Depressive symptoms mediate the relationship between changes in emotion regulation during treatment and abstinence among women with alcohol use disorders.
Women with alcohol use disorders (AUD) experience high rates of co-occurring conditions, such as depression and posttraumatic stress disorder (PTSD), which can complicate treatment engagement and response. Therefore, identifying factors that underlie alcohol use, depression, and PTSD symptoms in women with AUD has important treatment implications. The current study investigated emotion regulation as one such underlying factor. We tested a model that examined the extent to which changes in emotion regulation during treatment predicted women's depression and PTSD symptom severity at treatment completion and subsequent alcohol use following treatment. The study included 48 participants enrolled in a randomized controlled trial of interpersonal psychotherapy versus usual care for women with co-occurring alcohol dependence and major depression. Assessments were conducted at baseline, posttreatment (16 weeks), and follow-up (24 weeks). Descriptive statistics of baseline data revealed heightened levels of emotion dysregulation in this sample, which were related to fewer days abstinent from alcohol, more negative consequences from alcohol, and greater PTSD symptom severity. Women's lower depressive symptoms at the end of treatment were found to mediate the relationship between improved emotion regulation during the treatment period and greater abstinence following treatment. Posttreatment PTSD symptoms, however, were not found to mediate that relationship. These results suggest that improvements in depressive symptoms during treatment are associated with emotion regulation at the end of treatment, which may contribute to greater abstinence from alcohol following treatment. (PsycINFO Database Record


Family of prohormone convertases in Lymnaea: characterization of two alternatively spliced furin-like transcripts and cell-specific regulation of their expression.
The majority of neuropeptides in Lymnaea stagnalis are proteolytically processed from larger precursors at sites composed of single or multiple basic amino acid residues. Previous studies have identified several putative prohormone convertases in the brain of Lymnaea. To characterize the complete family, we undertook three independent approaches: reverse-transcribed polymerase chain reaction screening, and low-stringency cDNA and genomic library screenings. The central nervous system cDNA library screening yielded two cDNAs encoding Lfurin1 and its variant form, Lfurin1-X. Both proteins show the characteristic organization of (human) furin with a putative catalytic domain, a P domain, a Cys-rich domain, a transmembrane domain, and a cytoplasmic tail. Lfurin1 and Lfurin1-X are identical, apart from a putative alternatively spliced noncatalytic luminal protein domain, which is present exclusively in Lfurin1-X. In situ hybridization revealed that the Lfur1 gene is expressed throughout the Lymnaea brain, but that the level varies considerably from one neuron to another. Quantitative analysis of the expression level of the two alternatively spliced transcripts revealed that it is neuron type-specifically regulated. This probably indicates the functional importance of noncatalytic luminal protein domains in these enzymes. In addition, our findings suggest that apart from the identified convertases LPC2, Lfurin1/Lfurin1-X, and Lfurin2, additional prohormone convertase diversity is either not present or present only at low levels in the Lymnaea brain. Alternatively, additional prohormone convertases could exist with a lower degree of sequence conservation than the other Lymnaea prohormone convertase members. From our findings, it appears that the majority of prohormone processing in Lymnaea is carried out by the three thus far identified types of Kex2-related prohormone convertases despite the large number of neuropeptide precursors and diverse multiple basic cleavage sites hydrolyzed.


Age-related differences in prevalence of autism spectrum disorder symptoms in children and adolescents with Costello syndrome.
Dysregulation of the mitogen activated protein kinase (MAPK) pathway in Costello syndrome (CS) may contribute to increased risk for autism-spectrum disorder (ASD). We examined prevalence of ASD symptoms in 14 individuals (six females) age 1-18 years with molecularly confirmed CS. Caregivers completed the Modified Checklist for Autism in Toddlers (M-CHAT) for ages 0-4 years (n = 7), and the Social Communication Questionnaire (SCQ) for ages 4 and older (n = 7). Age was associated with meeting ASD criteria: 5/7 (71.4%) younger children met the ASD cut-off on the MCHAT, compared to 0/7 older children on the SCQ. The following medical and developmental factors were strongly associated with ASD criteria on the M-CHAT: having a gastrostomy tube at time of assessment, not eating solid food, not walking, and not being toilet trained. Two children who met stricter ASD criteria had significantly lower adaptive functioning and were physically much more impaired. Among older participants, SCQ subscale scores in communication, socialization, and repetitive behavior domains were comparable to the typically-developing normative sample. ASD symptoms were highly elevated in younger CS individuals. Older children did not differ from typically developing samples in prevalence of ASD symptoms. CS individuals may appear to fall on the autism spectrum in early childhood due to severe feeding and orthopedic problems that improve by age four, suggesting many of these children may eventually emerge out of an ASD presentation.


Evaluating the Energy Requirements of Assistive Technologies for Older Adults.
The successful adoption of assistive technologies for older adults requires considering and evaluating many different factors and dimensions such as effectiveness, usability, cost and equity of access, to name some of the most relevant. In line with this, the energy requirements to power such assistive technologies remains a hidden factor that might to some extent influence the success in their adoption and the user experience in a wider sense. Very often energy availability is taken for granted and its associated costs and operational requirements are mostly neglected. In this paper, the energy-related requirements of assistive technologies are analysed from a general perspective. This analysis is subsequently particularised for a use case within the SHAPES project, in the context of active and healthy ageing. This use case includes a wide variety of assistive technologies, namely: wearable devices, home sensors and a smart mirror, which provides connectivity and a set of software services. The energy requirements of all these technologies are evaluated and analysed to investigate their impact and relevance on the overall cost and user experience, following the proposed protocol.


Genomic characterization of New Delhi metallo-beta-lactamase-producing species of Morganellaceae, Yersiniaceae, and Enterobacteriaceae (other than Klebsiella) from Brazil over 2013-2022.
Over the last decade, New Delhi metallo-beta-lactamase (NDM) carbapenemase has silently spread in Brazil. In this study, we analyzed a large collection of Enterobacterales other than Klebsiella spp. received in our reference laboratory between 2013 and 2022. A total of 32 clinical isolates displaying different pulsed-field gel electrophoresis profiles, and represented by 11 species in the families Enterobacteriaceae (Citrobacter freundii, Citrobacter portucalensis, Enterobacter hormaechei, and Escherichia coli), Morganellaceae (Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Raoultella ornithinolytica), and Yersiniaceae (Serratia marcescens) had their whole genomes sequenced and further analyzed. Antimicrobial susceptibility was determined by disk diffusion, except for polymyxin B, assessed by broth microdilution. The blaNDM-1 allele was predominant (n = 29), but blaNDM-5 was identified in an E. coli specimen with a novel ST, and the blaNDM-7 allele was found in E. hormaechei ST45 and E. coli ST1049. Polymyxin was active against all but one Enterobacteriaceae isolate: an mcr-1-producing E. coli presenting minimal inhibitory concentration (4 mg/L). Isolates producing extended-spectrum β-lactamases were common: cefotaximase from Munich (CTX-M)-15 (n = 10), CTX-M-2 (n = 4), and CTX-M-8 (n = 3) were detected, and the mcr-1-producing E. coli was found to co-produce both CTX-M-8 and CTX-M-55 β-lactamases. The mcr-9 gene was found in 5/8 E. hormaechei isolates, distributed in four different sequence types, all of them presenting susceptibility to polymyxin. This study showed that NDM-producing Enterobacterales other than Klebsiella are already spread in Brazil, in diversified species, and cocarrying important resistance genes. Prompt detection and effective implementation of measures to prevent further spread are mandatory for mitigating the dissemination of NDM carbapenemase in hospital settings and preserving the already limited antimicrobial therapy options.


[Evaluation of vaccinal protection against rinderpest in Cameroon. III. General evaluation].
The national veterinary Laboratory, Garoua (Cameroon) has been carrying out rinderpest sero-surveillance since 1989 as part of an effort made by the Panafrican Rinderpest Campaign (PARC) to control rinderpest in Africa. In 1993, 8517 serum samples collected from 286 cattle herds (from 0 to 3 years old) randomly chosen from six provinces with large cattle population (Far-North, North, Adamaoua, East, West, North-West) were tested using the rinderpest competitive ELISA technique; the herd immunity level was 54%. Out of 2010 serum samples from 68 non-protected cattle herds tested using the peste des petits ruminants (PPR) ELISA technique, 91 samples were positive (4.5%): this does not significantly increase the cattle immunity level against rinderpest. Significant differences in the immunity rates between provinces were observed. Suggestions to increase the immunity level are discussed.


Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.
There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.


