Intraperitoneal enalapril ameliorates morphologic changes induced by hypertonic peritoneal dialysis solutions in rat peritoneum.
Peritoneal fibrosis (PF) is one of the most serious causes of technique failure in long-term peritoneal dialysis (PD). Although the mechanisms responsible for the genesis of PF are not well understood, angiotensin II is known to promote fibrosis and inflammation in various tissues and angiotensin converting enzyme inhibitors (ACEIs) have been shown to attenuate those effects. We previously showed that ACEIs have beneficial effects on peritoneal alterations induced by hypertonic (3.86% glucose) PD solutions. In the present study, we investigated the local effects of intraperitoneal (IP) enalapril on peritoneal alterations induced by 3.86% glucose PD solution in rats on chronic PD. One week after peritoneal catheter insertion, 23 non uremic male rats were randomly divided into two groups: group A (n = 11) received 20 mL 3.86% PD solution twice daily, and group B (n = 12) received 20 mL 3.86% PD solution containing 1 mg/L enalapril twice daily. After 4 weeks of such infusions, we measured net ultrafiltration (UF) volume and obtained samples of visceral peritoneum from the liver for thickness measurement. Net UF was significantly higher (6.6 +/- 0.2 mL vs. 5.6 +/- 0.2 mL) and peritoneal thickness was significantly lower (30 +/- 5 microm vs. 52 +/- 0.8 microm) in group B. We conclude that intraperitoneal enalapril (an ACEI) protects the peritoneal membrane from the effects of hypertonic glucose. This protection might be mediated by enalapril's interference with angiotensin though inhibition of cytokine overexpression.


Anomalous structure and dynamics of the Gaussian-core fluid.
It is known that there are thermodynamic states for which the Gaussian-core fluid displays anomalous properties such as expansion upon isobaric cooling (density anomaly) and increased single-particle mobility upon isothermal compression (self-diffusivity anomaly). Here, we investigate how temperature and density affect its short-range translational structural order, as characterized by the two-body excess entropy. We find that there is a wide range of conditions for which the short-range translational order of the Gaussian-core fluid decreases upon isothermal compression (structural order anomaly). As we show, the origin of the structural anomaly is qualitatively similar to that of other anomalous fluids (e.g., water or colloids with short-range attractions) and is connected to how compression affects static correlations at different length scales. Interestingly, we find that the self-diffusivity of the Gaussian-core fluid obeys a scaling relationship with the two-body excess entropy that is very similar to the one observed for a variety of simple liquids. One consequence of this relationship is that the state points for which structural, self-diffusivity, and density anomalies of the Gaussian-core fluid occur appear as cascading regions on the temperature-density plane; a phenomenon observed earlier for models of waterlike fluids. There are, however, key differences between the anomalies of Gaussian-core and waterlike fluids, and we discuss how those can be qualitatively understood by considering the respective interparticle potentials of these models. Finally, we note that the self-diffusivity of the Gaussian-core fluid obeys different scaling laws depending on whether the two-body or total excess entropy is considered. This finding, which deserves more comprehensive future study, appears to underscore the significance of higher-body correlations for the behavior of fluids with bounded interactions.


Chemical composition and antifungal activity of Matricaria recutita flower essential oil against medically important dermatophytes and soil-borne pathogens.
Fungal infections are potential public health threats all over the world. In the present study, effect of Matricaria recutita flower essential oil (EO) was evaluated against medically important dermatophytes and opportunistic saprophytes using microbioassay technique. Flower essential oil (EO) of M. recutita prepared by hydrodistillation was analyzed by gas chromatography/mass spectrometry (GC/MS). The effect of plant EO on the growth of pathogenic dermatophytes and opportunistic saprophytes was assessed using microbioassay technique. In the bioassay, fungi were cultured in 6-well flat-bottom microplates in presence of various concentrations of plant EO (2.5-1000μg/mL) for 4-10days at 28°C. A total of 14 compounds were identified in the plant oil by GC/MS accounting for 97.5% of the oil composition. The main compound identified was chamazulene (61.3%) followed by isopropyl hexadecanoate (12.7%), trans-trans-farnesol (6.9%) and E-β-farnesol (5.2%). Growth inhibition for the dermatophytes exposed to serial two-fold concentrations of plant EO (2.5 to 80μg/mL) was reported in the range of 3.24 to 68.15% for Microsporum gypseum, 24.48 to 100% for M. canis, 11.40 to 96.65% for Trichophyton mentagrophytes, 27.79 to 100% for T. rubrum and 45.73 to 100% for T. tonsurans. M. recutita EO inhibited the growth of opportunistic saprophytes by 3.98 to 64.29% for Aspergillus flavus, 6.38 to 93.62% for A. fumigatus, 3.52 to 89.45% for A. niger, 6.38 to 77.66% for Trichoderma harzianum and 17.41 to 89.41% for Fusarium oxysporum in serial two-fold concentrations of 15.62 to 1000μg/mL. Results of the present study indicate that M. recutita could be considered as a potential candidate for designing effective antifungal formulations suitable for treatment of dermatophytosis and other fungal infections.


Risk prediction models for patients with chronic kidney disease: a systematic review.
Patients with chronic kidney disease (CKD) are at increased risk for kidney failure, cardiovascular events, and all-cause mortality. Accurate models are needed to predict the individual risk for these outcomes. To systematically review risk prediction models for kidney failure, cardiovascular events, and death in patients with CKD. MEDLINE search of English-language articles published from 1966 to November 2012. Cohort studies that examined adults with any stage of CKD who were not receiving dialysis and had not had a transplant; had at least 1 year of follow-up; and reported on a model that predicted the risk for kidney failure, cardiovascular events, or all-cause mortality. Reviewers extracted data on study design, population characteristics, modeling methods, metrics of model performance, risk of bias, and clinical usefulness. Thirteen studies describing 23 models were found. Eight studies (11 models) involved kidney failure, 5 studies (6 models) involved all-cause mortality, and 3 studies (6 models) involved cardiovascular events. Measures of estimated glomerular filtration rate or serum creatinine level were included in 10 studies (17 models), and measures of proteinuria were included in 9 studies (15 models). Only 2 studies (4 models) met the criteria for clinical usefulness, of which 1 study (3 models) presented reclassification indices with clinically useful risk categories. A validated risk-of-bias tool and comparisons of the performance of different models in the same validation population were lacking. Accurate, externally validated models for predicting risk for kidney failure in patients with CKD are available and ready for clinical testing. Further development of models for cardiovascular events and all-cause mortality is needed. None.


Alternating Thalamic Deep Brain Stimulation for Essential Tremor: A Trial to Reduce Habituation.
DBS in the ventral intermediate nucleus (VIM) of the thalamus has been a revolutionary treatment for patients with essential tremor (ET) by reducing tremor. Unfortunately, some patients develop habituation to DBS and thus experience reduced efficacy and loss of tremor control. There are no standardized methods of addressing habituation to DBS. We propose alternating stimulation patterns as a way to reduce habituation. This was a randomized, placebo-controlled trial for patients with VIM DBS for ET. Patients were randomized to either experimental treatment arm of alternating stimulation patterns on a weekly basis or standard care arm of continuous stimulation settings for 12 weeks. Primary outcome was change in the performance subscale of The Essential Tremor Rating Assessment Scale (TETRAS), which was performed at initial visit and 12-week follow-up. Secondary outcome included change in the activities of daily living subscale of TETRAS. Twenty-two patients were enrolled in the trial, and 16 were analyzed at follow-up. Experimental treatment subjects displayed sustained tremor control compared to standard care, as measured by the change in TETRAS performance subscale (-0.6 vs. 6.7 point change, respectively) with a 7.3 difference between the arms (P = 0.006). Alternating stimulation patterns on a weekly basis for ET patients with VIM DBS reduced habituation in this pilot study. This study suggests that exposure to different stimulation groups may maintain better tremor control compared to constant stimulation parameters.


Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial.
Low dose oral vitamin K rapidly reverses warfarin-associated coagulopathy. Its effect in patients receiving acenocoumarol is uncertain. We compared the effect of withholding acenocoumarol and administering 1 mg oral vitamin K with simply withholding acenocoumarol in asymptomatic patients presenting with INR values between 4.5 and 10.0. The primary end-point of the study was the INR value on the day following randomisation. We found that patients receiving oral vitamin K had more sub-therapeutic INR levels than controls (36.6% and 13.3%, respectively; RR 1.83, 95% confidence interval 1.16, 2.89) and a lower, but non-significant, proportion of INR values in range (50% and 66.6%, respectively) on the day following randomisation. After 5 +/- 1 days, there were more patients with an INR value in range in the vitamin K group than in controls (74.1% and 44.8%, respectively). There were no clinical events during 1 month follow-up. We conclude that the omission of a single dose of acenocoumarol is associated with an effective reduction of the INR in asymptomatic patients presenting with an INR value of 4.5 to 10.0. Furthermore, the use of a 1 mg dose of oral vitamin K results in an excessive risk of over-reversal of the INR.


Improving handover between the transport team and neonatal intensive care unit staff in neonatal transports using the plan-do-study-act tool.
The aim was to achieve 100% effective handover from the critical care transport team to the neonatal intensive care unit (NICU) medical team. All patients transferred from referring hospitals by the critical care transport team to the Level IV NICU were included. Data for each infant was collected prospectively. The percentage of transported patients for which medical team and nursing handover occurred was recorded. A quality improvement project was launched using the Plan-Do-Study-Act (PDSA) tool. We implemented several processes including call from the transport team before arrival and the completion of a transfer of care form on arrival to the NICU. The process measures and the outcome measure of completion of handover were monitored. Run charts of process measures and the outcome measure were analyzed. Completion of medical handover increased from 95% (baseline) to 100% after 3 PDSA cycles and this has been maintained for 18 consecutive months. Medical handover from the critical care transport team to the NICU medical staff has been achieved and sustained for all neonatal transports.


