Inflammatory profile of oxidized phospholipids.
Lipid oxidation products and in particular oxidized phospholipids (OxPL) are increasingly recognized as inducers of chronic inflammation characteristic of atherosclerosis. OxPL stimulate production of chemokines and adhesion of monocytes to endothelial cells. However, accumulating data suggest that, in addition to the proatherogenic and proinflammatory effects, OxPL can stimulate antiinflammatory and tissue-protective mechanisms. Thus, depending on the biological situation, OxPL can either stimulate or inhibit inflammation. In this review, the inflammatory properties of OxPL are discussed together with the underlying receptor, signalling and transcriptional mechanisms.


JuBei Oral Liquid Induces Mitochondria-Mediated Apoptosis in NSCLC Cells.
Although gefitinib brings about tremendous advances in the treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, most of patients become incurable due to drug resistance. JuBei oral liquid (JB) has been widely used to treat pneumonia in clinic. Components of JB were reported to induce apoptosis in NSCLC, which indicated that JB could be a potential antitumor agent for NSCLC patients. In this study, we investigated the effect of JB on gefitinib-sensitive PC-9 and gefitinib-resistant PC-9/GR, H1975 cells as well as its underlying molecular mechanisms. PC-9, PC-9/GR and H1975 cells were treated with JB, LY294002, SCH772984, gefitinib alone or in combination. Then, cell viability, colony formation, cell death, expression of mitochondria-dependent pathway proteins, expression of EGFR, PI3K/AKT, MAPK signal pathway proteins, Bcl-2 mitochondrial translocation, ROS generation and cell apoptosis were examined by MTT, colony forming, live/dead cell staining, Western blot, immunofluorescence and flow cytometry assay. Our results showed that JB significantly induced cell growth inhibition and apoptotic cell death in PC-9, PC-9/GR and H1975 cells. JB activated mitochondria-mediated apoptotic pathway through inhibiting Bcl-2 mitochondrial translocation while inducing Bax translocated into mitochondria along with accumulated ROS production, thereby increasing the release of cytochrome c, subsequently cleaving procaspase9 into cleaved-caspase9 and then cleaving procaspase3 into cleaved-caspase3. Furthermore, the employment of protein kinase inhibitors LY294002 and SCH772984 revealed that the induction of mitochondria-mediated apoptosis by JB was reliant on inactivation of PI3K/AKT and MAPK signal pathways. Moreover, JB could synergize with gefitinib to induce apoptosis in PC-9, PC-9/GR and H1975 cells. These data indicated that JB could be a potential therapeutic agent for NSCLC patients harboring EGFR mutations as well as those under gefitinib resistance.


Does SARS Cov-2 infection affect the IVF outcome - A systematic review and meta-analysis.
What is the effect of SARS Cov-2 on IVF outcome? Mild or asymptomatic Covid-19 infection does not appear to affect clinical or ongoing pregnancy rate after IVF. Covid-19 has been shown to affect female and male fertility and reproductive function. Studies have shown variable results regarding impact of Covid-19 on IVF outcome with few reporting impaired ovarian reserve, oocyte and embryo quality, semen parameters, clinical pregnancy rate (CPR) and live birth rate (LBR) while others reported no effect on IVF outcome. An electronic database search of PubMed, EMBASE, SCOPUS, WHO Covid-19 database, Clinical trials.gov and Cochrane Central was performed for articles published in English language between 1st January 2020 and 15th October 2022 by two independent reviewers using predefined eligibility criteria We have included observational studies both prospective and retrospective, cohort studies, and case control studies and excluded narrative reviews, case studies, cost-effectiveness studies or diagnostic studies. Risk of bias was assessed using NOS and quality of evidence was graded by GRADE pro. Studies comparing women undergoing IVF and comparing Covid-19 affected with those unaffected by Covid-19 were included. Also, studies comparing immune group (infected or vaccinated) in the study group and unaffected as controls (historical controls, IVF cycles done prior to Covid-19 outbreak but matched with study group) were included. Those with no comparison group or published in language other than English language or duplicate studies were excluded. We identified 5046 records and after full text screening of 82 studies, 12 studies were selected for final review. For the clinical pregnancy rate, there was no difference in the CPR in covid recovered or control patients (OR 0.90, 95 % CI = 0.67 to1.21; I2 = 29 %). Similarly, there was no significant effect on implantation rate (RR 0.92, 95 % CI = 0.68 to1.23; I2 = 31 %) and ongoing pregnancy rate (RR 0.96, 95 % CI = 0.79 to 1.15;I2 = 21 %). The mean number of the oocyte retrieved per patient was not significantly different in both the groups (mean difference 0.52, 95 % CI = -1.45 to 2.49; I2 = 75 %). The certainty of the evidence was low. The meta-analysis is based on observational studies each involving small number of participants. Few studies reported outcomes as per patient while others reported as per cycle, for uniformity we have reported outcomes as per cycle. Sample size in most of studies was small. This systematic review has not shown any significant effect on the outcome of IVF cycles in patients post Covid-19 recovery compared to controls. But given the sample size, the findings should be considered with caution. The review protocol has been registered on PROSPERO (registration number CRD42022314515).