Reduced ability of calcitriol to promote augmented dopamine release in the lesioned striatum of aged rats.
Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder that affects over one million people in the United States. Previous studies, carried out in young adult rats, have shown that calcitriol, the active metabolite of vitamin D, can be neuroprotective in 6-hydroxydopamine (6-OHDA) models of PD. However, as PD usually affects older individuals, the ability of calcitriol to promote dopaminergic recovery was examined in lesioned young adult (4 month old), middle-aged (14 month old) and aged (22 month old) rats. Animals were given a single injection of 12 μg 6-OHDA into the right striatum. Four weeks later they were administered vehicle or calcitriol (1.0 μg/kg, s.c.) once a day for eight consecutive days. In vivo microdialysis experiments were carried out three weeks after the calcitriol or vehicle treatments to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. The calcitriol treatments significantly increased evoked overflow of DA from the lesioned striatum in both the young adult and middle-aged rats. However, the calcitriol treatments did not significantly augment DA overflow in the aged rats. Postmortem tissue levels of striatal DA were also increased in the young and middle-aged animals, but not in the aged animals. In the substantia nigra, the calcitriol treatments led to increased levels of DA in all three age groups. Thus, the effects of calcitriol were similar in the young adult and middle-aged animals, but in the aged animals the effects of calcitriol were diminished. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons; however, the effectiveness of calcitriol may be reduced in aging.


p120-catenin regulates REST and CoREST, and modulates mouse embryonic stem cell differentiation.
Although the canonical Wnt pathway and β-catenin have been extensively studied, less is known about the role of p120-catenin (also known as δ1-catenin) in the nuclear compartment. Here, we report that p120-catenin binds and negatively regulates REST and CoREST (also known as Rcor1), a repressive transcriptional complex that has diverse developmental and pathological roles. Using mouse embryonic stem cells (mESCs), mammalian cell lines, Xenopus embryos and in vitro systems, we find that p120-catenin directly binds the REST-CoREST complex, displacing it from established gene targets to permit their transcriptional activation. Importantly, p120-catenin levels further modulate the mRNA and protein levels of Oct4 (also known as POU5F1), Nanog and Sox2, and have an impact upon the differentiation of mESCs towards neural fates. In assessing potential upstream inputs to this new p120-catenin-REST-CoREST pathway, REST gene targets were found to respond to the level of E-cadherin, with evidence suggesting that p120-catenin transduces signals between E-cadherin and the nucleus. In summary, we provide the first evidence for a direct upstream modulator and/or pathway regulating REST-CoREST, and reveal a substantial role for p120-catenin in the modulation of stem cell differentiation.


Humic substances as a washing agent for Cd-contaminated soils.
Cost-effective and eco-friendly washing agents are in demand for Cd contaminated soils. Here, we used leonardite-derived humic substances to wash different types of Cd-contaminated soils, namely, a silty loam (Soil 1), a silty clay loam (Soil 2), and a sandy loam (Soil 3). Washing conditions were investigated for their effects on Cd removal efficiency. Cadmium removal was enhanced by a high humic substance concentration, long washing time, near neutral pH, and large solution/soil ratio. Based on the tradeoff between efficiency and cost, an optimum working condition was established as follows: humic substance concentration (3150 mg C/L), solution pH (6.0), washing time (2 h) and a washing solution/soil ratio (5). A single washing removed 0.55 mg Cd/kg from Soil 1 (1.33 mg Cd/kg), 2.32 mg Cd/kg from Soil 2 (6.57 mg Cd/kg), and 1.97 mg Cd/kg from Soil 3 (2.63 mg Cd/kg). Cd in effluents was effectively treated by adding a small dose of calcium hydroxide, reducing its concentration below the discharge limit of 0.1 mg/L in China. Being cost-effective and safe, humic substances have a great potential to replace common washing agents for the remediation of Cd-contaminated soils. Besides being environmentally benign, humic substances can improve soil physical, chemical, and biological properties.


Lumbar total disc replacement using ProDisc II: a prospective study with a 2-year minimum follow-up.
A lumbar total disc replacement (TDR) is believed to be a promising substitute in the surgical treatment for lumbar degenerative disc disease. The purpose of this study is to report the clinical and radiographic outcomes of 36 consecutive patients who underwent lumbar TDR using ProDisc II, and the factors associated with a better clinical outcome after a 2-year minimum follow-up. At the time of the latest follow-up, the success rate was 94% of 36 patients according to the criteria of the US Food and Drug Administration. Of the 10 patients unable to work preoperatively, 7 patients returned to work. Moreover, mean score on the visual analog scale for low back and leg pain improved significantly from 7.5 and 4.7 to 3.0 and 1.2, respectively (P<0.001). In addition, mean Oswestry disability index scores improved significantly from 69.2 to 21.0 (P<0.001). Mean disc height at the operative level increased significantly from 9.0 to 17.6 mm, and mean range of motion increased significantly from 9.7 to 12.7 degrees (P<0.01). Statistical analysis showed that the factors associated with a better clinical outcome were single level, and a higher postoperative segmental ROM at the operative level. At a minimum follow-up of 2 years, the lumbar TDR using ProDisc II showed excellent clinical and radiographic outcomes without any significant complication. However, future efforts need to be directed toward the evaluation of a larger number of patients with longer follow-up.


Defective mismatch repair and benefit from bevacizumab for colon cancer: findings from NSABP C-08.
National Surgical Adjuvant Breast and Bowel Project protocol C-08 tested the worth of adding 1 year of bevacizumab to oxaliplatin-based standard adjuvant chemotherapy regimen in the treatment of stage II/III colon cancer. Although the overall result was negative, the possibility that a molecularly defined subset could benefit from bevacizumab cannot be ruled out. We performed post hoc Cox regression analyses to test for marker-by-treatment interactions for standard pathological features and survival analyses using the Kaplan-Meier method. All statistical tests were two-sided and considered statistically significant at the .05 level. Patients diagnosed with mismatch repair defective (dMMR) tumors derived statistically significant survival benefit from the addition of bevacizumab (hazard ratio [HR] = 0.52; 95% confidence interval [CI] = 0.29 to 0.94; P = .02) in contrast with no benefit in patients diagnosed with mismatch repair proficient tumors (HR = 1.03; 95% CI = 0.84 to 1.27; p = .78; P(interaction)= .04). Although a post hoc finding, this data suggests that a molecularly defined subset of colon cancer patients may derive clinical benefit from antiangiogenesis agents and underscores the need for independent validation in other clinical trials.


[The correlation of the indices of animal longevity and mortality in stationary populations with a constant rate of mortality].
Equations have been derived on the basis of general ratios of the numbers of different age groups of animals that allow to estimate the mortality coefficient in populations with stationary age structure and intensity of mortality that does not depend on age at their continuous and discontinuous replenishing by frequency of occurrence of individuals of the maximal age. The proposed method of estimation of mortality has been tested on models with different numbers of animals and age classes. The equation gives a non-biased estimate of mortality coefficient for populations with discontinuous replenishing with young individuals at very small sample sizes (less than 10 individuals).


Fine-root carbon and nitrogen concentration of European beech (Fagus sylvatica L.) in Italy Prealps: possible implications of coppice conversion to high forest.
Fine-root systems represent a very sensitive plant compartment to environmental changes. Gaining further knowledge about their dynamics would improve soil carbon input understanding. This paper investigates C and N concentrations in fine roots in relation to different stand characteristics resulting from conversion of coppiced forests to high forests. In order to evaluate possible interferences due to different vegetative stages of vegetation, fine-root sampling was repeated six times in each stand during the same 2008 growing season. Fine-root sampling was conducted within three different soil depths (0-10; 10-20; and 20-30 cm). Fine-root traits were measured by means of WinRHIZO software which enable us to separate them into three different diameter classes (0-0.5, 0.5-1.0 and 1.0-2.0 mm). The data collected indicate that N concentration was higher in converted stands than in the coppiced stand whereas C concentration was higher in the coppiced stand than in converted stands. Consequently the fine-root C:N ratio was significantly higher in coppiced than in converted stands and showed an inverse relationship with fine-root turnover rate, confirming a significant change of fine-root status after the conversion of a coppice to high forest.


Synthesis of bacteriophage M13-specific proteins in a DNA-dependent cell-free system. II. In vitro synthesis of biologically active gene 5 protein.
It is shown that gene 5 protein of bacteriophage M13 is one of the major proteins synthesized in vitro under the direction of M13 replicative-form DNA. By means of DNA-cellulose chromatography, this protein has been purified to homogeneity and its biological characteristics have been compared with those of its native counterpart. Like native gene 5 protein, the purified, in vitro-synthesized protein binds tightly and selectively to single-stranded, but not to double-stranded, DNAs. These results suggest that truly functional gene 5 protein is made in the cell-free system.


Thymidine transport in phytohaemagglutinin-stimulated pig lymphocytes.
Thymidine and uridine transporters in peripheral pig lymphocytes have structural features in common, but are not identical. Accelerated entry of [3H]thymidine begins 12h after the addition of phytohaemagglutinin. The increased thymidine uptake into the cells is characterized by an increase in Vmax. Without alteration of the apparent Km(0.6+/-0.08muM). Thymidine kinase activity is increased 12h after stimulation. Both the increased thymidine uptake and the increased thymidine kinase activity are inhibited in cultures incubated with puromycin: rates of degradation of the two systems are unchanged after phytohaemagglutinin addition, and indicate similar half-lives of about 2h. Thymidine kinase is rate-limiting for thymidine entry up to 18h after phytohaemagglutinin addition; increase in its synthesis is detectable about 6h before net incorporation of thymidine into DNA is significantly promoted.


Selection, proliferation and differentiation of bone marrow-derived liver stem cells with a culture system containing cholestatic serum in vitro.
To explore the feasibility of direct separation, selective proliferation and differentiation of the bone marrow-derived liver stem cells (BDLSC) from bone marrow cells with a culture system containing cholestatic serum in vitro. Whole bone marrow cells of rats cultured in routine medium were replaced with conditioning selection media containing 20 mL/L, 50 mL/L, 70 mL/L, and 100 mL/L cholestatic sera, respectively, after they attached to the plates. The optimal concentration of cholestatic serum was determined according to the outcome of the selected cultures. Then the selected BDLSC were induced to proliferate and differentiate with the addition of hepatocyte growth factor (HGF). The morphology and phenotypic markers of BDLSC were characterized using immunohistochemistry, RT-PCR and electron microscopy. The metabolic functions of differentiated cells were also determined by glycogen staining and urea assay. Bone marrow cells formed fibroblast-like but not hepatocyte-like colonies in the presence of 20 mL/L cholestatic serum. In 70 mL/L cholestatic serum, BDLSC colonies could be selected but could not maintain good growth status. In 100 mL/L cholestatic serum, all of the bone marrow cells were unable to survive. A 50 mL/L cholestatic serum was the optimal concentration for the selection of BDLSC at which BDLSC could survive while the other populations of the bone marrow cells could not. The selected BDLSC proliferated and differentiated after HGF was added. Hepatocyte-like colony-forming units (H-CFU) then were formed. H-CFU expressed markers of embryonic hepatocytes (AFP, albumin and cytokeratin 8/18), biliary cells (cytokeratin 19), hepatocyte functional proteins (transthyretin and cytochrome P450-2b1), and hepatocyte nuclear factors (HNF-1alpha and HNF-3beta). They also had glycogen storage and urea synthesis functions, two of the critical features of hepatocytes. The selected medium containing cholestatic serum can select BDLSC from whole bone marrow cells. It will be a new way to provide a readily available alternate source of cells for clinical hepatocyte therapy.