Effect of caffeine consumption on tissue oxygen levels during hyperbaric oxygen treatment.
Ten men were exposed to hyperbaric oxygen (HBO2), and their tissue oxygen levels were monitored after they drank either placebo or caffeine beverages. Transcutaneous tissue oxygen (PtcO2) monitor measurements in a normobaric air environment were initially obtained from transducers on the subject's chest and foot. The subjects then consumed either the caffeine (3 mg.kg-1) or the placebo beverage, and after 20 min the subjects were pressurized in a hyperbaric chamber to 2.36 atm abs (1 atm = 101.3250 kPa). The test subjects began breathing 100% oxygen at 2.36 atm abs, 30 min after administration of the experimental beverage, and continued for 30 min, after which the final chest and foot PtcO2 measurements were recorded (1 h after ingestion of the test drink). Each subject underwent a second hyperbaric exposure during which the alternate drink was administered (either the placebo or the caffeine), and PtcO2 measurements were again obtained. The increase in right foot PtcO2 values during HBO2 exposure was significantly smaller after caffeine consumption than after placebo (P = 0.0018).


Effects of metformin and ethinyl estradiol-cyproterone acetate on clinical, endocrine and metabolic factors in women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a major endocrine abnormality that affects women of reproductive age. Oral contraceptive pills are usually the first choice of treatment for PCOS when fertility is not desired. Metformin, an insulin-sensitizing drug, has been shown to improve such metabolic abnormality. Aim. To compare the effects of a contraceptive pill in combination with metformin on the clinical, endocrine and metabolic parameters in obese and non-obese patients with PCOS. Sixty PCOS patients (25 obese, 35 non-obese) were enrolled in this prospective clinical study. PCOS was defined according to the Rotterdam criteria. Patients were randomized to oral treatment with Diane35 (35 microg ethinyl estradiol plus 2 mg cyproterone acetate), metformin or a combination of Diane35/metformin for 3 months. Body mass index (BMI), waist-to-hip ratio (WHR), Ferriman-Gallwey (FG) score, leuteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, fasting insulin and glucose/insulin ratio were measured at baseline and at the end of treatment. Diane35 resulted in a higher reduction of FG score in both obese and non-obese PCOS patients compared with metformin. Menstrual regularity was restored in all PCOS patients treated with Diane35 compared with only 28% of those receiving metformin. Metformin significantly decreased BMI and WHR in obese patients (p < 0.05). Testosterone levels decreased in all three groups. LH levels and LH/FSH ratio decreased with Diane35 and Diane35/metformin in both obese and non-obese patients. Metformin significantly decreased fasting insulin concentrations (p < 0.05 and p < 0.01) and increased the insulin sensitivity (p < 0.05) in both obese and non-obese PCOS patients, while no significant changes were observed in the Diane35 group. In addition, insulin levels also decreased (p < 0.05) in the Diane35/metformin group. Our data show that a combination of metformin and contraceptive pill may be more effective in suppressing the hyperandrogenemia of obese and non-obese PCOS patients than metformin alone and may reduce insulin levels more than contraceptive pill alone. Hence, combined treatment may become a more effective therapeutic option for PCOS.


RhBMP-2 loaded MBG/PEGylated poly(glycerol sebacate) composite scaffolds for rapid bone regeneration.
With the worldwide rising need of severe bone defect treatment, the development of available bone substitutes with optimal mechanical strength, sustained drug release, cell affinity and osteoinductivity remains a great challenge. In this study, an rhBMP-2 loaded polymer-coated mesoporous bioactive glass (MBG) composite scaffold was developed. The uncrosslinked poly(glycerol sebacate) (PGS) or PEGylated PGS (PEGS) coating modification had enhanced the mechanical strength of the composite scaffold, solved the brittleness problem of the MBG matrix, increased the cell affinity of the material surface, and diminished the initial burst release of rhBMP-2 from mesopores of MBG. The results indicated that the PGS coating promoted the proliferation of rat bone marrow stem cells (rBMSCs), while the PEGS coating exhibited an enhancement in the osteogenic differentiation of rBMSCs. The in vivo ectopic bone formation results provide strong evidence that the rhBMP-2-loaded MBG/PEGS composite scaffolds exhibited a rapid bone forming capacity and might yield extraordinary achievements in the field of bone tissue engineering. The design considerations can be extended to other artificial scaffolds and are expected to provide new thoughts on the development of future tissue engineering materials.


Assessing the molluscan hypothesis Serialia (Monoplacophora+Polyplacophora) using novel molecular data.
A consensus on molluscan relationships has yet to be achieved, largely because of conflicting morphological and molecular hypotheses. Monoplacophora show marked seriality of ctenidia, atria, muscles and nephridia and this has been interpreted as plesiomorphic for Mollusca, reflecting a segmented ancestry. More recently this seriality, also partly seen in Polyplacophora, has been seen as a derived condition. Analysis of the first published monoplacophoran DNA sequence from Laevilipilina antarctica Warén & Hain, 1992 [Giribet, G., Okusu, A., Lindgren, A.R., Huff, S., Schrödl, M., Nishiguchi, M.K., 2006. Evidence for a clade composed of molluscs with serially repeated structures: Monoplacophorans are related to chitons. Proc. Natl. Acad. Sci. USA 103, 7723-7728. 10.1073/pnas.0602578103], showed Monoplacophora inside Polyplacophora. These taxa were then grouped under the name Serialia, reflecting the hypothesis that their seriality is a synapomorphy. Subsequent examination revealed that part of the L. antarctica published sequence was the result of contamination with Polyplacophora (Giribet, Supplementary Material S1). We collected and sequenced another monoplacophoran, Laevipilina hyalina McLean, 1979, resulting in the first multi-gene dataset representing all molluscan classes. Our analyses did not show unambiguous support for Serialia. Model-based approaches strongly supported Serialia as a clade, however, parsimony analyses under dynamic and static homology did not resolve the position of Monoplacophora. Although our study provides support for Serialia and none for Conchifera, it appears that further resolution of molluscan relationships will require large increases of data.


Effectiveness of Masks and Respirators Against Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis quantified the protective effect of facemasks and respirators against respiratory infections among healthcare workers. Relevant articles were retrieved from Pubmed, EMBASE, and Web of Science. Meta-analyses were conducted to calculate pooled estimates. Meta-analysis of randomized controlled trials (RCTs) indicated a protective effect of masks and respirators against clinical respiratory illness (CRI) (risk ratio [RR] = 0.59; 95% confidence interval [CI]:0.46-0.77) and influenza-like illness (ILI) (RR = 0.34; 95% CI:0.14-0.82). Compared to masks, N95 respirators conferred superior protection against CRI (RR = 0.47; 95% CI: 0.36-0.62) and laboratory-confirmed bacterial (RR = 0.46; 95% CI: 0.34-0.62), but not viral infections or ILI. Meta-analysis of observational studies provided evidence of a protective effect of masks (OR = 0.13; 95% CI: 0.03-0.62) and respirators (OR = 0.12; 95% CI: 0.06-0.26) against severe acute respiratory syndrome (SARS). This systematic review and meta-analysis supports the use of respiratory protection. However, the existing evidence is sparse and findings are inconsistent within and across studies. Multicentre RCTs with standardized protocols conducted outside epidemic periods would help to clarify the circumstances under which the use of masks or respirators is most warranted.


Role of the zebrafish trilobite locus in gastrulation movements of convergence and extension.
Convergence and extension are gastrulation movements that participate in the establishment of the vertebrate body plan. Using new methods for quantifying convergence and extension movements of cell groups, we demonstrate that in wild-type embryos, dorsal convergence of lateral cells is initially slow, but speeds up between the end of the gastrula period and early segmentation. Convergence and extension movements of lateral cells in trilobite mutants are normal during the gastrula period but reduced by early segmentation. Morphometric studies revealed that during epiboly wild-type gastrulae become ovoid, whereas trilobite embryos remain rounder. By segmentation, trilobite embryos exhibit shorter, broader embryonic axes. The timing of these morphological defects correlates well with impaired cell movements, suggesting reduced convergence and extension are the main defects underlying the trilobite phenotype. Our gene expression, genetic, and fate mapping analyses show the trilobite mutation affects movements without altering dorsoventral patterning or cell fates. We propose that trilobite function is required for cell properties that promote increased speed of converging cells and extension movements in the dorsal regions of the zebrafish gastrula.


[Serum total cholesterol levels and eligibility for long-term care insurance: a prospective cohort study of the Tsurugaya project].
The purpose of this study was to examine the relationship between serum total cholesterol levels and certification eligibility for long-term care insurance in elderly Japanese individuals. The Tsurugaya Project was a comprehensive geriatric assessment conducted for community-dwelling elderly individuals aged ≥70 years in the Tsurugaya area, Sendai, Japan. Of the 2,925 inhabitants, 958 subjects participated in the Tsurugaya Project. For this analysis, we used 827 subjects who gave informed consent and were not qualified for long-term care insurance at the time of the baseline survey. Subjects were followed up for 6 years. We classified the subjects into 4 quintiles and used the fourth quintile (212-230 mg/dL) as a reference for statistical analysis. We used Cox proportional hazards model to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of certification eligibility for long-term care insurance according to total cholesterol levels in serum. During 6 years of follow-up, a total of 214 subjects were qualified for long-term care insurance certification. The lowest serum total cholesterol level (<177 mg/dL) was significantly associated with increased eligibility for long-term care insurance certification. Compared with the fourth quintile, multivariate HRs (95%CIs) of long-term care insurance certification were 1.91 (1.23-2.98), 1.36 (0.85-2.18), 0.99 (0.62-1.56), 1.38 (0.88-2.17), for <177 mg/dL, 177-194 mg/dL, 195-211 mg/dL, and ≤231 mg/dL, respectively. Moreover, the association was statistically significant even after excluding subjects with a history of liver disease or cancer, an abnormality in the liver function test, or high levels of high-sensitivity C-reactive protein. Low serum total cholesterol levels were significantly associated with increased eligibility for long-term care insurance certification even after adjusting for a variety of confounding factors.