Fetal midgut herniation into the umbilical cord: improved definition of ventral abdominal anomaly with the use of transvaginal sonography.
The most common anomalies of the fetal ventral abdominal wall include omphalocele and gastroschisis. Umbilical cord hernia is another abdominal wall defect that is poorly defined and usually mistakenly considered as a small omphalocele. The present report describes the sonographic features and clinical significance of four cases of umbilical cord hernia identified transvaginally in the early second trimester of pregnancy. These cases seemed to present a different entity from that of simple omphalocele. The transvaginal sonographic approach provided a clear image of the midgut protruding into the umbilical cord, precise localization of cord insertion in the region of the umbilical ring. Doppler flow evaluation of the umbilical vessels and their relation to the protruding mass. Serial sonographic observations revealed a stable umbilical cord mass in three fetuses, and an enlarging mass in one. Normal karyotype was determined and no associated malformations were detected prenatally. However, in one case that underwent immediate correction of the hernia after delivery at term, the neonate was subsequently found to have pulmonic stenosis and severe neonatal seizures developed at 4 months of age. In two cases, pregnancy was terminated due to parental request. The fourth fetus was delivered vaginally at term and catastrophic division of the umbilical cord containing a loop of small intestine was avoided only by the diligent observation of the midwife. We suggest that umbilical cord hernia is a distinct anomaly originating at a different stage of embryogenesis, thereby having a unique clinical significance, unlike simple omphalocele. Umbilical cord hernia should therefore be defined and considered as a separate entity.


Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response.
Despite the development of chemoresistance as a major concern in prostate cancer therapy, the underlying mechanisms remain elusive. In this report, we demonstrate that DU145-derived prostate cancer stem cells (PCSCs) progress slowly with more cells accumulating in the G1 phase in comparison to DU145 non-PCSCs. Consistent with the important role of the AKT pathway in promoting G1 progression, DU145 PCSCs were less sensitive to growth factor-induced activation of AKT in comparison to non-PCSCs. In response to etoposide (one of the most commonly used chemotherapeutic drugs), DU145 PCSCs survived significantly better than non-PCSCs. In addition to etoposide, PCSCs demonstrated increased resistance to docetaxel, a taxane drug that is commonly used to treat castration-resistant prostate cancer. Etoposide produced elevated levels of γH2AX and triggered a robust G2/M arrest along with a coordinated reduction of the G1 population in PCSCs compared to non-PCSCs, suggesting that elevated γH2AX plays a role in the resistance of PCSCs to etoposide-induced cytotoxicity. We have generated xenograft tumors from DU145 PCSCs and non-PCSCs. Consistent with the knowledge that PCSCs produce xenograft tumors with more advanced features, we were able to demonstrate that PCSC-derived xenograft tumors displayed higher levels of γH2AX and p-CHK1 compared to non-PCSC-produced xenograft tumors. Collectively, our research suggests that the elevation of DNA damage response contributes to PCSC-associated resistance to genotoxic reagents.


Post hoc mortality analysis of the efficacy trial of diaspirin cross-linked hemoglobin in the treatment of severe traumatic hemorrhagic shock.
The efficacy trial of diaspirin cross-linked hemoglobin (DCLHb) in traumatic hemorrhagic shock demonstrated an unexpected mortality imbalance, prompting a three-step review to better understand the cause of this finding. Patients were enrolled in this DCLHb hemorrhagic shock study using 28-day mortality as the primary endpoint. Mortality data were primarily analyzed using the TRISS method and a nonblinded clinical review, followed by an independent Pennsylvania Trauma Outcome Study (PTOS)-derived probability of survival analyses. Finally, a trauma expert conducted a blinded clinical review of cases incorrectly predicted by these PTOS analyses. More of the DCLHb patients predicted to survive using TRISS actually died than in the control subgroup (24% vs. 3%, p < 0.002). Nonblinded clinical review noted that 72% of the patients who died had prior traumatic arrest, a presenting Glasgow Coma Scale score of 3, or a base deficit > 15 mEq/L. DCLHb patients predicted to survive using PTOS also more often died than did control patients (30% vs. 8%, p < 0.04). Blinded clinical review determined that 94% of the deaths were clinically justified. Both the TRISS and the PTOS models gave an adjusted mortality relative risk of 2.3, similar to the unadjusted risk data. Mortality analysis in this shock study involved both clinical case reviews and mortality prediction models. Despite the observation that nearly all of the deaths were clinically justified, the TRISS and PTOS models demonstrated excess unpredicted deaths in the DCLHb subgroup. A combined process, using both mortality prediction models and clinical case reviews, is useful in trauma studies that use a mortality endpoint.


Management of airway obstruction and stridor in pediatric patients
Stridor is a result of turbulent air-flow through the trachea from upper airway obstruction, and although in children it is often due to croup, it can also be caused by noninfectious and/or congenital conditions as well as life-threatening etiologies. The history and physical examination guide initial management, which includes reduction of airway inflammation, treatment of bacterial infection, and, less often, imaging, emergent airway stabilization, or surgical management. This issue discusses the most common as well as the life-threatening etiologies of acute and chronic stridor and its management in the emergency department.