Comparison of the effects of losartan, captopril, angiotensin II type 2 receptor agonist compound 21, and MAS receptor agonist AVE 0991 on myocardial ischemia-reperfusion necrosis in rats.
Myocardial ischemia may occur as a result of pathophysiological and therapeutical applications such as atherosclerosis, thromboembolism, percutaneous transluminal coronary angioplasty, coronary artery bypass, and transplantation. In this study, we aimed to compare the effects of angiotensin (Ang) II type 2 (AT2 ) selective receptor agonist Compound 21 (C21), MAS receptor agonist AVE 0991, Ang II type 1 (AT1 ) selective receptor blocker losartan, and Ang-converting enzyme inhibitor captopril on haemodynamic parameters and infarct size on myocardial ischemia/reperfusion (MI/R)-induced necrosis in rats. To induce necrosis in the heart of rats, reperfusion for 2 h following ischemia for 30 min to the descending branch of the left main coronary artery was achieved. C21 (0.03 mg/kg), AVE 0991 (576 μg/kg), losartan (2 mg/kg), and captopril (3 mg/kg) were administered as an intravenous infusion at 10 min before and throughout the ischemia. Then, the infarct size and risk area were calculated from the heart. The percentage of myocardial infarct size to area at risk ratio (%IS/AR) of groups was Control (MI/R) group: 48.9 ± 8.8%; C21 group: 31.1 ± 7.8%; AVE 0991 group: 29.9 ± 4.8%; C21 + AVE 0991 group: 28.2 ± 3.3%; Losartan + AVE 0991 group: 30.8 ± 5.8%; Captopril + AVE 0991 group: 31.7 ± 7.7%. %IS/AR of the drug-treated groups decreased significantly when compared to the MI/R group (P < 0.05). Our results indicate that the importance of AT1 , AT2 , and MAS receptors in the MI/R injury. Inhibition of Ang II formation by captopril, blockade of AT1 receptor with losartan, and stimulation of AT2 receptor with C21 and MAS receptor with AVE 0991 showed beneficial effects by reducing infarct size.


Management of eight labor and delivery patients dependent on buprenorphine (Subutex™): A retrospective chart review.
Background: Opioid use during pregnancy is a growing concern in the United States. Buprenorphine has been recommended by "The American College of Obstetrics and Gynecology" as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy. The partial μ-opioid agonists' unique pharmacology, including its long half time and high affinity to the μ-opioid receptor, complicates patient management in a highly kinetic, and often urgent field like obstetric anesthesia. We reviewed our management and outcomes in this medically complex population. Methods: An Institutional Review Board (IRB) approved retrospective chart review was conducted of women admitted to the University of Washington Medical Center Labor and Delivery unit from July 2012 to November 2013 using buprenorphine. All deliveries, including intrauterine fetal demise, were included. Results: Eight women were admitted during this period to our L&D floor on buprenorphine. All required peri-partum anesthetic management either for labor and/or cesarean delivery management. Analgesic management included dilaudid or fentanyl PCA and/or continued epidural infusion, and in one instance ketamine infusion, while the pre-admission buprenorphine regimen was continued. Five babies were viable, two women experienced intrauterine fetal death at 22 and 36 weeks gestational age (GSA), respectively, and one neonate died shortly after delivery due to a congenital diaphragmatic hernia. Conclusions: This case series illuminates the medical complexity of parturients using buprenorphine. Different treatment modalities in the absence of evidence-based guidelines included additional opioid administration and continued epidural analgesia. The management of post-cesarean pain in patients on partial μ-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care.


MYC amplifications in myeloma cell lines: correlation with MYC-inhibitor efficacy.
In multiple myeloma, elevated MYC expression is related to disease initiation and progression. We found that in myeloma cell lines, MYC gene amplifications were common and correlated with MYC mRNA and protein. In primary cell samples MYC mRNA levels were also relatively high; however gene copy number alterations were uncommon. Elevated levels of MYC in primary myeloma cells have been reported to arise from complex genetic aberrations and are more common than previously thought. Thus, elevated MYC expression is achieved differently in myeloma cell lines and primary cells. Sensitivity of myeloma cell lines to the MYC inhibitor 10058-F4 correlated with MYC expression, supporting that the activity of 10058-F4 was through specific inhibition of MYC.


National responses to global health targets: exploring policy transfer in the context of the UNAIDS '90-90-90' treatment targets in Ghana and Uganda.
Global health organizations frequently set disease-specific targets with the goal of eliciting adoption at the national-level; consideration of the influence of target setting on national policies, programme and health budgets is of benefit to those setting targets and those intended to respond. In 2014, the Joint United Nations Programme on HIV/AIDS set 'ambitious' treatment targets for country adoption: 90% of HIV-positive persons should know their status; 90% of those on treatment; 90% of those achieving viral suppression. Using case studies from Ghana and Uganda, we explore how the target and its associated policy content have been adopted at the national level. That is whether adoption is in rhetoric only or supported by programme, policy or budgetary changes. We review 23 (14 from Ghana, 9 from Uganda) national policy, operational and strategic documents for the HIV response and assess commitments to '90-90-90'. In-person semi-structured interviews were conducted with purposively sampled key informants (17 in Ghana, 20 in Uganda) involved in programme-planning and resource allocation within HIV to gain insight into factors facilitating adoption of 90-90-90. Interviews were transcribed and analysed thematically, inductively and deductively, guided by pre-existing policy theories, including Dolowitz and Marsh's policy transfer framework to describe features of the transfer and the Global Health Advocacy and Policy Project framework to explain observations. Regardless of notable resource constraints, transfer of the 90-90-90 targets was evident beyond rhetoric with substantial shifts in policy and programme activities. In both countries, there was evidence of attempts to minimize resource constraints by seeking programme efficiencies, prioritization of programme activities and devising domestic financing mechanisms; however, significant resource gaps persist. An effective health network, comprised of global and local actors, mediated the adoption and adaptation, facilitating a shift in the HIV programme from 'business as usual' to approaches targeting geographies and populations.


Seeing is believing: hot electron based gold nanoplasmonic optical hydrogen sensor.
We report on the rapid optical detection of gaseous hydrogen using hot electrons generated from resonantly excited substrate-based gold nanohemispheres (Au NHs). We consider hot electron induced H2 dissociation and the subsequent formation of a metastable gold hydride (AuHx) to account for changes in optical transmission. The excitation wavelength was varied to demonstrate a maximum response at the localized surface plasmon resonance (LSPR) wavelength of the AuNHs. Numerical simulations, using the discrete dipole approximation, were employed to corroborate the optical changes associated with the formation of metastable AuHx. Finite time difference domain (FDTD) calculations were also performed to account for the enhanced photocatalytic activity arising due to the confinement of electric fields by the Au NHs. FDTD simulations show that the excitation of the Au NHs plasmon modes generates stronger electric fields at the interface in comparison to a spherical geometry of similar dimensions.


Imaging approaches to understand disease complexity: chronic obstructive pulmonary disease as a clinical model.
The clinical manifestations of chronic obstructive pulmonary disease (COPD) reflect an aggregate of multiple pulmonary and extrapulmonary processes. It is increasingly clear that full assessment of these processes is essential to characterize disease burden and to tailor therapy. Medical imaging has advanced such that it is now possible to obtain in vivo insight in the presence and severity of lung disease-associated features. In this review, we have assembled data from multiple disciplines of medical imaging research to review the role of imaging in characterization of COPD. Topics include imaging of the lungs, body composition, and extrapulmonary tissue metabolism. The primary focus is on imaging modalities that are widely available in clinical care settings and that potentially contribute to describing COPD heterogeneity and enhance our insight in underlying pathophysiological processes and their structural and functional effects.


Analysis of the exactness of mean-field theory in long-range interacting systems.
Relationships between general long-range interacting classical systems on a lattice and the corresponding mean-field models (infinitely long-range interacting models) are investigated. We study systems in arbitrary dimension d for periodic boundary conditions and focus on the free energy for fixed value of the total magnetization. As a result, it is shown that the equilibrium free energy of the long-range interacting systems are exactly the same as that of the corresponding mean-field models (exactness of the mean-field theory). Moreover, the mean-field metastable states can be also preserved in general long-range interacting systems. It is found that in the case that the magnetization is conserved, the mean-field theory does not give correct property in some parameter region.


A quantitative echocardiographic study of champion childhood swimmers.
An echocardiographic evaluation of 77 members of a championship childhood swim team showed dimensional variations from normal in most athletes. Cardiac walls were thicker than the 95th percentile of normal: right ventricular anterior wall exceeded the 95th percentile in 100%, interventricular septum in 83% and left ventricular posterior wall in 91%. The left ventricular and left atrial cavities in diastole had mean values at the 50th percentile of normal but showed considerable scatter. The left ventricular cavity in systole had a mean value less than the 5th percentile of normal and also showed wide scatter. The aortic root and the aortic intercusp dimension exceeded the 95th percentile of normal in most subjects, 74% and 77%, respectively. No correlation existed between the coach's estimate of championship ability and echocardiographic wall or chamber sizes. Children who participate extensively in athletic training programs such as swimming may have echocardiograms which are quantitatively different from those of nonathletic younsters.