Does the computerized display of charges affect inpatient ancillary test utilization?
The computerized display of charges for ancillary tests in outpatients has been found to affect physician-ordering behavior, but this issue has not been studied in inpatients. To assess whether the computerized display of charges for clinical laboratory or radiological tests affected physician-ordering behavior. Two prospective controlled trials, randomized by patient, were performed. Each trial included all medical and surgical inpatients at 1 large teaching hospital during 4 and 7 months: 3536 intervention and 3554 control inpatients in the group with clinical laboratory tests, and 8728 intervention and 8653 control inpatients in the group with radiological tests. The intervention consisted of the computerized display of charges for tests at the time of ordering. The number of clinical laboratory and radiological tests ordered per admission and the charges for these tests. For the clinical laboratory tests, during a 4-month study period, patients in the intervention group had 4.5% fewer tests ordered, and the total charges for these tests were 4.2% lower, although neither difference was statistically significant. Compared with historical controls from the same 4-month period a year before, the charges for the tests per admission had decreased 13.3%, but the decrease was temporally correlated with a restriction of future ordering of tests, and not with the introduction of the display of charges. For the radiological tests, during a 7-month period, the intervention group had almost identical numbers of tests ordered and charges for these tests. The computerized display of charges had no statistically significant effect on the number of clinical laboratory tests or radiological procedures ordered or performed, although small trends were present for clinical laboratory tests. More intensive interventions may be needed to affect physician test utilization.


shaven and sparkling are mutations in separate enhancers of the Drosophila Pax2 homolog.
We have previously shown that the sparkling gene, which like mammalian Pax2 plays an important role in eye development, is encoded by the Drosophila homolog of Pax2. Here we demonstrate that D-Pax2 also encodes the shaven function, which is crucial during bristle development. Both sv and spa alleles, previously thought to represent different genes, are mutations in two widely separated enhancers of D-Pax2. The sv function of D-Pax2 acts in at least two distinct steps of mechanosensory bristle development: the specification of the alternative fate of shaft as opposed to socket cell, and later the differentiation of the shaft cell.


Safety of amphotericin B colloidal dispersion.
The safety of amphotericin B colloidal dispersion (ABCD) was tested in five open-label Phase I/II clinical trials in 572 selected patients who had a fungal infection secondary to a severe underlying disease. In 442 cases ABCD was administered after therapy with amphotericin B, which had been withdrawn in 192 of them because of toxicity. One hundred and forty patients had pre-existing nephrotoxicity. ABCD doses of up to 6 mg/kg/day resulted in no differences in serum creatinine levels, even in patients with pre-existing renal failure. ABCD therapy resulted in no difference in liver function as measured by SGOT, alkaline phosphatase and total bilirubin levels in serum. Apart from thrombocytopenia, there was no significant alteration in hematological or other biochemical parameters in the blood. Adverse events attributable to ABCD requiring discontinuation of therapy occurred in 70 patients (12.2%). The most frequent of these were infusion-related adverse events, which occurred in 5.4% of patients. As a consequence, the maximum tolerated dose was set at 7.5 mg/kg/day. These studies show clearly that ABCD can be administered safely to patients without the risk of renal toxicity, even when renal impairment has already developed following therapy with conventional amphotericin B deoxycholate.


GATA-3 regulates the development and function of invariant NKT cells.
Although invariant NKT (iNKT) cells participate in many aspects of immune responses, the molecular mechanisms regulating their development, maturation, and activation are still poorly understood. GATA-3 is a T cell-specific transcription factor that is also expressed in iNKT cells. The critical role of GATA-3 in conventional alphabeta T cells has been well documented, but whether GATA-3 also regulates the development and function of iNKT cells is unknown. In the present study, we report that deficiency of GATA-3 results in cell-intrinsic defects in the thymic development and peripheral maturation of murine iNKT cells. In addition, GATA-3 is also required for survival, activation, and effector functions of this unique population of T cells. Our data also reveal a previously unidentified peripheral maturation step that is GATA-3 dependent.


Pituicytoma (pilocytic astrocytoma). Case report.
Tumors of the posterior pituitary are rare and the previous nomenclature has been confusing. A 40-year-old man presented with visual failure and disconnection hyperprolactinemia (830 mU/liter) due to a large invasive pituitary tumor shown to be a pituicytoma (pilocytic astrocytoma). Its astrocytic nature was confirmed by positive immunostaining for glial fibrillary acidic protein and the finding of cytoplasmic filaments on electron microscopy. This case report contains the pathological description of a pituicytoma and illustrates that a non-adenomatous pituitary lesion may masquerade as a pituitary adenoma. Large pituitary lesions associated with serum prolactin concentrations of less than 3000 mU/liter require early surgical biopsy.


The Arabidopsis thaliana natriuretic peptide AtPNP-A is a systemic regulator of leaf dark respiration and signals via the phloem.
Plant natriuretic peptides (PNPs) belong to a novel class of peptidic signaling molecules that share some structural similarity to the N-terminal domain of expansins and affect physiological processes such as water and ion homeostasis at nano-molar concentrations. Here we show that a recombinant Arabidopsis thaliana PNP (AtPNP-A) rapidly increased the rate of dark respiration in treated leaves after 5 min. In addition, we observed increases in lower leaves, and with a lag time of 10 min, the effect spread to the upper leaves and subsequently (after 15 min) to the opposite leaves. This response signature is indicative of phloem mobility of the signal, a hypothesis that was further strengthened by the fact that cold girdling, which affects phloem but not xylem or apoplastic processes, delayed the long distance AtPNP-A effect. We conclude that locally applied AtPNP-A can induce a phloem-mobile signal that rapidly modifies plant homeostasis in distal parts.


Prognostic value of vascular endothelial growth factor and hypoxia-inducible factor 1α in canine malignant mammary tumors.
Mammary tumors are the most common type of tumor in dogs, with approximately half of these tumors being malignant. Hypoxia, characterized by oxygen levels below normal, is a known adverse factor to cancer treatment. The hypoxia-inducible factor 1α (HIF-1α) is a central regulator of the pathophysiological response of mammalian cells to low oxygen levels. HIF-1α activates the transcription of vascular endothelial growth factor (VEGF), which in turn promotes angiogenesis through its ability to stimulate the growth, migration and invasion of endothelial cells to form new blood vessels, contributing to tumor progression. In this study, we evaluated the serum concentration and gene expression of VEGF and HIF-1α linking them with clinicopathological parameters and survival of dogs with mammary tumors in order to infer the possible prognostic value of these factors. We collected blood and tumor fragments of 24 female dogs with malignant mammary tumors (study group) and 26 non-affected female dogs (control group) to verify the gene expression of VEGF and HIF-1α by quantitative real-time PCR (qPCR) and the serum levels by ELISA (enzyme-linked immunosorbent). The results showed high serum levels of VEGF in the study group and its correlation between abundant vascularization, lymph node involvement, metastasis, death rate and low survival (p<0.05). The serum percentage of HIF-1α in female dogs with mammary neoplasia was lower than that in the control group and higher in female dogs with tumor metastasis and history of tumor recurrence (p<0.05). Regarding gene expression, there was a gene overexpression of VEGFA in female dogs with poor outcome, in contrast to the gene underexpression of HIF-1A. Taken together, these results suggested that VEGF is important in tumor progression and can be used as a potential prognostic marker in the clinic and may be useful in predicting tumor progression in dogs with mammary neoplasia.


Neuropsychological differences between first-admission schizophrenia and psychotic affective disorders.
The study compared the neuropsychological functioning of patients with first-admission schizophrenia with that of patients with first-admission psychotic affective disorders. Data came from the Suffolk County Mental Health Project, an epidemiological study of first-admission psychotic disorders. Subjects with a diagnosis of schizophrenia (N=102) and psychotic affective disorders, including bipolar disorder with psychotic features (N=72) and major depressive disorder with psychotic features (N=49), were compared on a battery of neuropsychological tests administered 2 years after the index admission. Subjects with schizophrenia performed worse than those with the psychotic affective disorders, even after adjusting the results for differences in demographic characteristics and general intellectual functioning. The most consistent differences were on tests of attention, concentration, and mental tracking. The two psychotic affective disorder groups were indistinguishable in performance on the neuropsychological tests. Even early in its course, schizophrenia is distinguishable from psychotic affective disorders by global and specific neuropsychological deficits. These deficits might contribute to the disability and poor outcome associated with schizophrenia in the mid- and long-term course.


The 4F2hc surface antigen is necessary for expression of system L-like neutral amino acid-transport activity in C6-BU-1 rat glioma cells: evidence from expression studies in Xenopus laevis oocytes.
Mammalian cells possess a variety of amino acid-transport systems with overlapping substrate specificity. System L is one of the major amino acid-transport systems in all non-epithelial cells. Its molecular structure is not known. To clone the neutral amino acid-transporter system L, we followed an expression cloning strategy using Xenopus laevis oocytes. A cDNA library derived from C6-BU-1 rat glioma cells was used as a source, because high expression of system L activity could be demonstrated with polyadenylated RNA isolated from these cells, when injected into Xenopus laevis oocytes [Bröer, Bröer and Hamprecht (1994) Biochim. Biophys. Acta 1192, 95-100]. A single clone (ILAT) was identified, the sense cRNA of which, on injection into Xenopus laevis oocytes, stimulated sodium-independent isoleucine transport by about 100-fold. Further characterization revealed that transport of cationic amino acids was also stimulated. Sequencing of the cDNA showed that the identified clone is the heavy chain of the rat 4F2 surface antigen, a marker of tumour cells and activated lymphocytes. Uptake of neutral and cationic amino acids was not stimulated by the presence of Na+ ions. Antisense cRNA transcribed from this clone or antisense oligonucleotides, when co-injected with polyadenylated RNA from C6-BU-1 rat glioma cells, completely suppressed system L-like isoleucine-transport activity. We conclude that ILAT is necessary for expression of system L-like amino acid-transport activity by polyadenylated RNA from C6-BU-1 rat glioma cells.