Counselor Efficiency at Providing Feedback in a Technology-Based Behavioral Weight Loss Intervention: Longitudinal Analysis.
Feedback for participants' self-monitoring is a crucial and costly component of technology-based weight loss interventions. Detailed examination of interventionist time when reviewing and providing feedback for online self-monitoring data is lacking. The aim of this study was to longitudinally examine the time counselors spent providing feedback on participant self-monitoring data (ie, diet, physical activity, weight) in a 12-month technology-based weight loss intervention. We hypothesized that counselors would compose feedback for participants more quickly over time. The time the lay counselors (N=10) spent reviewing self-monitoring records and providing feedback to participants via email was longitudinally examined for all counselors across the three years of study implementation. Descriptives were observed for counselor feedback duration across counselors by 12 annual quarters (ie, 3-month periods). Differences in overall duration times by each consecutive annual quarter were analyzed using Wilcoxon-Mann-Whitney tests. There was a decrease in counselor feedback duration from the first to second quarter (mean 53 to 46 minutes; P<.001), and from the second to third (mean 46 to 30 minutes; P<.001). A trend suggested a decrease from the third to fourth quarter (mean 30 to 26 minutes; P=.053), but no changes were found in subsequent quarters. Consistent with the hypothesis, counselors may be increasing their efficiency in providing feedback; across 12 months, counselors spent less time reviewing participant self-monitoring and composing feedback (decreasing from mean 53 to 26 minutes). Counselors used increasingly less time to review online self-monitoring data and compose feedback after the initial 9 months of study implementation. Results inform counselor costs for future technology-based behavioral weight loss interventions. For example, regardless of increasing counselor efficiency, 25-30 minutes per feedback message is a high cost for interventions. One possibility for reducing costs would be generating computer-automated feedback. ClinicalTrials.gov NCT02063178; https://clinicaltrials.gov/ct2/show/NCT02063178.


Elderly subjects' ability to recover balance with a single backward step associates with body configuration at step contact.
In the event of a slip or trip, one's ability to recover a stable upright stance by stepping should depend on (a) the configuration of the body at the instant of step contact and (b) the forces generated between the foot and ground during step contact. In this study, we tested whether these two variables associate with elderly subjects' ability to recover balance by taking a single backward step after sudden release from an inclined position. Twenty-six community-dwelling subjects (12 women, 14 men) of mean age 75+/-4 (SD) years each underwent five trials in which they were suddenly released from a backward inclination of 7 degrees and instructed to "recover balance with a single step." Body segment motions and foot contact forces were analyzed to determine step contact times, stepping angles, body lean angles at step contact, and the magnitudes and times (after step contact) of peak foot-floor contact forces and peak sagittal-plane torques at the ankle, knee, and hip of the stepping leg. Fifty percent of subjects were predominantly single steppers (successful at recovering with a single step in greater than three of five trials), 27% were multiple steppers (successful in less than two of five trials), and 23% were mixed response steppers (successful in two of five or three of five trials). Recovery style associated with the ratio of stepping angle divided by body lean angle at step contact (p = .003), which averaged 1.4+/-0.5 for single steppers and 0.6+/-0.5 for multiple steppers, but not with step contact time, stepping angle, or contact forces and joint torques during step contact. These results suggest that elderly subjects' ability to recover balance with a single backward step depends primarily on the configuration of the body (in particular, the ratio of stepping angle to body lean angle) at step contact.


Long-term impact of stroke on family caregiver well-being: a population-based case-control study.
Three-year changes in well-being were studied among family caregivers of an epidemiologically derived sample of stroke survivors from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and compared to matched noncaregivers. Family caregivers of REGARDS participants who experienced a stroke event completed telephone interviews assessing depressive symptoms, mental and physical health quality of life (QOL), life satisfaction, and leisure satisfaction at approximately 9, 18, 27, and 36 months after the stroke (n = 235). For each stroke caregiver, a family member of a stroke-free REGARDS participant was enrolled as a matched noncaregiving control (n = 235) and completed similar interviews. Multilevel longitudinal models found that caregivers showed poorer well-being at 9 months poststroke than controls on all measures except physical health QOL. Significant differences were sustained for 22 months after the stroke event for depressive symptoms, 31 months for mental health QOL, and 15 months for life satisfaction. For leisure satisfaction, differences were still significant at 36 months poststroke. Caregiving effects were similar across race and sex. Stroke caregiving is associated with persistent psychological distress, but life satisfaction, depression, and mental health QOL became comparable to noncaregivers by 3 years after stroke. Caregiver leisure satisfaction was chronically lower than in noncaregivers. Intervention for stroke caregivers should recognize both the strains faced by caregivers and their capacity for successful coping over time.


Phylogenetic classification and clinical aspects of a new putative Deltapapillomavirus associated with skin lesions in cattle.
Bovine papillomaviruses (BPVs) are recognized as causal agents of benign and malignant tumors in cattle. Thirteen types of BPVs have already been described and classified into 3 distinct genera. Divergences in the nucleotide sequence of the L1 gene are used to identify new viral types through the employment of PCR assays with degenerated primers. In the present study, a method for identifying BPVs based on PCR-RFLP and DNA sequencing allowed the identification of a new putative Deltapapillomavirus, designated JN/3SP (JQ280500.1). The analysis of the L1 gene showed that this strain was most closely related to the BPVs -1, -2, -13 , and OaPV1 (71-73% genetic similarity). In this study, we describe the detection of this new putative Deltapapillomavirus type and verify its phylogenetic position within the genus.