The association between mid-facial morphology and climate in northeast Europe differs from that in north Asia: Implications for understanding the morphology of Late Pleistocene Homo sapiens.
The climate of northeastern Europe is likely to resemble in many ways Late Pleistocene periglacial conditions in Europe, but there have been relatively few studies exploring the association between climate and morphology in the mid-face of modern northeastern European populations. To fill this gap, we sampled 540 male skulls from 22 European and Near Eastern groups, including 314 skulls from 11 populations from northeastern Europe, to test for possible climate-morphology association at the continental scale. Our results found a moderate and highly significant association (R = 0.48, p = 0.0013, Mantel test) between sets of 23 mid-facial measurements and eight climatic variables. A partial least squares analysis revealed this association to be mostly driven by differences between groups from northeastern Europe and populations from the Mediterranean and the Caucasus. Matrices of between-group genetic distances based on Y-chromosome and mtDNA markers, as well as cranial non-metric and geographic distance matrices, were used to control for the possible influence of shared population history. Irrespective of which measure of neutral between-population distances is taken into account, the association between cranial variables and climate remains significant. The pattern of association between climate and morphology of the mid-face in western Eurasia was then compared to that in east and north Asia. Although differences between the two were found, there were also similarities that support existing functional interpretations of morphology for the bony parts of the upper airways. Last, in a preliminary analysis using a reduced set of measurements, mid-facial morphology of several Upper Paleolithic European Homo sapiens specimens was found to be more similar to groups from northern and northeastern Europe than to southern European populations. Thus, the population of northeastern Europe rather than east and north Asian groups should be used as a model when studying climate-mediated mid-facial morphology of Upper Paleolithic European H. sapiens.


Isoproterenol-induced restoration of contraction in K+-depolarized hearts: relationship to cAMP.
The action of isoproterenol on inotropic state, cAMP concentration, and phosphorylase b-to-a conversion was studied under conditions that are known to alter membrane properties in guinea pig papillary muscles. In accord with the results of other investigators, contractile events induced by electrical stimulation were abolished by tetrodotoxin (10 microM) or 22 mM K+ and were subsequently restored by the addition of isoproterenol (10 nM-100 microM). However, in the presence of 22 mM K+, but not tetrodotoxin, the dose-response and temporal relationships between isoproterenol and elevations in cAMP concentration were shifted to the right, whereas those for phosphorylase activation were shifted to the left. Thus the low concentrations (less than 10 nM) of isoproterenol that restored tension development did not produce a measurable increase in cAMP. Contractile responses induced by 10 nM isoproterenol were blocked by (--)-propranolol but not by (+)-propranolol or phentolamine. Methoxamine did not restore contractile events in 22 mM K+-treated muscles or induce changes in cAMP content or phosphorylase activation. These results show that conditions can be obtained (e.g., partial depolarization of cardiac cell membranes) in which beta-adrenergic receptor activation leads to restoration of inotropic state in guinea pig myocardium without an obligatory increase in tissue cAMP content. The restoration of contractile events and enhancement of phosphorylase response under these conditions suggest that beta-adrenergic receptor activation may lead to Ca2+-channel activation directly or by increasing a small pool of cAMP and thereby altering localized protein phosphorylation in the cell membrane.


The Impact of Minimally Invasive Gastrectomy on Survival in the USA.
Minimally invasive surgical approaches for gastric adenocarcinoma are increasing in prevalence. Although recent studies suggest such approaches are associated with improvements in short-term outcomes, long-term outcomes have not been well studied. This study aimed to evaluate the impact of minimally invasive gastrectomy on long-term survival. The National Cancer Database (NCDB) was used to identify patients who underwent gastrectomy for adenocarcinoma between 2010 and 2015. Patient characteristics were stratified by open and minimally invasive approaches and compared using chi-square and t tests. Unadjusted survival functions were estimated using Kaplan-Meier methodology. Multivariable modeling of risks factors for survival was analyzed with Cox proportional hazard models. Covariate imbalance was controlled using propensity score matching. The study included 17,449 patients who underwent gastrectomy. Cox proportional hazard modeling demonstrated that minimally invasive surgery improved survival (hazard ratio = 0.86, P < 0.0001). Predictors of worsened survival included community facility type, comorbidities, tumor size, extent of gastrectomy, clinical T and N staging (P < 0.0060 for all). After propensity score matching, minimally invasive surgery had a significantly improved survival at 5 years compared to an open approach, 51.9% versus 47.7% (P < 0.0001). Survival was not significantly different between propensity score-matched patients who received laparoscopic and robotic approaches (P = 0.2611). Minimally invasive approaches for gastric carcinoma are associated with improved long-term survival. There was no significant difference in survival when comparing laparoscopic to robotic gastrectomy. The mechanisms that drive these improvements deserve further investigation.


Predicting the potential for risky behavior among those "too young" to drink as the result of appealing advertising.
A survey of 273 children in Washington state used a predrinking behavior index as a behavioral outcome to assess media effects on precursors to drinking among children for whom alcohol consumption is not yet occurring. It also examined age trends in relevant beliefs and behaviors. Perceptions of advertising desirability, the extent to which it seemed appealing, increased steadily from third to ninth grade, whereas identification with portrayals, the degree to which individuals wanted to emulate portrayals, leveled off after sixth grade. Expectancies, positive social benefits perceived to be associated with drinking alcohol, also increased with age, particularly between sixth and ninth grade. When demographics and grade level were controlled, desirability predicted identification, and both predicted expectancies, which is consistent with media decision-making theory. Expectancies correlated with alcohol predrinking behavior, and expectancies predicted risky behavior, with demographics and grade level controlled. Predrinking behavior and reported risky behavior were correlated. The results provide cross-sectional support for the view that beliefs and desires developing by third grade prime children for future decisions regarding substance use.


Remarkable water-mediated proton conductivity of two porous zirconium(IV)/hafnium(IV) metal-organic frameworks bearing porphyrinlcarboxylate ligands.
Obtaining crystalline materials with high structural stability as well as super proton conductivity is a challenging task in the field of energy and material chemistry. Therefore, two highly stable metal-organic frameworks (MOFs) with macro-ring structures and carboxylate groups, Zr-TCPP (1) and Hf-TCPP (2) assembled from low-toxicity as well as highly coordination-capable Zr(IV)/Hf(IV) cations and the multifunctional linkage, meso-tetra(4-carboxyphenyl)porphine (TCPP) have attracted our strong interest. Note that TCPP as a large-size rigid ligand with high symmetry and multiple coordination sites contributes to the formation of the two stable MOFs. Moreover, the pores with large sizes in the two MOFs favor the entry of more guest water molecules and thus result in high H2O-assisted proton conductivity. First, their distinguished structural stabilities covering water, thermal and chemical stabilities were verified by various determination approaches. Second, the dependence of the proton conductivity of the two MOFs on temperature and relative humidity (RH) is explored in depth. Impressively, MOFs 1 and 2 demonstrated the optimal proton conductivities of 4.5 × 10-4 and 0.78 × 10-3 S·cm-1 at 100 °C/98 % RH, respectively. Logically, based on the structural information, gas adsorption/desorption features, and activation energy values, their proton conduction mechanism was deduced and highlighted.


The C-H and alpha(C-X) bond dissociation enthalpies of toluene, C6H5-CH2X (X = F, Cl), and their substituted derivatives: a DFT study.
The homolytic C-H bond dissociation enthalpies (BDEs) of toluene and its para- and meta-substituted derivatives have been estimated by using the (RO)B3LYP/6-311++G(2df,2p)//(U)B3LYP/6-311G(d,p) procedure. The performance of two other hybrid functionals of DFT, namely, B3PWP91 and O3LYP, has also been evaluated using the same basis sets and molecules. Our computed results are compared with the available experimental values and are found to be in good agreement. The (RO)B3LYP and (RO)O3LYP procedures are found to produce reliable BDEs for the C-H bonds in toluene and the C-X (X = F, Cl) bond in alpha-substituted toluene (C6H5-CH2X) and their substituted derivatives. The substituent effect on the BDE values has been analyzed in terms of the ground-state effect and the radical effect. The effect of polarization of the C-H bond on the substituent effect is also analyzed. The BDE(C-H) and BDE(C-X) values for alpha-substituted (X = F and Cl) toluenes with a set of para substituents are presented for the first time.


Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation.
S-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma. Female BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFκB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings. N6022 attenuated AHR (ED50 of 0.015 ± 0.002 mg/kg; Mean ± SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFκB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh. The significant bronchodilatory and anti-inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease.


Tropical seagrass Halophila stipulacea shifts thermal tolerance during Mediterranean invasion.
Exotic species often face new environmental conditions that are different from those that they are adapted to. The tropical seagrass Halophila stipulacea is a Lessepsian migrant that colonized the Mediterranean Sea around 100 years ago, where at present the minimum seawater temperature is cooler than in its native range in the Red Sea. Here, we tested if the temperature range in which H. stipulacea can exist is conserved within the species or if the exotic populations have shifted their thermal breadth and optimum due to the cooler conditions in the Mediterranean. We did so by comparing the thermal niche (e.g. optimal temperatures, and upper and lower thermal limits) of native (Saudi Arabia in the Red Sea) and exotic (Greece and Cyprus in the Mediterranean Sea) populations of H. stipulacea. We exposed plants to 12 temperature treatments ranging from 8 to 40°C for 7 days. At the end of the incubation period, we measured survival, rhizome elongation, shoot recruitment, net population growth and metabolic rates. Upper and lower lethal thermal thresholds (indicated by 50% plant mortality) were conserved across populations, but minimum and optimal temperatures for growth and oxygen production were lower for Mediterranean populations than for the Red Sea one. The displacement of the thermal niche of exotic populations towards the colder Mediterranean Sea regime could have occurred within 175 clonal generations.