Enzyme-instructed self-assembly with photo-responses for the photo-regulation of cancer cells.
Using a short peptide precursor modified by the biaryltetrazole with intramolecular photo-click reactivity, we realized the photo-regulation of the pericellular nanofibers formed by the enzyme-instructed self-assembly on the cell membrane. Upon light irradiation, the fluorescence of nanofibers could be turned on to monitor both enzyme-instructed self-assembly and photo-induced disassembly processes. Moreover, the cell fate could be controlled through the photo-regulation.


The Effect of Boron-Containing Nano-Hydroxyapatite on Bone Cells.
Metabolic diseases or injuries damage bone structure and self-renewal capacity. Trace elements and hydroxyapatite crystals are important in the development of biomaterials to support the renewal of bone extracellular matrix. In this study, it was assumed that the boron-loaded nanometer-sized hydroxyapatite composite supports the construction of extracellular matrix by controlled boron release in order to prevent its toxic effect. In this context, boron release from nanometer-sized hydroxyapatite was calculated by ICP-MS as in large proportion within 1 h and continuing release was provided at a constant low dose. The effect of the boron-containing nanometer-sized hydroxyapatite composite on the proliferation of SaOS-2 osteoblasts and human bone marrow-derived mesenchymal stem cells was evaluated by WST-1 and compared with the effects of nano-hydroxyapatite and boric acid. Boron increased proliferation of mesenchymal stem cells at high doses and exhibited different effects on osteoblastic cell proliferation. Boron-containing nano-hydroxyapatite composites increased osteogenic differentiation of mesenchymal stem cells by increasing alkaline phosphatase activity, when compared to nano-hydroxyapatite composite and boric acid. The molecular mechanism of effective dose of boron-containing hydroxyapatite has been assessed by transcriptomic analysis and shown to affect genes involved in Wnt, TGF-β, and response to stress signaling pathways when compared to nano-hydroxyapatite composite and boric acid. Finally, a safe osteoconductive dose range of boron-containing nano-hydroxyapatite composites for local repair of bone injuries and the molecular effect profile in the effective dose should be determined by further studies to validation of the regenerative therapeutic effect window.


Estimating the Evolution of Urban Mining Resources in Hong Kong, Up to the Year 2050.
Rapid urban metabolism is causing many resources to flow from consumption to waste. But many of these wastes could be secondary resources, and cities could become urban mines and an increasing supply of future resources. Hong Kong, one of the most developed and populated cities in the world, has demonstrated a completely metabolic evolution to be an urban mine, since the 1970s. Covering 14 types of e-waste and eight types of end-of-life vehicles, this study first investigates Hong Kong's evolution as an urban mine. The potential output weight of the urban mine quickly grew from 117 kt in 2000 to 368 kt in 2014, and it is estimated to remain in the range of 300-350 kt over the years 2015-2050, with 40-50 kg/cap/year. The economic potential of urban mining, for 18 metals, plastic, glass, and rubber tires, will be approximately US$2 billion annually, mainly contributed by precious and rare metals. All the obtained results contribute to Hong Kong's waste management and promise to have positive impact on urban mining and circular economy for other, less-developed cities or regions.


Complete genome sequence of Arthrobacter alpinus ERGS4:06, a yellow pigmented bacterium tolerant to cold and radiations isolated from Sikkim Himalaya.
Arthrobacter alpinus ERGS4:06, a yellow pigmented bacterium which exhibited tolerance to cold and UV radiations was isolated from the glacial stream of East Rathong glacier in Sikkim Himalaya. Here we report the 4.3Mb complete genome assembly that has provided the basis for potential role of pigments as a survival strategy to combat stressed environment of cold and high UV-radiation and additionally the ability to produce cold active industrial enzymes.


Association of aggression and non-suicidal self injury: a school-based sample of adolescents.
Non-suicidal self-injury (NSSI) in adolescent has drawn increasing attention because it is associated with subsequent depression, drug abuse, anxiety disorders, and suicide. In the present study, we aimed to estimate the prevalence of non-suicidal self-injury (NSSI) in a school-based sample of Chinese adolescents and to explore the association between aggression and NSSI. This study was part of a nationwide study on aggression among adolescents in urban areas of China. A sample of 2907 school students including 1436 boys and 1471 girls were randomly selected in Guangdong Province, with their age ranging from 10 to 18 years old. NSSI, aggression, emotional management and other factors were measured by self-administrated questionnaire. Multinomial logistic regression was used to estimate the association between aggression and NSSI, after adjustment for participants' emotional management, and other potential confounding variables. The one year self-reported prevalence of NSSI was 33.6%. Of them, 21.7% engaged in 'minor NSSI', 11.9% in 'moderate/severe NSSI'. 96.9% of self-injuries engaged in one to five different types of NSSI in the past year. Hostility, verbal and indirect aggression was significantly associated with self-reported NSSI after adjusting for other potential factors both in 'minor NSSI' and 'moderate/severe NSSI'. Hostility, verbal and indirect aggression was significantly associated with greater risk of 'minor NSSI' and 'moderate/severe NSSI' in those who had poor emotional management ability. These findings highlight a high prevalence of NSSI and indicate the importance of hostility, verbal and indirect aggression as potentially risk factor for NSSI among Chinese adolescents.


Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study.
Many investigators have suggested that malaria infection predisposes individuals to bacteraemia. We tested this hypothesis with mendelian randomisation studies of children with the malaria-protective phenotype of sickle-cell trait (HbAS). This study was done in a defined area around Kilifi District Hospital, Kilifi, Kenya. We did a matched case-control study to identify risk factors for invasive bacterial disease, in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16, 1999, and July 31, 2002. We aimed to match two controls, by age, sex, location, and time of recruitment, for every case. We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased. Cases were children aged 0-13 years who were admitted to hospital with bacteraemia between Jan 1, 1999, and Dec 31, 2007. Controls were born in the study area between Jan 1, 2006, and June 23, 2009. Finally, we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression. In the matched case-control study, we recruited 292 cases-we recruited two controls for 236, and one for the remaining 56. Sickle-cell disease, HIV, leucocyte haemozoin pigment, and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia (odds ratio 0·36; 95% CI 0·20-0·65). In the longitudinal case-control study, we assessed data from 1454 cases and 10,749 controls. During the study period, the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45, with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel (p=0·0008). The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45. The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 (95% CI 1·31-34·3) and, at a community parasite prevalence of 29% in 1999, 62% (8·2-91) of bacteraemia cases were attributable to malaria. Malaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas. Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease. Wellcome Trust.


[Nephrology: where we stand and where we should go].
In the last year, the Italian National Health Service as a whole and the Nephrology community have been severely challenged by the pandemic. It has been a dramatic stress test for the entire healthcare system, not only in Italy but worldwide. The general organization of our Nephrology units and our models of care were put under extreme pressure, and we had to quickly adopt unprecedented clinical practice recommendations and organizational models to overcome the impasse caused by the pandemic. The time has come to evaluate these new experiences, ask how we could have been better prepared and look for change. In this editorial, we outline a few proposals and suggestions for the future, weighing the information gathered in the 2018 Nephrology Census against the new organizational requirements imposed by the COVID-19 pandemic.


Mechanics and energetics of excavation by burrowing wolf spiders, Geolycosa spp.
Burrowing wolf spiders, Geolycosa sp. (Araneae:Lycosidae), excavate vertical burrows and inhabit them throughout their lives or, in the case of males, until they mature and wander in search of mates. Three species: G. fatifera Kurata, G. missouriensis Banks, and G. rogersi Wallace were studied to understand how and at what expense the burrowing is accomplished. Normal and high-speed videography coupled with scanning electron microscopy revealed (a) that the convex surfaces of the two fangs, together, constitute the digging tool, (b) that boluses of soil are transported to the burrow entrance on the anterior surfaces of the chelicerae held there by the pedipalps, and (c) that each bolus is either incorporated into the growing turret or flung away, propelled by the forelegs. To elucidate the energetics of burrow construction, burrow volumes were calculated and then the costs associated with dislodging, elevating, and throwing the known volumes of soil were measured. A typical Geolycosa burrow, at a volume of 23.6 ± 2.0 ml and a depth of 13.2 ± 0.7 cm, required the removal of 918 boluses each weighing about 34 mg. The aggregate dislodging cost was close to 1.9 Joules in sand/sandy loam and 5.6 J in clayey subsoil, the work against gravity necessary to raise all of the boluses to the surface was about 0.13 J, and the aggregate cost of flinging the boluses was close to 0.014 J. Assuming that the ratio of external work to metabolic cost of external work is between 0.20 and 0.25 in spiders, the real cost of burrow construction would be between 8 J and 29 J, depending primarily on soil type. This is a small but not negligible cost when placed in the context of reproductive effort: a single Geolycosa egg, dozens to hundreds of which are produced in a clutch, contains about 10 J.


Regulation of proteins in the cholesterol side-chain cleavage system in JEG-3 and Y-1 cells.
The conversion of cholesterol to pregnenolone, the rate-limiting step in steroid hormone synthesis, occurs on mitochondrial cytochrome P450scc, which catalyzes this reaction by receiving electrons from NADPH via a flavoprotein [adrenodoxin reductase (AdRed)] and an iron sulfur protein [adrenodoxin (Adx)]. The behavior of the genes and mRNAs encoding these proteins has been studied in several systems, but little is known about the behavior of the human proteins. Using cloned cDNAs for human P450scc and AdRed, we constructed bacterial expression vectors to make milligram quantities of the corresponding proteins. These, plus purified human Adx similarly prepared by Dr. L. Vickery, were injected into rabbits to raise antiserum to each of the proteins. Each antiserum was highly specific and did not cross-react with other mitochondrial proteins detectable by Western blotting. Human JEG-3 choriocarcinoma cells and mouse Y-1 adrenocortical carcinoma cells were then incubated for 0-24 h with 1 mM 8-bromo-cAMP (8Br-cAMP) or 30 nM phorbol 12-myristate 13-acetate (PMA; phorbol ester) plus 1 microM A23187 (calcium ionophore) to activate the protein kinase-A and -C pathways, respectively. In JEG-3 cells, 8Br-cAMP increased and PMA/A23187 slightly decreased the abundance of P450scc and Adx, but neither treatment had a detectable effect on AdRed. The production of pregnenolone by these cells increased 3-fold in response to 8Br-cAMP and fell to one third in response to PMA/A23187. In Y-1 cells, 8Br-cAMP increased the abundance of all three proteins, while PMA/A23187 decreased the abundance of P450scc and Adx. The production of pregnenolone by these cells increased 9-fold in response to 8Br-cAMP and was unaffected by TPA/A23187. These studies show that the three proteins of the cholesterol side-chain cleavage system behave in response to 8Br-cAMP and PMA/A23187 as predicted from the study of their genes and mRNAs, indicating that the chronic regulation of steroidogenesis in these cell systems is regulated principally at the level of mRNA abundance.