ZebraShare: a new venue for rapid dissemination of zebrafish mutant data.
In the past decade, the zebrafish community has widely embraced targeted mutagenesis technologies, resulting in an abundance of mutant lines. While many lines have proven to be useful for investigating gene function, many have also shown no apparent phenotype, or phenotypes not of interest to the originating lab. In order for labs to document and share information about these lines, we have created ZebraShare as a new resource offered within ZFIN. ZebraShare involves a form-based submission process generated by ZFIN. The ZebraShare interface (https://zfin.org/action/zebrashare) can be accessed on ZFIN under "Submit Data". Users download the Submission Workbook and complete the required fields, then submit the completed workbook with associated images and captions, generating a new ZFIN publication record. ZFIN curators add the submitted phenotype and mutant information to the ZFIN database, provide mapping information about mutations, and cross reference this information across the appropriate ZFIN databases. We present here examples of ZebraShare submissions, including phf21aa, kdm1a, ctnnd1, snu13a, and snu13b mutant lines. Users can find ZebraShare submissions by searching ZFIN for specific alleles or line designations, just as for alleles submitted through the normal process. We present several potential examples of submission types to ZebraShare including a phenotypic mutants, mildly phenotypic, and early lethal mutants. Mutants for kdm1a show no apparent skeletal phenotype, and phf21aa mutants show only a mild skeletal phenotype, yet these genes have specific human disease relevance and therefore may be useful for further studies. The p120-catenin encoding gene, ctnnd1, was knocked out to investigate a potential role in brain development or function. The homozygous ctnnd1 mutant disintegrates during early somitogenesis and the heterozygote has localized defects, revealing vital roles in early development. Two snu13 genes were knocked out to investigate a role in muscle formation. The snu13a;snu13b double mutant has an early embryonic lethal phenotype, potentially related to a proposed role in the core splicing complex. In each example, the mutants submitted to ZebraShare display phenotypes that are not ideally suited to their originating lab's project directions but may be of great relevance to other researchers. ZebraShare provides an opportunity for researchers to directly share information about mutant lines within ZFIN, which is widely used by the community as a central database of information about zebrafish lines. Submissions of alleles with a phenotypic or unexpected phenotypes is encouraged to promote collaborations, disseminate lines, reduce redundancy of effort and to promote efficient use of time and resources. We anticipate that as submissions to ZebraShare increase, they will help build an ultimately more complete picture of zebrafish genetics and development.


An integrative review of guidelines for anal cancer screening in HIV-infected persons.
HIV-infected individuals are 28 times more likely than the general population to be diagnosed with anal cancer. An integrative review of recommendations and guidelines for anal cancer screening was performed to provide a succinct guide to inform healthcare clinicians. The review excluded studies that were of non-HIV populations, redundant articles or publications, non-English manuscripts, or nonclinical trials. The review found no formal national or international guidelines exist for routine screening of anal cancer for HIV-infected individuals. To date, no randomized control trial provides strong evidence supporting efficaciousness and effectiveness of an anal cancer screening program. The screening recommendations from seven international-, national-, and state-based reports were reviewed and synthesized in this review. These guidelines suggest anal cancer screening, albeit unproven, may be beneficial at decreasing the incidence of anal cancer. This review highlights the paucity of screening-related research and is an area of need to provide clear direction and to define standard of care for anal cancer screening in HIV-infected persons.


DevR-mediated adaptive response in Mycobacterium tuberculosis H37Ra: links to asparagine metabolism.
The DevR transcriptional switch that defines the response of Mycobacterium tuberculosis to the lack of oxygen is now well established and likely helps the bacteria shift to a state of persistence. The M. tuberculosis two component signal transduction system (TCS), DevR-DevS, implicated in this transition to latency, is differentially expressed in H37Ra and H37Rv strains. Despite originating from the H37 ancestral strain, H37Ra and H37Rv have significant differences in their growth, physiology, and virulence. To further dissect the role of DevR in growth adaptive processes of M. tuberculosis, we investigated the hypoxic response of the avirulent H37Ra strain. Our results show that the DevR-DevS TCS in H37Ra is responsive to hypoxia and capable of target gene regulation, indicating similar DevR-DevS signaling pathways in H37Ra and H37Rv. A key finding of this study was the constitutive expression of the Rv3134c-devR-devS operon and a subset of sentinel DevR-regulated genes in aerobic cultures of H37Ra but not H37Rv grown in Dubos-Tween-albumin medium. Asparagine and/or catabolites of asparagine metabolism were implicated in aerobic induction of the DevR-DevS TCS in H37Ra. This is the first report of medium-specific constitutive expression of the DevR regulon in an avirulent strain and suggests a potential role for metabolite(s) in the activation of the DevR-DevS TCS.


Hearing Preservation Outcomes for 139 Cochlear Implant Recipients Using a Thin Straight Electrode Array.
To assess the hearing preservation outcomes in a large group of adult cochlear implant recipients implanted with a thin straight electrode array using atraumatic surgical techniques. Factors affecting hearing preservation will be investigated. Prospective cohort study undertaken at the Royal Victorian Eye and Ear Hospital in Melbourne, Australia from December 2010 to May 2015. Tertiary academic hospital. One hundred thirty-nine adults undergoing cochlear implantation (CI). Primary outcome measure of interest was pre and postoperative pure-tone audiometry. Median low-frequency hearing change for the whole group of 139 recipients was -22.5 dB at the 3 months postop point. Eighty-six participants had functional preoperative low-frequency hearing (≤70 dB average at 250 and 500 Hz). Of these, 90.7% retained measureable hearing at 3 months postimplant. 39.5% of this original 86 participants retained functional hearing at 3 months postimplant. At 12 months postimplant, those who retained functional hearing at 3 months had no significant change in hearing. The group who lost functional hearing continued to have a significant deterioration in low-frequency hearing. Degree of hearing loss preimplant was identified as a predictor for the preservation of hearing postoperatively. Preservation of hearing is possible following atraumatic cochlear implant surgery with a thin straight electrode array. The amount of hearing preserved seems to be variable, and factors related to this variability are not yet known. The results of the present study suggest preoperative low-frequency hearing at or better than 45 dB may be related to preservation of functional hearing.