The role of TGF-beta in epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II).
The role of transforming growth factor-beta (TGF-beta) in epithelial malignancy is complex, but it is becoming clear that, in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-beta can function to advance tumor progression. We review the evidence to show that the pro-oncogenic functions of TGF-beta are associated with (1) a partial loss of response to the ligand, (2) defects of components of the TGF-beta signal transduction pathway, (3) over-expression and/or activation of the latent complex, (4) epithelial-mesenchymal transition, and (5) recruitment of signaling pathways which act in concert with TGF-beta to facilitate the metastatic phenotype. These changes are viewed in the context of what is known about the pathogenesis of oral cancer and whether this knowledge can be translated into the development of new therapeutic modalities.


Treatment of type 2 diabetes mellitus via reversing insulin resistance and regulating lipid homeostasis in vitro and in vivo using cajanonic acid A.
The present study investigated the effects of cajanonic acid A (CAA), extracted from the leaves of Cajanus cajan (L.) Millsp with a purity of 98.22%, on the regulatory mechanisms of glucose and lipid metabolism. HepG2 cells transfected with a protein‑tyrosine phosphatase 1B (PTP1B) overexpression plasmid were established. The cells, induced with insulin resistance by dexamethasone (Dex) treatment, together with type 2 diabetes mellitus (T2DM) model rats and ob/ob mice, were used in the present study. The effects of CAA treatment on the differentiation of 3T3‑L1 adipocytes were determined using Oil Red O. The expression levels of insulin signaling factors were detected via reverse transcription‑quantitative polymerase chain reaction and western blot analyses. The results revealed that the overexpression of PTP1B contributed to insulin resistance, which was reversed by CAA treatment via inhibiting the activity of PTP1B and by regulating the expression of associated insulin signaling factors. The treatment of cell lines with Dex led to increased expression of PTP1B but decreased glucose consumption, and decreased tyrosine phosphorylation of insulin receptor, insulin receptor substrate 1, and phosphoinositide 3‑kinase. Treatment with CAA not only reduced the fasting blood glucose levels and protected organs from damage, but also reduced the serum fasting levels of total cholesterol, triglycerides and low‑density lipoprotein cholesterol in the T2DM rats. CAA treatment also inhibited adipocyte differentiation and decreased the mRNA levels of various adipogenic genes. Furthermore, CAA treatment restored the transduction of insulin signaling by regulating the expression of PTP1B and associated insulin signaling factors. Treatment with CAA also reduced the problems associated with hyperglycemia and hyperlipidemia. In conclusion, CAA may be used to cure T2DM via restoring insulin resistance and preventing obesity.


Environmental characteristics associated with the presence of the Spinetail devil ray (Mobula mobular) in the eastern tropical Pacific.
In the eastern Pacific Ocean, the tropical tuna purse-seine fishery incidentally captures high numbers of five mobulid bycatch species; all of which are classified as mortalities by the Inter-American Tropical Tuna Commission due to uncertainties in post-release mortality rates. To date, the factors (operational or environmental) leading to the capture of these species by the fishery have not been well studied. Here, we developed Generalized Additive Models for fisheries observer data to analyze the relationships between the presence/absence of Mobula mobular bycatch and oceanographic conditions, the spatial and temporal variability in fishing location, and the set type (associated with dolphins, free-swimming tuna schools or floating objects). Our results suggest that chlorophyll concentration and sea surface height are the most important variables to describe the presence of M. mobular in conjunction with geographic location (latitude and longitude) and set type. Presence of the species was predicted in waters with chlorophyll concentrations between 0.5-1 mg·m-3 and with sea surface height values close to 0; which indicates direct relationships with productive upwelling systems. Seasonally, M. mobular was observed more frequently during December-January and August-September. We also found the highest probability of presence observed in School sets, followed by Dolphin sets. Three areas were observed as important hotspots: the area close to the coastal upwelling of northern Peru, the area west to Islands Colon Archipelago (Galapagos) and the area close to the Costa Rica Dome. This information is crucial to identify the mobulids habitat and hotspots that could be managed and protected under dynamic spatial management measures to reduce the mortality of mobulid rays in the eastern Pacific purse-seine fishery and, hence, ensure the sustainability of the populations of these iconic species.


Refractory generalised convulsive status epilepticus : a guide to treatment.
The patient with status epilepticus has continuous or rapidly repeating seizures. Generalised convulsive status epilepticus (GCSE) is the most common form of the disorder and is a life-threatening condition that requires prompt medical management. Status epilepticus that does not respond to first-line benzodiazepines (lorazepam or diazepam) or to second-line antiepileptic drugs (phenytoin/fosphenytoin, phenobarbital or valproate) is usually considered refractory and requires more aggressive treatment. The optimal treatment of refractory GCSE has not been defined, but patients should be treated in an intensive care unit, as artificial ventilation and haemodynamic support are required. Invasive haemodynamic monitoring is often necessary and EEG monitoring is essential. The drug treatment of refractory GCSE involves general anaesthesia with continuous intravenous anaesthetics given in doses that abolish all clinical and electrographic epileptic activity, often requiring sedation to the point of burst suppression on the EEG. Barbiturate anaesthetics, pentobarbital in the US and thiopental sodium in Europe and Australia, are the most frequently used agents and are highly effective for refractory GCSE both in children and adults. Indeed, they remain the only way to stop seizure activity with certainty in severely refractory cases. Other options are midazolam for adults and children and propofol for adults only.Regardless of the drug selected, intravenous fluids and vasopressors are usually required to treat hypotension. Once seizures have been controlled for 12-24 hours, continuous intravenous therapy should be gradually tapered off if the drug being administered is midazolam or propofol. Gradual tapering is probably not necessary with pentobarbital or thiopental sodium. Continuous EEG monitoring is required during high-dose treatment and while therapy is gradually withdrawn. During withdrawal of anaesthetic therapy, intravenous phenytoin/fosphenytoin or valproate should be continued (these agents having been administered during earlier phases of GCSE) to ensure an adequate baseline of antiepileptic medication so as to prevent the recurrence of status epilepticus. If additional medication is needed, the most appropriate antiepileptic drugs are gabapentin for focal seizures and levetiracetam and topiramate for all seizure types, as these drugs can be started at high doses with a low risk of idiosyncratic reactions. Even with current best practice, mortality in patients who experience refractory GCSE is about 50% and only the minority return to their premorbid functional baseline. Therefore, new treatment options are urgently needed. The ideal new drug for refractory GCSE would be one that has the ability to stop seizures more effectively and safely than current drugs, and that has neuroprotective properties to prevent the brain damage and neurological morbidity caused by GCSE.


ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors.
ARQ-197 is an oral, selective c-Met inhibitor under development by ArQule Inc, in partnership with Daiichi Sankyo Co Ltd and Asian licensee Kyowa Hakko Kirin Co Ltd, for the potential treatment of solid tumors, including NSCLC, hepatocellular carcinoma and pancreatic cancer, as well as microphthalmia transcription factor-driven tumors. c-Met, a key cell surface receptor tyrosine kinase involved in diverse regulatory functions, is often aberrantly activated in human cancers. While the precise mechanism of action of ARQ-197 remains undefined, data from preclinical studies have demonstrated that ARQ-197 inhibits c-Met activation in numerous human tumor cell lines and specifically targets c-Met in various cancer types; uniquely, ARQ-197 inhibits c-Met in a non-ATP-competitive manner. Phase I/II clinical trials demonstrated promise in terms of both tolerability and tumor response. Intriguingly, dose-limiting adverse effects were hematological in nature. Combinational trials are also ongoing to take advantage of the signaling crosstalk between c-Met and other oncogenic signaling systems. Prioritization of the clinical development of c-Met inhibitors, such as ARQ-197, among different tumor disease types is a key challenge at present; an improved understanding of the prediction of molecular determinants in tumors with respect to c-Met kinase as the driver oncogenic receptor, and of the prediction of tumor response, is still urgently needed.


Barriers and facilitators to hepatitis C (HCV) screening and treatment-a description of prisoners' perspective.
Hepatitis C virus (HCV) infection is a global epidemic with an estimated 71 million people infected worldwide. People who inject drugs (PWID) are overrepresented in prison populations globally and have higher levels of HCV infection than the general population. Despite increased access to primary health care while in prison, many HCV infected prisoners do not engage with screening or treatment. With recent advances in treatment regimes, HCV in now a curable and preventable disease and prisons provide an ideal opportunity to engage this hard to reach population. To identify barriers and enablers to HCV screening and treatment in prisons. A qualitative study of four prisoner focus groups (n = 46) conducted at two prison settings in Dublin, Ireland. The following barriers to HCV screening and treatment were identified: lack of knowledge, concerns regarding confidentiality and stigma experienced and inconsistent and delayed access to prison health services. Enablers identified included; access to health care, opt-out screening at committal, peer support, and stability of prison life which removed many of the competing priorities associated with life on the outside. Unique blocks and enablers to HCV treatment reported were fear of treatment and having a liver biopsy, the requirement to go to hospital and in-reach hepatology services and fibroscanning. The many barriers and enablers to HCV screening and treatment reported by Irish prisoners will inform both national and international public health HCV elimination strategies. Incarceration provides a unique opportunity to upscale HCV treatment and linkage to the community would support effectiveness.