Rapid detection and identification of a pathogen's DNA using Phi29 DNA polymerase.
Zoonotic pathogens including those transmitted by insect vectors are some of the most deadly of all infectious diseases known to mankind. A number of these agents have been further weaponized and are widely recognized as being potentially significant biothreat agents. We describe a novel method based on multiply-primed rolling circle in vitro amplification for profiling genomic DNAs to permit rapid, cultivation-free differential detection and identification of circular plasmids in infectious agents. Using Phi29 DNA polymerase and a two-step priming reaction we could reproducibly detect and characterize by DNA sequencing circular DNA from Borrelia burgdorferi B31 in DNA samples containing as little as 25 pg of Borrelia DNA amongst a vast excess of human DNA. This simple technology can ultimately be adapted as a sensitive method to detect specific DNA from both known and unknown pathogens in a wide variety of complex environments.


The human and mouse replication-dependent histone genes.
The multigene family encoding the five classes of replication-dependent histones has been identified from the human and mouse genome sequence. The large cluster of histone genes, HIST1, on human chromosome 6 (6p21-p22) contains 55 histone genes, and Hist1 on mouse chromosome 13 contains 51 histone genes. There are two smaller clusters on human chromosome 1: HIST2 (at 1q21), which contains six genes, and HIST3 (at 1q42), which contains three histone genes. Orthologous Hist2 and Hist3 clusters are present on mouse chromosomes 3 and 11, respectively. The organization of the human and mouse histone genes in the HIST1 cluster is essentially identical. All of the histone H1 genes are in HIST1, which is spread over about 2 Mb. There are two large gaps (>250 kb each) within this cluster where there are no histone genes, but many other genes. Each of the histone genes encodes an mRNA that ends in a stemloop followed by a purine-rich region that is complementary to the 5' end of U7 snRNA. In addition to the histone genes on these clusters, only two other genes containing the stem-loop sequence were identified, a histone H4 gene on human chromosome 12 (mouse chromosome 6) and the previously described H2a.X gene located on human chromosome 11. Each of the 14 histone H4 genes encodes the same protein, and there are only three histone H3 proteins encoded by the 12 histone H3 genes in each species. In contrast, both the mouse and human H2a and H2b proteins consist of at least 10 non-allelic variants, making the complexity of the histone protein complement significantly greater than previously thought.


Convergent Evolution of Effector Protease Recognition by Arabidopsis and Barley.
The Pseudomonas syringae cysteine protease AvrPphB activates the Arabidopsis resistance protein RPS5 by cleaving a second host protein, PBS1. AvrPphB induces defense responses in other plant species, but the genes and mechanisms mediating AvrPphB recognition in those species have not been defined. Here, we show that AvrPphB induces defense responses in diverse barley cultivars. We also show that barley contains two PBS1 orthologs, that their products are cleaved by AvrPphB, and that the barley AvrPphB response maps to a single locus containing a nucleotide-binding leucine-rich repeat (NLR) gene, which we termed AvrPphB Response 1 (Pbr1). Transient coexpression of PBR1 with wild-type AvrPphB but not with a protease inactive mutant triggered defense responses, indicating that PBR1 detects AvrPphB protease activity. Additionally, PBR1 coimmunoprecipitated with barley and Nicotiana benthamiana PBS1 proteins, suggesting mechanistic similarity to detection by RPS5. Lastly, we determined that wheat cultivars also recognize AvrPphB protease activity and contain two putative Pbr1 orthologs. Phylogenetic analyses showed, however, that Pbr1 is not orthologous to RPS5. Our results indicate that the ability to recognize AvrPphB evolved convergently and imply that selection to guard PBS1-like proteins occurs across species. Also, these results suggest that PBS1-based decoys may be used to engineer protease effector recognition-based resistance in barley and wheat.


Direct evaluation of antigen binding to human T lymphocyte clones: involvement of major histocompatibility complex products in antigen binding.
Cloned human helper T lymphocytes reactive with a defined peptide (p20; residues 306-329) of the HA-1 molecule of influenza virus hemagglutinin were analyzed for their capacity to specifically bind peptide antigen. Three different methods of analyzing antigen binding to T cell receptors were compared. One method involved the binding of radiolabeled T cells to antigen-pulsed populations of sheep erythrocyte rosette-negative (E-) cells (B cells and monocytes). The binding was antigen specific, in that only E- cells pulsed with the appropriate antigen bound the treated T cells, and was inhibitable by free peptide. Furthermore, antigen binding was major histocompatibility complex-restricted in that only E- cells histocompatible at the HLA-D region locus bound the T cells, and monoclonal antibody of the relevant specificity was able to inhibit the binding. Secondly, it was demonstrated that tritiated T cells could bind to insolubilized antigen (p20) in the absence of E- cells. The binding was inhibited by anti-class II antibody suggesting that the interaction of antigen with the T cells involves recognition of T cell major histocompatibility complex class II determinants. Finally, radiolabeled peptides were also used to detect binding to the appropriate clones in the absence of presenting cells. This binding was specific, inhibitable by the appropriate unlabeled peptide and temperature dependent. These studies demonstrate that the process of antigen binding to receptors is analyzable and should in turn facilitate the analysis of the mechanism of T cell activation.


Genetic susceptibility to postherniotomy pain. The influence of polymorphisms in the Mu opioid receptor, TNF-α, GRIK3, GCH1, BDNF and CACNA2D2 genes.
Despite improvements in surgical technique, 5%-8% of patients undergoing herniorrhaphy still suffer from clinically relevant persistent postherniotomy pain. This is a problem at both individual and society levels. The aim of this study was to determine whether or not a single nucleotide polymorphism in a specific gene contributes to the development of persistent pain after surgery. One hundred individuals with persistent postherniotomy pain, along with 100 without pain matched for age, gender and type of surgery were identified in a previous cohort study on patients operated for groin hernia. All patients underwent a thorough sensory examination and blood samples were collected. DNA was extracted and analysed for single nucleotide polymorphism in the Mu opioid receptor, TNF-α, GRIK3, GCH1, BDNF and CACNA2D2 genes. Patients with neuropathic pain were found to have a homozygous single nucleotide polymorph in the TNF-α gene significantly more often than pain-free patients (P=0.036, one-tailed test). SNP in the TNF-α gene has a significant impact on the risk for developing PPSP. The result suggests the involvement of genetic variance in the development of pain and this requires further investigation.


Heterogeneous distribution of ITGCNU in an adult testis: consequences for biopsy-based diagnosis.
Carcinoma in situ (CIS) of the testis, also referred to as intratubular germ cell neoplasia unclassified (ITGCNU), is currently accepted as the common precursor for all malignant germ cell tumors of adolescents and adults- that is, the seminomatous and nonseminoma cancers. These preinvasive cells have specific cellular characteristics, which can be used for the early diagnosis-routinely done by morphological analysis, sometimes supported by immunohistochemistry-of tissue obtained by an open surgical biopsy. False-negative biopsy results can occur mostly because of the nonrandom distribution of ITGCNU within the testis, misdiagnosis, or suboptimal tissue treatment and analysis. In this article, we demonstrate the potential pitfalls in the diagnosis of ITGCNU. The results support the use of the highly specific and sensitive immunohistochemical marker OCT3/4 for the diagnosis of ITGCNU and provide evidence for the nonrandom distribution of ITGCNU, which is a significant limitation in the diagnosis of this preinvasive lesion.


Developmental patterns in the expression of Myf5, MyoD, myogenin, and MRF4 during myogenesis.
By using the polymerase chain reaction to amplify specific regions of the respective cDNAs, we have studied the expression of genes encoding the myogenic regulatory factors Myf5, MyoD, Myogenin, and MRF4 (Myf6, herculin) in cultured mouse muscle cells (inducible and permissive C2 cells and Sol8 cells). These cell lines may represent distinct stages in the progression of determined, or committed, muscle cells toward terminal differentiation. Transcripts for Myf5 were detected at the myoblast stage in all the committed muscle cells tested. Expression of the gene for MyoD appeared to be optional at the myoblast stage (MyoD is present in permissive myoblasts and absent from inducible myoblasts) but, like Myogenin, was found to accompany terminal differentiation. Furthermore, forced expression of MyoD converted inducible C2 cells into permissive cells. Expression of MRF4 was found to follow expression of the three other factors and to occur after the onset of terminal differentiation. Of particular interest was the finding that expression of MRF4 was temporally correlated with expression of the gene for the acetylcholine receptor epsilon-subunit that is characteristic of the adult receptor. In vivo, the only transcripts for myogenic regulatory factors to be detected in 8-day mouse embryos were those for Myf5, while expression of MRF4 followed expression of Myf5, MyoD, and Myogenin in developing limbs. Temporal and phenotypic differences related to the expression of Myf5, MyoD, Myogenin, and MRF4 suggest that these factors fulfil distinct roles in the control of myogenesis.