The significance of preserving the energy status and microcirculation in liver grafts from non-heart-beating donor.
To complete a successful liver transplantation (LTx) from non-heart-beating donors (NHBD), it is necessary to both improve the energy status in liver grafts and to reduce the exposure to free radicals. This study investigated the effects of short perfusion with oxygenated buffer on the grafts prior to cold preservation. In addition, the effects of the antioxidant, biliverdin, for reduction of free radicals was investigated. Male Wistar rats were used. Livers were retrieved, preserved in UW solution, and perfused for 60 min with oxygenated Krebs-Henseleit solution. Rats were allocated to six groups as follows (n=5): (i) control group-no warm ischemia (WI) and cold preservation, (ii) HBD group--no WI with cold preservation for 6 h; (iii) NHBD group--with 30 min of WI and cold preservation, (iv) NM group--with WI including nafamostat mesilate infusion before cardiac arrest and cold preservation; (v) PRE group--with WI, 30-min pre-cold preservation perfusion with oxygenated buffer after cardiac arrest, and cold preservation, (vi) BV group-with the same treatment as the PRE group plus the addition of biliverdin to the pre-cold preservation perfusion. The portal flow volume, bile production, AST, and TNF-alpha in perfusate, energy charge (EC), and ATP level in the tissue, and histological findings were investigated. The portal flow volume in the NM, PRE, and BV groups were higher than in the NHBD group. The bile production in the PRE and BV groups were also higher than in the NHBD group. The EC and ATP level of the BV group after reperfusion were higher than those of the NHBD group. Pre-cold preservation perfusion and addition of biliverdin to perfusate improved viability of grafts from NHBD. The results indicate that the preservation of the energy status and microcirculation of the graft is important for successful LTx from NHBD.


Electrophoretic heterogeneity of ribosomal protein AT-L30 among actinomycete genera.
The ribosomal proteins from 17 type strains of species belonging to various actinomycete genera were compared by two-dimensional polyacrylamide gel electrophoresis. I detected a striking variability among certain ribosomal proteins (designated AT-L30 proteins) with respect to electrophoretic mobility in the first dimension. In contrast, such variability was not observed among ribosomal L30 proteins from other bacteria, such as Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Staphylococcus aureus. Although actinomycete AT-L30 proteins from different taxa exhibited considerable heterogeneity in electrophoretic mobility, within each genus the proteins had a specific mobility characteristic. On the basis of this observation, the ribosomal AT-L30 proteins from 11 type strains of species belonging to the mycolic acid-containing genera Nocardia, Rhodococcus, Gordona, and Tsukamurella were analyzed. The relative electrophoretic mobilities of AT-L30 protein preparations from these strains, as determined by two-dimensional gel electrophoresis, revealed that the genera Nocardia, Rhodococcus, Gordona, and Tsukamurella can be sharply separated from each other. My results are consistent with the previously discussed view that each of these genera merits separate genus status.


Hemostatic cardiovascular risk factors, common carotid-intima medial thickness and peripheral arterial disease in South Asians and African Caribbeans: a substudy to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study.
To determine whether ethnic differences exist in inflammatory (interleukin-6 and C-reactive protein) and hemostatic biomarkers (soluble P-selectin [sP-sel], von Willebrand factor [VWF], and fibrin D-dimer) between South Asian (people originating from India, Pakistan, and Bangladesh) and African Caribbean (Black Caribbean and Black African) groups, the two largest minority ethnic groups in the UK; and to determine associations between these biomarkers and common carotid intima-media thickness and peripheral artery disease (PAD). We recruited 572 subjects (356 South Asian and 216 Black) aged ≥ 45 years as a substudy to a community screening project, the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study. All subjects completed an interviewer-led questionnaire, anthropometric measurements were taken, and blood sampling was performed if consent was granted. Ankle brachial pressure index (ABPI) was calculated, and the common carotid intima-media thickness (CCIMT) was measured. PAD was defined as ABPI < 0.9. ELISA was used to quantify inflammatory and hemostatic biomarkers. The incidence of hypertension (> 70%) and diabetes (> 27%) was high, but non-significantly different between the two ethnic groups. South Asians had higher platelet count and sP-sel levels than African Caribbeans (P < 0.0001 for both), despite there being no significant difference in antiplatelet medication. African Caribbeans had higher D-dimer levels (P = 0.0052). Among South Asians, VWF correlated with ABPI (P = 0.047) and mean (P = 0.002) and maximum CCIMT (P = 0.011) on univariate analysis, and remained an independent predictor of mean and maximum CCIMT on multivariate analysis with traditional cardiovascular risk factors (P = 0.034 and P = 0.046, respectively). In African Caribbeans, D-dimer levels were was higher in PAD than in normal ABPI participants (P = 0.04), and was associated with ABPI in both univariate analysis (P = 0.014) and multivariate analysis (P < 0.0001) with traditional cardiovascular risk factors. Ethnic differences are evident in inflammatory and hemostatic factors, as well as in their associations with CCIMT and PAD. These may reflect differences in cardiovascular risk factors or pathophysiologic processes that characterize each ethnic group.


