. These data suggest that H1-receptors do not modulate gastric acid secretion at the level of the gastric fundus in the dog.


The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia.
The birth incidence of neural tube defect (NTD) cases in British Columbia (B.C.), and elsewhere in North America, is reported to be declining. This decline is being attributed to folic acid (FA) supplementation and food fortification, but 2nd trimester prenatal screening of pregnancies for NTDs and other congenital anomalies has increased during this timeframe, as well. This descriptive, population-based study evaluates the impact of prenatal screening of NTD-affected pregnancies on (1) pregnancy outcome and (2) reporting of NTD births to the provincial Health Status Registry (B.C.H.S.R.); and it assesses (3) the use of periconceptional FA supplementation. NTD cases were ascertained from medical records of health centres providing care to families with NTD-affected pregnancies and newborns; and from NTD cases reported to the B.C.H.S.R. In 1997-1999, the B.C.H.S.R. published a NTD incidence of 0.77/1000. In this study, 151 NTD-affected pregnancies were identified, with an incidence of 1.16/1000. Partial Reporting of induced abortions in a NTD incidence 45.5% low than the actual incidence. Medical records were available for review on 144/151 pregnancies. Prenatal screening identified 86.1% (124/144) of NTD-affected pregnancies, with 72.6% (90/124) resulting in pregnancy termination, and 27.4% (34/124) continuing to term. Use of FA supplementation in the periconceptional period was recorded in 36.4% of pregnancies (39/107). Thus in B.C. the decline in the NTD incidence is due predominantly to pregnancy terminations following prenatal diagnosis, which reduces the NTD incidence by 60%, from 1.16/1000 to 0.47/1000. Continued efforts for primary and the option of secondary prevention of NTDs are recommended in order to improve newborn health in B.C. and elsewhere. These interventions need to be monitored, however, for optimal health care planning.


Oncocytic Variant of Medullary Thyroid Carcinoma - A Case Report.
Medullary thyroid carcinoma (MTC) is a rare tumor arising from parafollicular C-cells. The oncocytic variant of MTC is an extremely rare diagnosis, with less than 20 cases reported. Here we present the case of a 36-year-old male patient with complaints of neck swelling and dysphagia. On fine needle aspiration cytology (FNAC), a Hürthle cell neoplasm was suggested. Finally with histopathology and immunohistochemistry (IHC), a diagnosis of MTC oncocytic variant was established. This tumor can be easily misdiagnosed for any thyroid Hürthle cell lesions. An accurate diagnosis is important because MTC has different treatment protocols, and its oncocytic variant is expected to be associated with poorer patient survival. Thus, the oncocytic variant of MTC is a difficult diagnosis on FNAC. Histopathology and rel- evant IHC markers are necessary for a correct diagnosis.