Effectiveness of the Middle East respiratory syndrome-coronavirus protocol in enhancing the function of an Emergency Department in Qatar.
This study aimed to investigate the effectiveness of a Middle East respiratory syndrome coronavirus (MERS-CoV) surveillance protocol in the Emergency Department (ED) at Hamad General Hospital. Effectiveness was measured by: (a) reduction in the number of patients admitted into the MERS-CoV tracking system; (b) identification of positive MERS-CoV cases; (c) containment of cross infectivity; and (d) increased efficiency in ED functioning. A retrospective chart review was carried out of all ED patients suspected of MERS-CoV during the height of the epidemic (August to October 2013). An algorithm was created on the basis of international guidelines to screen and triage suspected MERS-CoV patients. Once identified, patients were isolated, had a chest roentgenogram [chest radiography (CXR)] taken, and a nasopharyngeal swab for polymerase chain reaction (PCR) was sent with sputum samples for testing. Patients with normal CXR and mild respiratory symptoms were discharged with home isolation instructions until nasopharyngeal and sputum PCR results were available. Patients with fever and acute respiratory distress, with or without abnormal CXR, were treated in the hospital until tests proved negative for MERS-CoV. The protocol successfully reduced the number of patients who needed to be tested for MERS-CoV from 12,563 to 514, identified seven positive cases, and did not lead to apparent cross infectivity that resulted in serious illness or death. The protocol also increased the efficiency of ED and cut the turnaround time for nasopharyngeal swab and sputum results from 3 days to 1 day. A highly protocolized surveillance system limited the impact of MERS-CoV on ED functioning by identifying and prioritizing high-risk patients. The emergence of new infectious diseases requires constant monitoring of interventions to reduce the impact of epidemics on population health and health services.


Three-dimensional assessment of curvature, torsion, and canal flare index of the humerus of skeletally mature nonchondrodystrophic dogs.
OBJECTIVE To assess 3-D geometry of the humerus of dogs and determine whether the craniocaudal canal flare index (CFI) is associated with specific geometric features. SAMPLE CT images (n = 40) and radiographs (38) for 2 groups of skeletally mature nonchondrodystrophic dogs. PROCEDURES General dimensions (length, CFI, cortical thickness, and humeral head offset), curvature (shaft, humeral head, and glenoid cavity), version (humeral head and greater tubercle), and torsion were evaluated on CT images. Dogs were allocated into 3 groups on the basis of the craniocaudal CFI, and results were compared among these 3 groups. The CT measurements were compared with radiographic measurements obtained for another group of dogs. RESULTS Mean ± SD humeral head version was -75.9 ± 9.6° (range, -100.7° to -59.4°). Mean mechanical lateral distal humeral angle, mechanical caudal proximal humeral angle, and mechanical cranial distal humeral angle were 89.5 ± 3.5°, 50.2 ± 4.5°, and 72.9 ± 7.8°, respectively, and did not differ from corresponding radiographic measurements. Mean humeral curvature was 20.4 ± 4.4° (range, 9.6° to 30.5°). Mean craniocaudal CFI was 1.74 ± 0.18 (range, 1.37 to 2.10). Dogs with a high craniocaudal CFI had thicker cranial and medial cortices than dogs with a low craniocaudal CFI. Increased body weight was associated with a lower craniocaudal CFI. Radiographic and CT measurements of craniocaudal CFI and curvature differed significantly. CONCLUSIONS AND CLINICAL RELEVANCE CT-based 3-D reconstructions allowed the assessment of shaft angulation, torsion, and CFI. Radiographic and CT measurements of shaft curvature and CFI may differ.


CD4+Foxp3+T Regulatory Cells Promote Transplantation Tolerance by Modulating Effector CD4+ T Cells in a Neuropilin-1-Dependent Manner.
Several mechanisms of immune suppression have been attributed to Foxp3+ T regulatory cells (Treg) including modulation of target cells via inhibition of cell proliferation, alteration of cytokine secretion, and modification of cell phenotype, among others. Neuropilin-1 (Nrp1), a co-receptor protein highly expressed on Treg cells has been involved in tolerance-mediated responses, driving tumor growth and transplant acceptance. Here, we extend our previous findings showing that, despite expressing Foxp3, Nrp1KO Treg cells have deficient suppressive function in vitro in a contact-independent manner. In vivo, the presence of Nrp1 on Treg cells is required for driving long-term transplant tolerance. Interestingly, Nrp1 expression on Treg cells was also necessary for conventional CD4+ T cells (convT) to become Nrp1+Eos+ T cells in vivo. Furthermore, adoptive transfer experiments showed that the disruption of Nrp1 expression on Treg cells not only reduced IL-10 production on Treg cells, but also increased the frequency of IFNγ+ Treg cells. Similarly, the presence of Nrp1KO Treg cells facilitated the occurrence of IFNγ+CD4+ T cells. Interestingly, we proved that Nrp1KO Treg cells are also defective in IL-10 production, which correlates with deficient Nrp1 upregulation by convT cells. Altogether, these findings demonstrate the direct role of Nrp1 on Treg cells during the induction of transplantation tolerance, impacting indirectly the phenotype and function of conventional CD4+ T cells.


Localized solution structure refinement of an F45W variant of ubiquitin using stochastic boundary molecular dynamics and NMR distance restraints.
The local structure within an 8-A radius around residue 45 of a recombinant F45W variant of human ubiquitin has been determined using 67 interproton distance restraints measured by two-dimensional proton NMR. Proton chemical shift evidence indicates that structural perturbations due to the F45W mutation are minimal and limited to the immediate vicinity of the site of mutation. Simulated annealing implemented with stochastic boundary molecular dynamics was applied to refine the structure of Trp 45 and 10 neighboring residues. The stochastic boundary method allowed the entire protein to be reassembled from the refined coordinates and the outlying unrefined coordinates with little distortion at the boundary. Refinement began with four low-energy indole ring orientations of F45W-substituted wild-type (WT) ubiquitin crystal coordinates. Distance restraints were derived from mostly long-range NOE cross peaks with 51 restraints involving the Trp 45 indole ring. Tandem refinements of 64 structures were done using either (1) upper and lower bounds derived from qualitative inspection of NOE crosspeak intensities or (2) quantitative analysis of cross-peak heights using the program MARDIGRAS. Though similar to those based on qualitative restraint, structures obtained using quantitative NOE analysis were superior in terms of precision and accuracy as measured by back-calculated sixth-root R factors. The six-membered portion of the indole ring is nearly coincident with the phenyl ring of the WT and the indole NH is exposed to solvent. Accommodation of the larger ring is accompanied by small perturbations in the backbone and a 120 degrees rotation of the chi 2 dihedral angle of Leu 50.


The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens.


From lighthouse to hothouse: hospital hygiene, antibiotics and the evolution of infectious disease, 1950-1990.
Upon entering clinical medicine in the 1940s, antibiotic therapy seemed to complete a transformation of hospitals that originated in the late nineteenth century. Former death sinks had become harbingers of therapeutic progress. Yet this triumph was short-lived. The arrival of pathologies caused by resistant bacteria, and of nosocomial infections whose spread was helped by antibiotic therapies, seemed to be intimately related to modern anti-infective therapy. The place where such problems culminated were hospitals, which increasingly appeared as dangerous environments where attempts to combat infectious diseases had instead created hothouses of disease evolution. This paper will focus on one aspect of that history. It caused clinical medicine and hospital hygiene in particular to pay attention to a dimension of infectious disease it had previously paid little attention to thus far: The evolution of infectious disease-previously a matter of mostly theoretical interest-came to be useful in explaining many phenomena observed. This did not turn hospital hygienists into geneticists, though it did give them an awareness that the evolution of infectious disease in a broad sense was something that did matter to them. The paper advances its argument by looking at three phases: The growing awareness of the hospital as a dangerous environment in the 1950s, comprehensive attempts at improving antibiotic therapy and hospital hygiene that followed from the 1960s and lastly the framing of such challenges as risk factors from the 1970s. In conclusion, I will argue that hospital hygiene, being inspired in particular by epidemiology and risk factor analysis, discussed its own specific version of disease emergence and therefore contributed to the 1980s debates around such topics. Being loosely connected to more specialized studies, it consisted of a re-interpretation of infectious disease centred around the temporality of such phenomena as they were encountered in day-to-day dealings of clinical wards.


Anosognosia and Its Relation to Psychiatric Symptoms in Early-Onset Alzheimer Disease.
We investigated differences in the prevalence of anosognosia and neuropsychiatric symptoms (NPSs) characteristics according to disease severity in patients with early-onset Alzheimer disease (EOAD). We recruited 616 patients with EOAD. We subdivided participants into 2 groups based on the presence or absence of anosognosia and then again by Clinical Dementia Rating (CDR) scale. We compared the differences in the Neuropsychiatric Inventory (NPI) scores according to anosognosia and disease severity. The percentage of patients with anosognosia in each CDR group steadily increased as the CDR rating increased (CDR 0.5 8.6% vs CDR 1 13.6% vs CDR 2 26.2%). The NPI total score was significantly higher in patients with anosognosia in the CDR 0.5 and 1 groups; by contrast, it had no association in the CDR 2 group. Frontal lobe functions were associated with anosognosia only in the CDR 0.5 and 1 groups. After stratification by CDR, in the CDR 0.5 group, the prevalence of agitation ( P = .040) and appetite ( P = .013) was significantly higher in patients with anosognosia. In the CDR 1 group, patients with anosognosia had a significantly higher prevalence of delusions ( P = .032), hallucinations ( P = .048), and sleep disturbances ( P = .047). In the CDR 2 group, we found no statistical difference in the frequency of symptoms between patients with and without anosognosia. These results confirm that the prevalence of anosognosia as well as the individual NPS and cognitive functions associated with it differ according to EOAD severity.