Longer stitch interval in the Krackow stitch for tendon graft fixation leads to poorer biomechanical property.
The purpose of this study was to analyze the effects of different intervals between stitch throws on tendon graft fixation with the Krackow stitch. Forty-four porcine flexor profundus tendons were randomly divided into four groups of 11 specimens each. The Krackow stitch with various stitch intervals (2.5, 5.0, 7.5, and 10.0 mm) were evaluated, and named the K-2.5, K-5.0, K-7.5, and K-10.0 groups, respectively. A braided nonabsorbable suture was used to complete each suture-tendon construct. All specimens were pretensioned to 100 N for three cycles, cyclically loaded from 50 to 200 N for 200 cycles, and then finally loaded to failure. Elongation after cyclic loading, ultimate load to failure, and the mode of failure were recorded. There were significant differences in elongation after cyclic loading among the K-2.5 (31% ± 5%), K-5.0 (32% ± 4%), K-7.5 (34% ± 5%), and K-10.0 (41% ± 8%) groups ( p = 0.004); the post hoc analysis showed significantly smaller values in the K-2.5 and K-5.0 groups than in the K-10.0 group ( p = 0.002 and 0.003, respectively). The stitch interval was correlated with elongation after cyclic loading ( r = 0.52, p < 0.001). Ultimate loads to failure and cross-sectional area were not significantly different across the four groups. The Krackow stitch with stitch intervals of 2.5 and 5.0 mm had significantly smaller elongation after cyclic loading than with an interval of 10.0 mm in this porcine biomechanical study. The stitch interval was moderately correlated with elongation after cyclic loading.


Protection against LPS-induced pulmonary edema through the attenuation of protein tyrosine phosphatase-1B oxidation.
One hallmark of acute lung injury is the disruption of the pulmonary endothelial barrier. Such disruption correlates with increased endothelial permeability, partly through the disruption of cell-cell contacts. Protein tyrosine phosphatases (PTPs) are known to affect the stability of both cell-extracellular matrix adhesions and intercellular adherens junctions (AJs). However, evidence for the role of select PTPs in regulating endothelial permeability is limited. Our investigations noted that the inhibition of PTP1B in cultured pulmonary endothelial cells (ECs), as well as in the vasculature of intact murine lungs via the transient overexpression of a catalytically inactive PTP1B, decreased the baseline resistance of cultured EC monolayers and increased the formation of edema in murine lungs, respectively. In addition, we observed that the overexpression of wild-type PTP1B enhanced basal barrier function in vitro. Immunohistochemical analyses of pulmonary ECs and the coimmunoprecipitation of murine lung homogenates demonstrated the association of PTP1B with the AJ proteins β-catenin, p120-catenin, and VE-cadherin both in vitro and ex vivo. Using LPS in a model of sepsis-induced acute lung injury, we showed that reactive oxygen species were generated in response to LPS, which correlated with enhanced PTP1B oxidation, inhibited phosphatase activity, and attenuation of the interactions between PTP1B and β-catenin, as well as enhanced β-catenin tyrosine phosphorylation. Finally, the overexpression of a cytosolic PTP1B fragment, shown to be resistant to nicotinamide adenine dinucleotide phosphate-reduced oxidase-4 (Nox4)-mediated oxidation, significantly attenuated LPS-induced endothelial barrier dysfunction and the formation of lung edema, and preserved the associations of PTP1B with AJ protein components, independent of PTP1B phosphatase activity. We conclude that PTP1B plays an important role in maintaining the pulmonary endothelial barrier, and PTP1B oxidation appears to contribute to sepsis-induced pulmonary vascular dysfunction, possibly through the disruption of AJs.


Cardiovascular Programming During and After Diabetic Pregnancy: Role of Placental Dysfunction and IUGR.
Intrauterine growth restriction (IUGR) is a condition whereby a fetus is unable to achieve its genetically determined potential size. IUGR is a global health challenge due to high mortality and morbidity amongst affected neonates. It is a multifactorial condition caused by maternal, fetal, placental, and genetic confounders. Babies born of diabetic pregnancies are usually large for gestational age but under certain conditions whereby prolonged uncontrolled hyperglycemia leads to placental dysfunction, the outcome of the pregnancy is an intrauterine growth restricted fetus with clinical features of malnutrition. Placental dysfunction leads to undernutrition and hypoxia, which triggers gene modification in the developing fetus due to fetal adaptation to adverse utero environmental conditions. Thus, in utero gene modification results in future cardiovascular programming in postnatal and adult life. Ongoing research aims to broaden our understanding of the molecular mechanisms and pathological pathways involved in fetal programming due to IUGR. There is a need for the development of effective preventive and therapeutic strategies for the management of growth-restricted infants. Information on the mechanisms involved with in utero epigenetic modification leading to development of cardiovascular disease in adult life will increase our understanding and allow the identification of susceptible individuals as well as the design of targeted prevention strategies. This article aims to systematically review the latest molecular mechanisms involved in the pathogenesis of IUGR in cardiovascular programming. Animal models of IUGR that used nutrient restriction and hypoxia to mimic the clinical conditions in humans of reduced flow of nutrients and oxygen to the fetus will be discussed in terms of cardiac remodeling and epigenetic programming of cardiovascular disease. Experimental evidence of long-term fetal programming due to IUGR will also be included.