Variability of cost trajectories over the last year of life in patients with advanced breast cancer in the Netherlands.
In breast cancer patients, treatment at the end of life accounts for a major share of medical spending. However, little is known about the variability of cost trajectories between patients. This study aims to identify underlying latent groups of advanced breast cancer patients with similar cost trajectories over the last year before death. Data from deceased advanced breast cancer patients, diagnosed between 2010 and 2017, were retrieved from the Southeast Netherlands Advanced Breast Cancer (SONABRE) Registry. Costs of hospital care over the last twelve months before death were analyzed, and the variability of longitudinal patterns between patients were explored using group-based trajectory modeling. Descriptive statistics and multinomial logistic regression were applied to investigate differences between the identified latent groups. We included 558 patients. Over the last twelve months before death, mean hospital costs were €2,255 (SD = €492) per month. Costs increased over the last five months and reached a maximum of €3,614 in the last month of life, driven by hospital admissions, while spending for medication declined over the last three months of life. Based on patients' individual cost trajectories, we identified six latent groups with distinct longitudinal patterns, of which only two showed a marked increase in costs over the last twelve months before death. Latent groups were constituted of heterogeneous patients, and clinical characteristics explained membership only to a limited extent. The average costs of advanced breast cancer patients increased towards the end of life. However, we uncovered several latent groups of patients with divergent cost trajectories, which did not reflect the overall increasing trend. The mechanisms underlying the variability in cost trajectories warrants further research.


Transparent surface orientation from polarization imaging using vector operation.
The existing methods for shape measurement using polarization of transparent objects are based on two assumptions: (1) the paraxial assumption, assuming that the reflected ray is parallel to the optical axis of the imaging system; and (2) the s-component approximation assumption, which assumes that the s-component of the reflected light is predominant and the p-component is neglected. To overcome limitations posed by these two assumptions, this paper proposes a method based on the polarization characteristics of reflection from a transparent surface and vector operation. To overcome the paraxial assumption, the normal vector of the transparent surface is deduced by vector operation, analyzing the relationships between the direction vector of reflection, the normal vector of the reflection plane, the intersection line of the reflection plane and imaging plane, and the normal vector of the transparent surface. To overcome the limitations of the s-component approximation assumption, the angle between the s-component and the polarization direction of the reflected light is analyzed, which yields improved measurement precision. An experiment was performed with transparent targets (flat glass positioned at different angles), and the results show that the measurement error with this method is significantly less than those of existing methods. Thus, we believe this method overcomes the abovementioned limitations while also improving measurement precision.


The role of the physical and traffic environment in child pedestrian injuries.
To identify environmental risk factors on residential streets for pediatric pedestrian injuries. The sample consisted of 39 Latino children 0 to 14 years of age injured as pedestrians on a street in the same block as their home and 62 randomly selected neighborhood control subjects matched to the case by city, age or year of birth, ethnicity, and gender. The cases were identified from a population-based hospital and coroner's office surveillance system established in north-central Orange County, CA. Neighborhood assessments were performed from 3:45 PM to 5 PM, a fairly active time for young pedestrians. The cases were compared with the controls using conditional logistic regressions; in this study design, the odds ratios were interpreted as estimates of the incidence rate ratios. Children living in a multifamily residence had an incidence of injury greater than that of children living in single-family residence on a single lot (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.3-7.6). The ORs in the highest category were several times those in the lowest category for both parked vehicles (OR 9.6, 95% CI 2.6-36) and total number of pedestrians observed (OR 4.7, 95% CI 1.4-16). Vehicle parking, total pedestrians, vehicular traffic volume, and speed were examined in a multivariate model. The association of vehicles parked on the street with pedestrian injury risk remained significant. Unlike the crude results, progressively greater vehicular speed was associated with a marked increase in risk. Progressively higher vehicular traffic volume was associated with a progressively lower adjusted OR. The results of this analysis would indicate that residential streets with a high proportion of multifamily residence, over 50% of the curb occupied with parked vehicles, and a large number of pedestrians observed in unenclosed areas should receive high priority for intervention programs to reduce pediatric pedestrian injuries. The analysis suggests that on these streets, measures to reduce the amount of street parking (thus increasing visibility) and reductions in vehicular speed should be considered to decrease pedestrian injuries.


Does intravenous lidocaine prevent laryngospasm after extubation in children?
One hundred otherwise healthy children undergoing tonsillectomy were investigated in a double-blind study to examine the effect of intravenous lidocaine in preventing laryngospasm upon extubation. The children were anesthetized with N2O-O2-halothane and orally intubated. They were randomly given lidocaine, 1.5 mg/kg, or saline intravenously prior to extubation, which took place at the same depth of anesthesia, namely when there were signs of swallowing activity. Eleven children (2%) in each group of 50 developed laryngospasm. From our findings it is concluded that lidocaine, 1.5 mg/kg, does not prevent laryngospasm upon extubation when extubation is carried out at the start of swallowing activity.


[Tuberculosis trend in Madrid region in native and foreign population (2009-2018).]
Tuberculosis is a major public health problem and most cases are concentrated in vulnerable populations. The objective was to describe the incidence rates trend in native and foreign population (2009-2018) in Madrid Region. Retrospective analysis of cases from the Tuberculosis Regional Registry of cases of Madrid Region 2009-2018. Annual incidence rates were calculated by country of birth (Spain, other), sex and age group (<15, 15-34, 35-44, 45-64, >64), using the annual January 1st continuous register population. The infection rate trend and the annual percentage change (APC) were calculated, along with the best jointpoint adjustment using Jointpoint regression. 7,696 cases were analyzed, 48.2% were foreign-born individuals. Average age in native population was 50 years old (SD: 23.96) and 35 (DS: 36.64) in foreign-born individuals (p<0.001). The overall incidence rate decreased from 17.30 in 2009 to 9.00 per 100,000 in 2018 and was higher in men. Pulmonary tuberculosis reduced from 11.90 to 6.55. Among native population, the incidence of TB fell from 10.29 to 5.24 with an APC of -7.3% (95%IC: -8.9; -5.7) (p<0.05), no jointpoint was identified. Among foreign-born individuals the incidence of tuberculosis declined from 46.54 to 25.49, a joint point was identified in 2013, observing an incidence decrease for the period 2009-2013 and APC of -13.8% (IC95%: -17.5; -10.0). The global incidence rate in this period has decreased by approximately 7% per year. However, this reduction occurred mainly in native population. In foreign-born individuals the incidence decreased by approximately 14% during the 2009-2013 period, after this period there have been no significant incidence changes.


Translation, cross-cultural adaptation and factor analysis of the Persian version of ankle instability instrument.
Background: Ankle Instability Instrument (AII) is a questionnaire for determination of ankle stability status. The aim of this study is to cross-culturally translate and investigate the reliability and validity of AII in a sample of Persian-speaking Iranians, suffering from ankle sprain. Methods: One hundred twenty persons with a history of ankle sprain were recruited in the study. All participants completed the Persian version of Ankle Instability Instrument, Cumberland Ankle Instability Tool (CAIT), Foot and Ankle Ability Measure (FAAM) and Foot and Ankle Outcome Score (FAOS) at the baseline. Out of them, 60 randomly selected subjects completed the questionnaires once more, one week later. Face validity, Test-retest reliability, internal consistency, standard error of measurement, minimal metric detectable change, spearman's correlation coefficient and confirmatory factor analysis of AII measured. We used Lisrel v 8.80 software with significant level of p<0.05. Results: Persian version of AII is clear and unambiguous and its qualitative face validity was confirmed in the pilot study on the 20 subjects with a lateral ankle sprain. The interclass correlation coefficient, Cronbach's alpha, standard error of measurement and minimal metric detectable change were 0.93, 0.87, 0.81 and 2.25 (95% confidence interval, 0.85-0.96). The Spearman correlations coefficients between AII, and CAIT, FAAM and FAOS measures were 0.91, 0.71 and 0.69 respectively. The original three factor structure of AII was replicated based on the confirmatory factor analysis. Which showed an adequate fit of the model to the data and goodness-of-various fit indices. Conclusion: The Ankle Instability Instrument Persian Version (AII-PV) is a reliable and valid measure for assessing the ankle stability status.


Rethinking Electronic Effects in Photochemical Hydrogen Evolution Using CuInS2@ZnS Quantum Dots Sensitizers.
Molecular catalysts based on coordination complexes for the generation of hydrogen via photochemical water splitting exhibit a large versatility and tunability of the catalytic properties through chemical functionalization. In the present work, we report on light-driven hydrogen production in an aqueous solution using a series of cobalt polypyridine complexes as hydrogen evolving catalysts (HECs) in combination with CuInS2@ZnS quantum dots (QDs) as sensitizers, and ascorbate as the electron donor. A peculiar trend in activity has been observed depending on the substituents present on the polypyridine ligand. This trend markedly differs from that previously recorded using [Ru(bpy)3]2+ (where bpy = 2,2'-bipyridine) as the sensitizer and can be ascribed to different kinetically limiting pathways in the photochemical reaction (viz. protonation kinetics with the ruthenium chromophore, catalyst activation via electron transfer from the QDs in the present system). Hence, this work shows how the electronic effects on light-triggered molecular catalysis are not exclusive features of the catalyst unit but depend on the whole photochemical system.