Heat shock protein 27 is the major differentially phosphorylated protein involved in renal epithelial cellular stress response and controls focal adhesion organization and apoptosis.
We used two-dimensional difference gel electrophoresis to determine early changes in the stress-response pathways that precede focal adhesion disorganization linked to the onset of apoptosis of renal epithelial cells. Treatment of LLC-PK1 cells with the model nephrotoxicant 1,2-(dichlorovinyl)-L-cysteine (DCVC) resulted in a >1.5-fold up- and down-regulation of 14 and 9 proteins, respectively, preceding the onset of apoptosis. Proteins included those involved in metabolism, i.e. aconitase and pyruvate dehydrogenase, and those related to stress responses and cytoskeletal reorganization, i.e. cofilin, Hsp27, and alpha-b-crystallin. The most prominent changes were found for Hsp27, which was related to a pI shift in association with an altered phosphorylation status of serine residue 82. Although both p38 and JNK were activated by DCVC, only inhibition of p38 with SB203580 reduced Hsp27 phosphorylation, which was associated with accelerated reorganization of focal adhesions, cell detachment, and apoptosis. In contrast, inhibition of JNK with SP600125 maintained cell adhesion as well as protection against apoptosis. Active JNK co-localized at focal adhesions after DCVC treatment in a FAK-dependent manner. Inhibition of active JNK localization at focal adhesions did not prevent DCVC-induced phosphorylation of Hsp27. Overexpression of a phosphorylation-defective mutant Hsp27 acted as a dominant negative and accelerated the DCVC-induced changes in the focal adhesions as well as the onset of apoptosis. Our data fit a model whereby early p38 activation results in a rapid phosphorylation of Hsp27, a requirement for proper maintenance of cell adhesion, thus suppressing renal epithelial cell apoptosis.


Vitamin K2 in multiple sclerosis patients.
Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n). It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated. Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS). We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment. Overall, 45 MS patients (31 females and 39 of the relapsing-remitting type) and 29 healthy controls (19 females) were included in the analysis. The MS patients had vastly lower VK2 blood levels than controls (235 ± 100 ng/ml vs. 812 ± 154 ng/ml, respectively). Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found. The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions. No consistent relationship with medications was detected. The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1. The role of VK2 in MS development and progress deserves further study.


Intensive management of severe acute pancreatitis.
To investigate an optimal management bundle to improve the survival rate of severe acute pancreatitis (SAP). We constructed a treatment bundle based on our clinical investigation, literature, and empirical practice. Intensive management during the acute response stage and infection stage comprised eight main issues: etiology, diagnosis, fluid resuscitation, support of organ function, abdominal compartment syndrome (ACS), enteral nutrition, intestinal function, and antibiotics. The intensive management plan included a time-dependent plan for the eight main issues and goal-directed therapy. The plan must be started within the prescribed time (time-dependent endeavors) and must involve the right strategies, right sequence, and right ward for each individual. Effective goal-directed therapy and essential treatment measures must be performed within a specified period of time, and treatment efficacy should be regularly assessed. In 2010, intensive management was initiated in China. Intensive management has significant effects on SAP. This strategy was adopted by 36 hospitals in China, resulting in significant improvements in prognoses. Some criteria of intensive management were adopted by the International Association of Pancreatology (IAP)/American Pancreatic Association Working Group Acute Pancreatitis Guidelines in 2013. Intensive management is an important efficacy-based treatment strategy that can significantly ameliorate prognoses.


Natural selection. VI. Partitioning the information in fitness and characters by path analysis.
Three steps aid in the analysis of selection. First, describe phenotypes by their component causes. Components include genes, maternal effects, symbionts and any other predictors of phenotype that are of interest. Second, describe fitness by its component causes, such as an individual's phenotype, its neighbours' phenotypes, resource availability and so on. Third, put the predictors of phenotype and fitness into an exact equation for evolutionary change, providing a complete expression of selection and other evolutionary processes. The complete expression separates the distinct causal roles of the various hypothesized components of phenotypes and fitness. Traditionally, those components are given by the covariance, variance and regression terms of evolutionary models. I show how to interpret those statistical expressions with respect to information theory. The resulting interpretation allows one to read the fundamental equations of selection and evolution as sentences that express how various causes lead to the accumulation of information by selection and the decay of information by other evolutionary processes. The interpretation in terms of information leads to a deeper understanding of selection and heritability, and a clearer sense of how to formulate causal hypotheses about evolutionary process. Kin selection appears as a particular type of causal analysis that partitions social effects into meaningful components.


Metabolomic profiling of the response of susceptible and resistant soybean strains to foxglove aphid, Aulacorthum solani Kaltenbach.
Aphid infection reduces soybean (Glycine max [L.] Merr.) yield. Consequently, cultivation of aphid-resistant strains is a promising approach to pest control, and understanding the resistance mechanism is of importance. Here, we characterized the resistance of soybeans to foxglove aphid, Aulacorthum solani Kaltenbach, at the metabolite level. First, we evaluated aphid mortality and settlement rates on the leaves of two soybean strains, 'Tohoku149' and 'Suzuyutaka', and found that the former had strong resistance soon after introduction of the aphids. The metabolomic response to aphid introduction was analyzed using capillary electrophoresis-time-of-flight mass spectrometry. We found the following three features in the profiles: (1) concentrations of citrate, amino acids, and their intermediates were intrinsically higher for Tohoku149 than Suzuyutaka, (2) concentrations of several metabolites producing secondary metabolites, such as flavonoids and alkaloids, drastically changed 6h after aphid introduction, and (3) concentrations of TCA cycle metabolites increased in Tohoku149 48 h after aphid introduction. We also profiled free amino acids in aphids reared on both soybean strains and under starvation, and found that the profile of the aphids on Tohoku149 was similar to that of the starved aphids, but different to that of aphids on Suzuyutaka. These tests confirmed that aphids suck phloem sap even from Tohoku149. This study demonstrates the metabolomic profiles of both soybean strains and aphids, which will contribute to the molecular level understanding of mechanisms of soybean resistance to aphids.


Short-term high-fat feeding induces islet macrophage infiltration and β-cell replication independently of insulin resistance in mice.
Short-term high-fat consumption stimulates mouse islet β-cell replication through unknown mechanisms. Resident macrophages (MΦs) are capable of secreting various factors involved in islet development and tissue remodeling. We hypothesized that a short-term high-fat diet (HFD) promotes MΦ infiltration in pancreatic islets and that MΦs serve as a regulator of β-cell replication. To test these hypotheses and dissect mechanisms involved in HFD-induced β-cell replication, adult C57BL/6J mice were fed a HFD for 7 days with or without administration of clodronate-containing liposomes, an MΦ-depleting agent. Mouse body and epididymal fat pad weights, and nonfasting blood glucose and fasting serum insulin levels were measured, and pancreatic islet β-cell replication, oxidative stress, and MΦ infiltration were examined. Short-term HFD promoted an increase in body and epididymal fat pad weight and blood glucose levels, along with an increased fasting serum insulin concentration. β-Cell replication, islet MΦ infiltration, and the percentage of inducible NO synthase positive MΦs in the islets increased significantly in mice fed the HFD. Immunofluorescence staining for 8-oxo-2'-deoxyguanosine or activated caspase-3 revealed no significant induction of DNA damage or apoptosis, respectively. In addition, no change in stromal-derived factor 1-expressing cells was found induced by HFD. Despite continuous elevation of nonfasting blood glucose and fasting serum insulin levels, depletion of MΦs through treatments of clodronate abrogated HFD-induced β-cell replication. These findings demonstrated that HFD-induced MΦ infiltration is responsible for β-cell replication. This study suggests the existence of MΦ-mediated mechanisms in β-cell replication that are independent of insulin resistance.


A reevaluation of the symptom of morning stiffness.
To study, both qualitatively and quantitatively, morning stiffness in consecutive patients attending a rheumatology clinic. A detailed interview from 93 patients with rheumatoid arthritis (RA) and 46 patients with noninflammatory joint disease. Occurrence, duration and severity of morning stiffness were similar in both groups, as was its detailed qualitative description. Patients with RA with active disease had higher severity scores of morning stiffness than those with inactive disease. Morning stiffness is a poor discriminator between RA and noninflammatory joint disease. Its assessment by a severity score is better than one based on duration.


Follow-up for pregnant women during the COVID-19 pandemic: French national authority for health recommendations.
In the context of the stage 3 SARS-Cov-2 epidemic situation, it is necessary to put forward a method of rapid response for an HAS position statement in order to answer to the requests from the French Ministry of Solidarity and Health, healthcare professionals and/or health system users' associations concerning follow-up of pregnant women during the COVID-19 outbreak. A simplified 7-step process that favours HAS collaboration with experts (healthcare professionals, health system users' associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. A short and specific dissemination format, which can be quickly updated in view of the changes in available data has been chosen.


Double-blind test of the effects of distant intention on water crystal formation.
The hypothesis that water "treated" with intention can affect ice crystals formed from that water was pilot tested under double-blind conditions. A group of approximately 2,000 people in Tokyo focused positive intentions toward water samples located inside an electromagnetically shielded room in California. That group was unaware of similar water samples set aside in a different location as controls. Ice crystals formed from both sets of water samples were blindly identified and photographed by an analyst, and the resulting images were blindly assessed for aesthetic appeal by 100 independent judges. Results indicated that crystals from the treated water were given higher scores for aesthetic appeal than those from the control water (P = .001, one-tailed), lending support to the hypothesis.


Assortative mating and persistent reproductive isolation in hybrids.
The emergence of new species is driven by the establishment of mechanisms that limit gene flow between populations. A major challenge is reconciling the theoretical and empirical importance of assortative mating in speciation with the ease with which it can fail. Swordtail fish have an evolutionary history of hybridization and fragile prezygotic isolating mechanisms. Hybridization between two swordtail species likely arose via pollution-mediated breakdown of assortative mating in the 1990s. Here we track unusual genetic patterns in one hybrid population over the past decade using whole-genome sequencing. Hybrids in this population formed separate genetic clusters by 2003, and maintained near-perfect isolation over 25 generations through strong ancestry-assortative mating. However, we also find that assortative mating was plastic, varying in strength over time and disappearing under manipulated conditions. In addition, a nearby population did not show evidence of assortative mating. Thus, our findings suggest that assortative mating may constitute an intermittent and unpredictable barrier to gene flow, but that variation in its strength can have a major effect on how hybrid populations evolve. Understanding how reproductive isolation varies across populations and through time is critical to understanding speciation and hybridization, as well as their dependence on disturbance.