Social beliefs and women's role in sanitation decision making in Bihar, India: An exploratory mixed method study.
In low- and middle-income countries, poor autonomy prevents women from making financial decisions, which may impact their access to improved sanitation facilities. Inadequate access to improved sanitation disproportionately affects women's and children's health and wellbeing. Although socio-cultural factors are known contributors to gender inequity, social beliefs that potentially motivate or dissuade women from making sanitation-related household decisions are not well understood. These beliefs may vary across settlement types. To empower more women to make sanitation-related decisions, the relevant socio-cultural norms and underlying social beliefs need to be addressed. In this mixed methods study, we explored women's role in sanitation-related decision making in three settlement types, urban slums, peri-urban, and rural communities in Bihar. Trained qualitative researchers conducted six focus group discussions with women of two age groups: 18-30 years old, and 45-65 years old to understand the norm-focused factors around women's role in getting a toilet for their household. Using insights generated from these group discussions, we developed and conducted a theory-driven survey in 2528 randomly selected participants, to assess the social beliefs regarding women making toilet construction decisions in these communities. Overall, 45% of the respondents reported making joint decisions to build toilets that involved both men and women household members. More women exclusively led this decision-making process in peri-urban (26%) and rural areas (35%) compared to urban slums (12%). Social beliefs that men commonly led household decisions to build toilets were negatively associated with women's participation in decision making in urban slums (adjusted prevalence ratio, aPR: 0.53, 95% CI: 0.42, 0.68). Qualitative insights highlighted normative expectations to take joint decisions with elders, especially in joint family settings. Surrounding norms that limited women's physical mobility and access to peers undermined their confidence in making large financial decisions involved in toilet construction. Women were more likely to be involved in sanitation decisions in peri-urban and rural contexts. Women's involvement in such decisions was perceived as widely acceptable. This highlights the opportunity to increase women's participation in sanitation decision making, particularly in urban contexts. As more women get involved in decisions to build toilets, highlighting this norm may encourage gender-equitable engagement in sanitation-related decisions in low-resource settings.


Does Flavonoid Supplementation Alleviate Non-Alcoholic Fatty Liver Disease? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Higher flavonoid intake is associated with reduced risk of non-alcoholic fatty liver disease (NAFLD). However, there is a large discrepancy in the effects of flavonoid supplementation on NAFLD. To fill such knowledge gap, we systematically reviewed randomized clinical trials (RCTs) to critically assess flavonoid supplementation effect on liver function, lipid profile, inflammation, and insulin resistance in adults with NAFLD. A systematic search was conducted from 4 databases from inception until May 2023. Twelve RCTs were included in the final analysis demonstrating beneficial effects of flavonoids on ALT (SMD = -3.59, p = 0.034), AST (SMD = -4.47, p = 0.001), GGT (SMD = -8.70, p = 0.000), CK-18M30 (SMD = -0.35, p = 0.042), TG (SMD = -0.37, p = 0.001), LDL-C (SMD = -0.38, p = 0.039), TC (MD = -0.25 mmol/l, p = 0.017), steatosis score (MD = -18.97, p = 0.30), TNF-α (MD = -0.88, p = 0.000), and NF-κB (MD = -1.62, p = 0.001). This meta-analysis suggests that flavonoid alleviates NAFLD through exerting favourable effects on liver function, lipid profile, and inflammation, indicating flavonoid supplementation presents a promising drug regimen for the management of NAFLD and its associated complications.


Identification and functional characterization of Caspase-9 in goldfish (Carassius auratus L.) in response to Aeromonas hydrophila infection.
Apoptosis plays a pivotal role in the immune response to combat pathogen infections. In mammals, caspase-9, abbreviated as Casp9, plays an irreplaceable role in the initiation phase of the apoptotic cascade. To investigate the role of Casp9 in teleosts, we conducted a functional characterization of Casp9 in goldfish (Carassius auratus L.). The open reading frame of GfCasp9 spans 1296 base pairs (bp), encoding a protein composed of 431 amino acids. GfCasp9 was ubiquitously expressed in various tissues, with the spleen and brain showing the highest levels of expression. Subcellular localization analysis revealed that GfCasp9 is distributed in both the cytoplasm and nucleus. Overexpressing of GfCasp9 in HEK293 cells elicits a robust apoptotic response. Additionally, infection with Aeromonas hydrophila significantly increases the mRNA and protein expression of GfCasp9. These findings underscore the critical importance of GfCasp9 in immune responses and apoptosis against bacterial infections.


Control of the growth and development of murine preantral follicles in a biomimetic ovary using a decellularized porcine scaffold.
This study aimed to derive mature oocytes from murine preantral follicles cultured in a biomimetic ovary with a porcine scaffold using decellularization technology. We evaluated the DNA content and the presence of cell and extracellular matrix (ECM) components, including collagen, elastin, and glycosaminoglycans (GAGs), in decellularized (decell) porcine ovaries. The DNA content inthe decell ovarian tissues was approximately 94 % less than that in native tissues (66 ± 9.8 ng/mg vs. 1139 ± 269 ng/mg). Furthermore, the ECM component integrity was maintained in the decell ovarian tissue. The soluble collagen concentration of native ovarian tissue (native) was 195.34 ± 15.13 μg/mg (dry wt.), which was less than 878.6 ± 8.24 μg/mg for the decell ovarian tissue due to the loss of cellular mass. Hydrogels derived from decell porcine ovaries were prepared to develop an in vitro biomimetic ovary with appropriate ECM concentration (2-6 mg/mL). Scanning electron microscope (SEM) imagining revealed that the complex fiber network and porous structure were maintained in all groups treated with varying ECM concentration (2-6 mg/mL). Furthermore, rheometer analysis indicated that mechanical strength increased with ECM concentration in a dose-dependently. The preantral follicles cultured with 4 mg/mL ECM showed high rates of antral follicle (66 %) and mature oocyte (metaphase II) development (47 %). The preantral follicles cultured in a biomimetic ovary with a decell porcine scaffold showed a higher rate of antral follicle and mature oocytes than those cultured in other biomaterials such as collagen and Matrigel. In mature oocytes derived from antral follicles, meiotic spindles and nuclei were stained using a tubulin antibody and Hoechst, respectively. Two-cell embryos were developed from MII oocytes following parthenogenetic activation. Preantral follicles were cultured in a biomimetic ovary derived from the ECM of a decell porcine ovary, and embryos were generated from MII oocytes. This biomimetic ovary could contribute to restoring fertility in infertile women with reduced ovarian function, benefit mating efforts for endangered species, and maintain animals with valuable genetic traits.