Significant efficacy of new transcatheter arterial chemoembolization technique for hepatic metastases of pancreatic neuroendocrine tumors.
The liver is the most frequent site of metastasis of pancreatic neuroendocrine tumors (PNETs). Moreover, hepatic metastasis is a strong prognostic factor for patients with advanced PNETs and is often difficult to treat and cure. We employed our recently developed new transcatheter arterial chemoembolization technique using a fine-powder formulation of cisplatin mixed with degradable starch microspheres (DSM) for the treatment of unresectable hepatic metastases from PNET in five consecutive patients. A total of 24 sessions of TACE was performed. The responses were complete response in one, partial response in three, and stable disease in one patient. All patients were alive at the time of analysis with a median survival of 36 (3-70) months after the initial treatment of TACE. There were no severe toxicities or adverse effects. This new treatment induced a significant effect on hepatic metastases of PNET. The response rate was very high, which has not been achieved even by recent new agents. Our findings may warrant further prospective studies of this therapy.


Brain hemispheric involvement in visuospatial and verbal divergent thinking.
Hemispheric lateralization for creative thinking remains a controversial topic. Early behavioral and neuroimaging research supported right hemisphere dominance in creative thinking, but more recent evidence suggests the left hemisphere plays an equally important role. In addition, the extent to which hemispheric lateralization in specific brain regions relates to individual creative ability, and whether hemispheric dominance relates to distinct task performance, remain poorly understood. Here, using multivariate predictive modeling of resting-state functional MRI data in a large sample of adults (N = 502), we estimated hemispheric segregation and integration for each brain region and investigated these lateralization indices with respect to individual differences in visuospatial and verbal divergent thinking. Our analyses revealed that individual visuospatial divergent thinking performance could be predicted by right-hemispheric segregation within the visual network, sensorimotor network, and some regions within the default mode network. High visuospatial divergent thinking was related to stronger functional connectivity between the visual network, fronto-parietal network, and default mode network within the right hemisphere. In contrast, high verbal divergent thinking performance could be predicted by inter-hemispheric balance within regions mainly involved in complex semantic processing (e.g., lateral temporal cortex and inferior frontal gyrus) and cognitive control processing (e.g., inferior frontal gyrus, middle frontal cortex, and superior parietal lobule). The current study suggests that two distinct forms of functional lateralization support individual differences in visuospatial and verbal divergent thinking. These findings have important implications for our understanding of hemispheric interaction mechanisms of creative thinking.


Ongoing shielding behavior one year post COVID-19: results from a longitudinal study of patients with inflammatory arthritis.
Many patients with inflammatory arthritis (IA) were instructed to shield during the COVID-19 pandemic. Despite the ending of lockdowns and vaccination, large proportions of IA patients were continuing to shield when it is no longer needed. Given the detrimental effects of shielding on mental and physical health, understanding the rates and reasons for shielding is needed to help clinicians advise patients accordingly. This study was a 12-month prospective study following participants with IA during the COVID-19 pandemic. The proportions of IA patients shielding at each time point were calculated. Additionally, regressions and odds ratios for shielding were determined to assess medication type, mental health, and risk perception. While the extent of shielding fluctuated over the year of lockdowns, nearly all IA patients (93.5%) were still engaging in some shielding in 2021, with nearly half (43%) still shielding most or all of the time. Medications that were previously considered higher risk were not significantly associated with higher rates of shielding (OR = 1.60, p = 0.29), but greater symptoms of depression in June 2020 (OR = 1.07, p = 0.03) was both associated with increased the odds of shielding in June 2021. The high rates of IA patients continuing to shield in 2021 put more strain on patients and professionals as social isolation is linked with worsening mental and physical health, as well as greater difficulty with self-management. It is important for clinicians to be aware of this trend to ease the stress on patients.


A statistical approach to IMRT patient-specific QA.
The intensity modulated radiation therapy (IMRT) patient-specific quality assurance (QA) (referred to as QA in this paper for simplicity) process is a time and resource intensive effort in every clinic. The use of a global QA tolerance criterion for all treatment sites may be too tight for some complex sites increasing false negatives and rejections of QA measurements which typically results in wasted efforts, treatment delays, and decreased efficiency. At the same time, other sites requiring a less complex plan might have a high false positive leading to approvals of QA measurements that actually need to be rejected. This work is an effort to adopt statistical tools to1. develop a tool to identify statistical variations in the process, monitor trends, detect outliers, and proactively identify drifts in the overall QA results;2. analyze the results of the QA process, identify similarities and differences between treatment plans of different treatment sites, and evaluate the possibility of site-specific tolerance levels for QA approval tolerances. The analysis was performed for QA measurements made using two ion chamber points. A custom software tool was developed for data processing and analysis. This tool facilitated QA data collection, retrieval, visualization, real-time feedback, and advanced statistical analysis of the data. Statistical techniques based on analysis of variance were used to evaluate the need for site-specific tolerances and statistical process control was used to study statistical variations in the process. A retrospective analysis of the QA process variability was performed in order to identify site-specific tolerances for the QA measurements and to reduce false positive and false negative QA results. From the data, it can be seen that the treatment sites are significantly different and need site-specific tolerance levels for QA approval. The in-house developed tool was used to further monitor the QA process using individual (I), standard deviations (S), and exponentially weighted moving averages charts for process variability studies. The authors have studied the analysis of variance on ion chamber measurements made for IMRT treatment plans on different sites, identified similarities and differences between different sites, and thereby evaluated the need for site-specific tolerances for QA acceptance policy. The authors have proposed a way to calculate the appropriate tolerances for different treatment sites and illustrated the clinical usage. Variability at each step of the process increases the uncertainty in the process. The authors have explained the different approaches taken to reduce the variability at each step of the entire process. This process can be used for the benefit during∕as part of an IMRT commissioning process in any clinic. The authors have also developed a tool to automate the process of data collection, analysis, and monitoring the process quality via standard deviations and EWMA charts.


Effects of novobiocin, coumermycin A1, clorobiocin, and their analogs on Escherichia coli DNA gyrase and bacterial growth.
Novobiocin, coumermycin A1, and clorobiocin, structurally related compounds that antagonize the B subunit of the essential bacterial enzyme DNA gyrase, were compared with 18 of their analogs for the inhibition of Escherichia coli DNA gyrase supertwisting activity in vitro and of bacterial multiplication. This family of compounds has a 4-hydroxy-8-methylcoumarin core substituted in the 7 and 3 positions. Important for enzyme inhibition in vitro is a 7 ether linkage to a 3'-substituted noviose sugar. The 3'-ester-linked 5-methylpyrrole, found in the coumermycin series, conferred at least 10-fold more inhibitory activity than did the similarly linked amide, found in the novobiocin series; lack of the pyrrole and amide results in the loss of inhibitory activity. Of many aryl and alkyl substituents linked as an amide at the 3 position, the 4-hydroxyl-3-(3-methyl-2-butenyl)benzoic acid moiety, found in novobiocin and clorobiocin, and the reduplication of the coumarin-noviose-5-methylpyrrole, found in coumermycin A1, were most effective in gyrase inhibition. In vivo, the ability of these compounds to inhibit the growth of E. coli varied greatly. The enhanced inhibition of gyrase in vitro conferred by a 5-methylpyrrole relative to an amide in the 3'-noviose position was reflected in inhibition of bacterial multiplication. Several substitutions at the 3 position of the coumarin core conferring similar antagonism of gyrase in vitro resulted in substantially different inhibitory activities for E. coli, suggesting that these moieties at the 3 position affect drug access to the intracellular target. This target was shown for isobutyryl PNC-NH2 (PNC-NH2 is 3-amino-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl)noviosyloxy] coumarin) and confirmed for novobiocin, coumermycin A1, and clorobiocin to be in the B subunit of DNA gyrase.


The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis.
Pharmacological treatment of diffuse systemic sclerosis (SSc) directed at the tissue fibrosis has generally been ineffective. Many immunosuppressive drugs have been tried as therapy for SSc, regardless of the disease subtype and/or stage. The aim of this study was to show the efficacy and the toxicity of oral cyclophosphamide and prednisolone therapy on the prevention of fibrosis-based tissue damage in the early stages of the diffuse SSc. Twenty-seven patients with early diffuse SSc were treated with oral cyclophosphamide (1-2 mg/kg/day) plus oral prednisolone (40 mg/every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. All the patients were evaluated using clinical and laboratory parameters every 6 months for 2 years. There was a significant improvement on the skin score, maximal oral opening, flexion index, predicted forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) in the cyclophosphamide group. The decrease in skin score in the cyclophosphamide group started earlier than in the D-penicillamine group. No life-threatening or irreversible adverse reaction was observed. This open study supports the use of oral cyclophosphamide plus prednisolone therapy to prevent fibrosis and its complications in the early stages of diffuse SSc.


Effect of cryoprotectant-induced intracellular ice formation and crystallinity on bactria during cryopreservation.
Cryopreservation is widely used for the long-term storage of bacteria. Glycerol is one of the traditional cryoprotectants used widely to prevent cryoinjury during the cryopreservation of bacteria,although it may be toxic to the cells. To overcome these issues, synthetic antifreeze polymers are also used as cryoprotectants to inhibit ice formation. In the study, we compared the performance of various antifreeze synthetic polymers including poly(vinyl alcohol) (PVA), poly(vinylpyrrolidone), poly(ethylene glycol), and dextran with glycerol, among which PVA performed best on decreasing the ice growth rate.The impacts of glycerol, trehalose, combined with PVA on the survival of S. thermophilus were also explored. Notably,. S. thermophilus stored in 100 mg/mL trehalose and 1 mg/mL PVA +50 mg/mL trehalose combo showed significantly enhanced survival when compared with those in traditional cryoprotectant (20% [v/v] glycerol), which achieved the survival percentage of only 41.03 ± 0.09%. The effects of the freezing temperature and crystallinity on the survival of S. thermophilus were elucidated.