The use of nerve and muscle biopsy in the diagnosis of vasculitis: a 5 year retrospective study.
Peripheral nerve vasculitis is an important condition which can be diagnostically challenging and is one of the principal current indications for nerve and muscle biopsy. Previous studies have suggested that combined nerve and muscle biopsy (usually of the superficial peroneal nerve and peroneus brevis muscle) produces a higher diagnostic yield than nerve biopsy alone in the investigation of vasculitis. To determine whether in our two centres combined nerve (usually the sural) and muscle (usually the vastus lateralis) biopsy improved diagnostic yield compared with nerve biopsy alone. We interrogated our database of all nerve biopsies (usually of the sural nerve) performed at our institutions over 5 years and identified 53 cases of biopsy proven peripheral nerve vasculitis. Clinicopathological and neurophysiological data in these patients were reviewed. The most common clinical presentation was with a painful asymmetric axonal polyneuropathy or mononeuritis multiplex (66% of cases). Nerve biopsy demonstrated definite vasculitis in 36%, probable vasculitis in 62% and no vasculitis in 2% of cases. In 24 patients a muscle biopsy (usually the vastus lateralis) was also performed and vasculitis was demonstrated in 46% of these (in 13% showing definite and 33% probable vasculitis). There was only one patient in whom vasculitis was demonstrated in muscle but not in peripheral nerve. Combined nerve (usually sural) and vastus lateralis muscle biopsy did not significantly increase the diagnostic yield compared with nerve biopsy alone. A sensible approach to the diagnosis of peripheral nerve vasculitis is to choose a nerve to biopsy which is clinically affected and amenable to biopsy. If the sural nerve is chosen, the data suggest that it is not routinely worth doing a vastus lateralis biopsy at the same time, whereas if the superficial peroneal nerve is chosen, it seems appropriate to do a combined superficial peroneal nerve and peroneus brevis biopsy. It is still not known if both the sural and superficial peroneal nerves are involved clinically which one gives the higher yield if biopsied.


CLADISTICS: WHAT'S IN A WORD?
Abstract- Cladistics has changed considerably with the availability of new methods and sources of data, and the increasing realization that cladograms are relevant to all manner of historical questions. Criticisms of, and justifications for, consensus hypotheses in phylogenetic inference are reviewed. The conclusion is overwhelmingly against taxonomic congruence which deliberately seeks consensus propositions. The total evidence approach is not so burdened. A preference for suboptimal cladograms is also critized, as is the protocol for mapping characters of special interest onto a phylogenetic hypothesis derived from other evidence. The bootstrap and jackknife resampling techniques are questioned because their underlying assumptions are violated and they are sensitive to character frequencies. These findings suggest that cladistics is being redefined in ways that contradict the practices and principles responsible for its pre-eminence in phylogenetic inference.


Effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of cancer-related fatigue: A meta-analysis.
Cancer-related fatigue has a multidimensional nature and complaints typically increase during adjuvant treatment for breast cancer. Physical exercise might prevent or reduce cancer-related fatigue. So far, no meta-analysis has investigated the effects of physical exercise on different dimensions of fatigue. The aim of the present meta-analysis was to investigate the effects of physical exercise during adjuvant breast cancer treatment on physical and psychosocial dimensions of fatigue. We performed a systematic literature search in PubMed, Embase and the Cochrane Library in June 2015. Randomised controlled trials reporting the effects of physical exercise during adjuvant breast cancer treatment on different dimensions of fatigue were included. Pooled effects of 6 exercise programmes (including 784 patients) showed significant beneficial exercise effects on general fatigue (ES: -0.22, 95% CI -0.38; -0.05) and physical fatigue (ES: -0.35, 95% CI -0.49; -0.21). Effects on fatigue subscales 'reduced activity' (ES: -0.22, 95% CI -0.38; -0.05) and 'reduced motivation' (ES: -0.18, 95% CI -0.35; -0.01) were also in favour of physical exercise. No effects were found on cognitive and affective fatigue. Including only the supervised exercise programmes (n=4 studies), slightly larger pooled effect estimates were found on general fatigue (ES: -0.25, 95% CI -0.47; -0.04) and physical fatigue (-0.39, 95% CI -0.56; -0.23). In conclusion, physical exercise during adjuvant breast cancer treatment has beneficial effects on general fatigue, physical fatigue, 'reduced activity' and 'reduced motivation', but did not show effects on cognitive and affective fatigue. Largest effect sizes are found for physical fatigue, suggesting that this is the fatigue dimension most sensitive to physical exercise.


Periacinar retraction clefting in proliferative prostatic atrophy and prostatic adenocarcinoma.
To evaluate the presence and extent of periacinar retraction clefting in proliferative prostatic atrophy and carcinoma in radical prostatectomy specimens. Atrophic foci and neoplastic glands were analysed in specimens from 50 patients who underwent radical prostatectomy. Analysed atrophic glands were classified in two main groups, proliferative atrophy (PA) and proliferative inflammatory atrophy (PIA); each group was subclassified into simple atrophy (SA) and postatrophic hyperplasia (PAH). According to the presence and extent of periacinar retraction clefting, atrophic and neoplastic glands were classified as: group 1, glands without clefts or with clefts affecting <or=50% of gland circumference; group 2, glands with clefts that affected >50% of the circumference in <50% of examined glands; and group 3, glands with clefts that affected >50% of the circumference in >or=50% of examined glands. Forty-four (88.0%) atrophic foci were without periacinar clefts or clefts were present in less than half of the gland circumference (group 1). In 6 (12.0%), atrophic foci clefts affected >50% of gland circumference (groups 2 and 3). Forty-five (90.0%) carcinomas were with clefts which affected more than 50% of gland circumference (groups 2 and 3); and in five carcinomas only, clefts were not found or affected <50% of gland circumference (group 1). Results indicate that periacinar retraction clefting represents a reliable criterion in differential diagnosis between proliferative atrophy and carcinoma.


A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression.
Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.


Temperature and strain dependence of the power level and frequency of spontaneous Brillouin scattering in optical fibers.
The strain dependence of the optical power of Brillouin scattering in optical fibers has been measured for the first time to our knowledge. Together with measurements of the dependence of Brillouin power on temperature and the variation of Brillouin frequency with temperature and strain, we demonstrate, for what we believe to be the first time, the feasibility of a simultaneous temperature and strain sensor based on spontaneous Brillouin scattering.


Assessing barriers and facilitators of implementing an integrated HIV prevention and property rights program in Western Kenya.
Despite the recognized need for structural HIV prevention interventions, few scientific programs have integrated women's property and inheritance rights with HIV prevention and treatment. The current study focused on a community-led land and property rights intervention that was implemented in two rural areas of Western Kenya with high HIV prevalence rates (24-30%). The program was designed to respond to women's property rights violations in order to reduce HIV risk at the local level. Through in-depth interviews with twenty program leaders, we identified several facilitators to program implementation, including the leadership of home-based HIV caregivers and involvement of traditional leaders in mediating property rights disputes. We also identified the voluntary basis of the intervention and its lack of integration with the formal justice system as implementation barriers. Our findings can guide future research and design of structural HIV prevention strategies that integrate women's economic empowerment through property and inheritance rights.


Effectiveness of environment-based interventions for people with Alzheimer's disease and related dementias.
A systematic review of evidence for the efficacy of environment-based interventions on the affect, behavior, and performance of people with Alzheimer's disease and related dementias was conducted as part of the American Occupational Therapy Association's Evidence-Based Literature Review Project. Thirty-three reports met inclusion criteria. Results suggest that ambient music, aromatherapy, and Snoezelen are modestly effective in reducingagitation but do not consistently have long-term effects. Visually complex environments that give the illusion of barriers deter people from wandering to unsafe places but do not reduce the urge to wander. Evidence that bright light therapy can aid in regulating mood and the sleep-wake cycle and thus help people remain awake during the day is preliminary. Montessori-based programming can be useful in matching activities to the person's remaining skills. Further research is needed to evaluate the long-term effect, contraindications, and best dosages of these interventions.


Is the non-respect of ethical principles by health professionals during first-trimester sonographic Down syndrome screening damaging to patient autonomy?
To evaluate the understanding of health professionals involved in first-trimester ultrasound screening of the ethical stakes involved by addressing three questions regarding: how much these professionals know about Down syndrome screening by nuchal translucency thickness measurement; their personal opinion with respect to this screening test; and their attitude with respect to their patients, in order to answer the question: 'Are ethical principles respected when women are proposed ultrasound screening during the first trimester of pregnancy?' We studied the medical population in the east part of France by sending a questionnaire to each of 460 medical correspondents. This questionnaire attempted to evaluate the respondent's level of medical knowledge, their personal opinion with respect to first-trimester screening and their attitude towards their patients. We adapted the three-dimensional diagram designed by Marteau et al. to develop a measure of informed choice regarding screening. Only health professionals who were relatively well informed and adopted an autonomy-oriented approach were considered to be in a position to obtain true consent from their patients, respecting ethical principles in terms of competence and the autonomy of patients. We received 276 (60%) responses to the questionnaire. Only 31.9% of health professionals had an approach that facilitated obtaining true consent from their patients and respected the ethical principles of competence and patient autonomy; 46% were in favor of the screening test and adopted an autonomy-oriented approach but were poorly informed; and 15.4% had a directive-authoritarian approach combined with poor knowledge. Regression analysis showed that two independent factors (speciality (P = 0.031) and location of practice (P = 0.034)) affected the level of medical knowledge, and two independent factors (location of practice (P = 0.034) and the type of medical practice i.e. public or private (P < 0.05)) affected the opinion of health professionals about the screening test. Two independent factors (speciality (P < 0.001) and the age of the health professional (P = 0.02)) affected the attitudes of health professionals towards their patients. The answer to the question 'Are ethical principles respected when women are proposed ultrasound screening during the first trimester of pregnancy?' is clearly 'No'. Major effort is required to ensure that the decisions made by patients are based on a possibility of true choice.