Movers and shakers: Microglial dynamics and modulation of neural networks.
Microglia are multifaceted cells that act as immune sentinels, with important roles in pathological events, but also as integral contributors to the normal development and function of neural circuits. In the last decade, our understanding of the contributions these cells make to synaptic health and dysfunction has expanded at a dizzying pace. Here we review the known mechanisms that govern the dynamics of microglia allowing these motile cells to interact with synapses, and recruit microglia to specific sites on neurons. We then review the molecular signals that may underlie the function of microglia in synaptic remodeling. The emerging picture from the literature suggests that microglia are highly sensitive cells, reacting to neuronal signals with dynamic and specific actions tuned to the need of specific synapses and networks.


Performance Evaluation of the Newly Developed BD Phoenix NMIC-500 Panel Using Clinical Isolates of Gram-Negative Bacilli.
The emergence of carbapenem resistance among gram-negative bacilli (GNB), mediated by carbapenemase production, has necessitated the development of a simple and accurate device for detecting minimum inhibitory concentrations (MICs) and resistance mechanisms, especially carbapenemase production. We evaluated the performance of the BD Phoenix NMIC-500 panel (BD Diagnostic Systems, Sparks, MD, USA) for antimicrobial susceptibility testing (AST) and carbapenemase-producing organism (CPO) detection. We used 450 non-duplicate clinical GNB isolates from six general hospitals in Korea (409 Enterobacteriaceae and 41 glucose non-fermenting bacilli [GNFB] isolates). AST for meropenem, imipenem, ertapenem, ceftazidime, and ceftazidime/avibactam, and CPO detection were performed using the Phoenix NMIC-500 panel. Broth microdilution was used as the reference method for AST. The rates of categorical agreement (CA), essential agreement (EA), minor error (mE), major error (ME), and very major error (VME) were calculated in each antimicrobial. In addition, PCR and sequencing were performed to evaluate the accuracy of CPO detection by the BD Phoenix NMIC-500 panel, and the rate of correct identification was calculated. The CA rates were >90% for all antimicrobials tested with the Enterobacteriaceae isolates, except for imipenem (87.2%). The GNFB CA rates ranged from 92.7% to 100% for all antimicrobials. The ME rates were 1.7% for Enterobacteriaceae and 0% for GNFB. The panel identified 97.2% (243/250) of the carbapenemase-producing isolates. The BD Phoenix NMIC-500 panel shows promise for AST and CPO detection.


The plasma cell associated antigen detectable by antibody VS38 is the p63 rough endoplasmic reticulum protein.
To characterise the 64 kDa intracellular antigen present on normal and neoplastic plasma cells detected by monoclonal antibody VS38 and by another antibody, MC186, of similar reactivity. The VS38 monoclonal antibody was used to screen a bacterially expressed peripheral blood cDNA library, and the immunocytochemical staining of the two antibodies was compared with those raised specifically to the protein identified as the VS38 antigen. A partial cDNA encoding the VS38 antigen was cloned and shown to be identical to the human p63 gene. p63 is a non-glycated, reversibly palmitoylated type II transmembrane protein which is found in rough endoplasmic reticulum. Antibody MC186 also recognised this protein and both VS38 and MC186 together with two antibodies raised to p63 gave identical immunostaining patterns. The VS38 antigen was identified as the rough endoplasmic reticulum protein p63. While it is not exclusively expressed on plasma cells, the presence of p63 distinguishes plasma cells from other lymphoid cells because of their high secretory activity.


Capillary LC coupled with high-mass measurement accuracy mass spectrometry for metabolic profiling.
We have developed an efficient and robust high-pressure capillary LC-MS method for the identification of large numbers of metabolites in biological samples using both positive and negative ESI modes. Initial efforts focused on optimizing the separation conditions for metabolite extracts using various LC stationary phases in conjunction with multiple mobile-phase systems, as applied to the separation of 45 metabolite standards. The optimal mobile and stationary phases of those tested were determined experimentally (in terms of peak shapes, theoretical plates, retention of small, polar compounds, etc.), and both linear and exponential gradients were applied in the study of metabolite extracts from the cyanobacterium Cyanothece sp. ATCC 51142. Finally, an automated dual-capillary LC system was constructed and evaluated for the effectiveness and reproducibility of the chromatographic separations using the above samples. When coupled with a commercial LTQ-orbitrap MS, approximately 900 features were reproducibly detected from Cyanothece sp. ATCC 51142 metabolite extracts. In addition, 12 compounds were tentatively identified, based on accurate mass, isotopic distribution, and MS/MS information.


Clinical and genetic analysis of 26 Chinese patients with neonatal intrahepatic cholestasis due to citrin deficiency.
Neonatal intrahepatic cholestasis due to citrin deficiency (NICCD) is an autosomal recessive disorder caused by SLC25A13 genetic mutations. We retrospectively analyzed 26 Chinese infants with NICCD (years 2014-2022) in Quanzhou City. The plasma citrulline (CIT) concentration analyzed by tandem mass spectrometry (MS/MS), biochemical parameters and molecular analysis results are presented. Twelve genotypes were discovered. The relationship between the CIT concentration and genotype is uncertain. In total, 8 mutations were detected, with 4 variations, c.851_854delGTAT, c.615 + 5G > A, c.1638_1660dup and IVS16ins3kb, constituting the high-frequency mutations. Specifically, we demonstrated 2 patients with NICCD combined with another inborn errors of metabolism (IEM). Patient No. 22 possessed compound heterozygous mutations of c.615 + 5G > A and c.790G > A in the SLC25A13 gene accompanied by compound heterozygous variations of c.C259T and c.A155G in the PTS gene. Additionally, Patient No. 26 carried c.51C > G and c.760C > T in the SLC22A5 gene as well as c.615 + 5G > A and IVS16ins3kb in the SLC25A13 gene. We report a case of the simultaneous occurrence of primary carnitine deficiency (PCD) and NICCD.


Total free energy analysis of fully hydrated proteins.
The total free energy of a hydrated biomolecule and its corresponding decomposition of energy and entropy provides detailed information about regions of thermodynamic stability or instability. The free energies of four hydrated globular proteins with different net charges are calculated from a molecular dynamics simulation, with the energy coming from the system Hamiltonian and entropy using multiscale cell correlation. Water is found to be most stable around anionic residues, intermediate around cationic and polar residues, and least stable near hydrophobic residues, especially when more buried, with stability displaying moderate entropy-enthalpy compensation. Conversely, anionic residues in the proteins are energetically destabilized relative to singly solvated amino acids, while trends for other residues are less clear-cut. Almost all residues lose intraresidue entropy when in the protein, enthalpy changes are negative on average but may be positive or negative, and the resulting overall stability is moderate for some proteins and negligible for others. The free energy of water around single amino acids is found to closely match existing hydrophobicity scales. Regarding the effect of secondary structure, water is slightly more stable around loops, of intermediate stability around β strands and turns, and least stable around helices. An interesting asymmetry observed is that cationic residues stabilize a residue when bonded to its N-terminal side but destabilize it when on the C-terminal side, with a weaker reversed trend for anionic residues.


[Citrobacter persistence in the intestinal tract of guinea pigs depending on the microecological status].
Gnotobiological studies were conducted on germ-free guinea pigs. Association of the animals with the citrobacteria 5396/38 strain led to the reproduction of these bacteria in numbers exceeding the sum total number of all the representatives of the normal microbial flora in the conventional animals. Association lasting for a period of 46 days caused no antibody formation in the blood serum of these animals in difference to conventional guinea pigs immunized parenterally. Conventionalization of the monoflora guinea pigs served as the beginning of population of the intestinal tract by other microbial representatives which replaced the first culture. Biochemical properties of the citrobacteria strains isolated from the monoflora strains were identical to the properties of the initial culture. After the monoflora animals were let out of the isolation cage the citrobacteria strains displayed changes of some differential-diagnostic signs. Passage through the macroorganism of the citrobacteria stain proved to lead to the changes in the antigenic structure.


Epidemiological characteristics, clinical manifestations, and mental health status of human mpox cases: A multicenter cross-sectional study in China.
Human mpox is occurring worldwide, however, evidence from the Asian Pacific Region is limited. In this multicenter cross-sectional study, information of confirmed mpox cases diagnosed between June 1 and July 31, 2023 in China. Information included demographic and epidemiological characteristics, and clinical manifestations, laboratory results, and mental health status of mpox cases. A total of 115 confirmed mpox cases were enrolled. All cases were men. A total of 102 (90.3%) identified as homosexual. The median age was 31.0 years (interquartile range 27.0-36.5). A total of 65 (56.5%) were HIV-positive, of whom 92.3% were receiving antiretroviral therapy (ART). A total of 19/39 (40.4%) had a CD4 cell count <500 cells/μL. Systemic features such as fever (73.0%), lymphadenopathies (49.6%), and myalgia (28.7%) were commonly observed. Skin lesions were present in all participants: 49.6% in the genital area and 27.0% in the perianal area. Vesicular rash (78.3%) and papular rash (44.3%) were the most common lesion morphologies. People living with HIV were more likely to have anxiety than those living without HIV. The majority of mpox cases had primary genital lesions and sexual activities before diagnosis, which supports the likelihood of sexual contact transmission. Guidelines on hospitalization and isolation protocols for mpox patients necessitate further confirmation.


The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability.
Mitochondrial calcium (mCa2+) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial. Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells. Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa2+ overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa2+ efflux in cellular function and suggest that augmenting mCa2+ efflux may be a viable therapeutic strategy in disease.