Effects of anaemia on cardiovascular status.
Cardiomyopathy is a common, heterogeneous and important cause of cardiac morbidity and mortality in uraemic patients. The risks of ischaemic heart disease, cardiac failure, and death increase progressively from lowest risk in patients with concentric left-ventricular hypertrophy, to medium risk in patients with left-ventricular dilatation but intact systolic function, to highest risk in patients with systolic dysfunction. Anaemia and hypertension are the reversible risk factors most consistently linked with the development of cardiomyopathy in these patients. Longitudinal data show that anaemia predisposes individuals to initial left ventricular dilatation, with compensatory hypertrophy, which may progress to systolic dysfunction. This process typically begins at glomerular filtration rates between 25 and 50 ml/min, and haemoglobin concentrations that are even slightly below normal are associated with progressive cardiac enlargement. Several observational studies have suggested that the correction of anaemia may reduce mortality and hospitalization rates in dialysis patients. The available evidence supports maintaining haemoglobin concentrations to greater than 11 g/dl. Whether a haemoglobin threshold exists above which no further benefit is seen remains controversial, partially because recent randomized controlled trials have intervened relatively late in the anaemia cardiomyopathy cardiac failure death continuum. One large randomized controlled trial showed no benefit from normalizing the haemoglobin concentration in haemodialysis patients with well-established cardiac disease; however, these patients had been exposed to anaemia for long periods of time and were at the extreme end of the cardiorenal disease spectrum. Other researchers have demonstrated a protective effect of normalizing the haemoglobin concentration in patients with asymptomatic, and hence presumably early, cardiomyopathy. The psychological benefits and improvements in exercise tolerance and quality of life resulting from normalization of the haemoglobin concentration are becoming clearer. However, conclusive evidence of the cardiovascular benefits of earlier, more aggressive treatment of renal anaemia as well as of the exact target haemoglobin concentration at which risk begins to develop is still lacking. The results of ongoing trials should help to clarify both of these issues within the next 5 years.


Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation.
The Mre11.Rad50.nibrin protein complex plays an essential role in the mammalian cellular response to DNA double-strand breaks. The disorder Nijmegen breakage syndrome (NBS) results from mutations in the NBS1 gene that encodes nibrin, and NBS cells are radiosensitive and defective in S-phase checkpoint activation following irradiation. In response to radiation, nibrin is phosphorylated by Atm, and the Mre11.Rad50.nibrin complex relocalizes to form punctate nuclear foci. The N terminus of nibrin contains a forkhead-associated (FHA) domain and a breast cancer C-terminal (BRCT) domain, the functions of which are unclear. To determine the role of the FHA and BRCT domains in nibrin function, we have performed site-directed mutagenesis of conserved residues in these motifs. Mutations in the nibrin FHA and BRCT domains did not affect interaction with Mre11.Rad50 or nuclear localization of the complex. However, mutation of conserved residues in either domain disrupted nuclear focus formation and blocked nibrin phosphorylation after irradiation, suggesting that these events may be functionally interdependent. Despite an effect on nibrin phosphorylation, expression of the FHA or BRCT mutants in NBS cells restored the downstream phosphorylation of Chk2 and Smc1, necessary for S-phase checkpoint activation. None of the mutations revealed separate functions for the FHA or BRCT domains, suggesting they do not function independently.


Regulated secretion: SNARE density, vesicle fusion and calcium dependence.
SNAREs such as VAMP, SNAP-25 and syntaxin are essential for intracellular trafficking, but what are their exact molecular roles and how are their interactions with other proteins manifest? Capitalizing on the differential sensitivity of SNAREs to exogenous proteases, we quantified the selective removal of identified SNAREs from native secretory vesicles without loss of fusion competence. Using previously established fusion assays and a high sensitivity immunoblotting protocol, we analyzed the relationship between these SNARE proteins and Ca2+-triggered membrane fusion. Neither the extent of fusion nor the number of intermembrane fusion complexes per vesicle were correlated with the measured density of identified egg cortical vesicle (CV) SNAREs. Without syntaxin, CVs remained fusion competent. Surprisingly, for one (but not another) protease the Ca2+ dependence of fusion was correlated with CV SNARE density, suggesting a native protein complex that associates with SNAREs, the architecture of which ensures high Ca2+ sensitivity. As SNAREs may function during CV docking in vivo, and as further proteolysis after SNARE removal eventually ablates fusion, we hypothesize that the triggered steps of regulated fusion (Ca2+ sensitivity and the catalysis and execution of fusion) require additional proteins that function downstream of SNAREs.


WOLD decomposition of the backscatter echo in ultrasound images of soft tissue organs.
Deals with a method of detecting and estimating the scatterer spacing between the regularly spaced resolvable coherent scatterers in tissue. Scatterer spacing has been successfully used in classifying tissue structure, in differentiating between normal and cirrhotic liver, and in detecting diffuse liver disease. This paper presents a WOLD decomposition of the radio frequency (RF) field into its diffused and coherent components from which maximum likelihood estimates (MLE) or minimum mean square error (MMSE) estimates of the scattering spacing are easily computed. The MLE are efficient and for relatively long record are unbiased. They result in accurate estimates in low signal-to-noise (SNR) ratios. Unfortunately, they require nonlinear minimization and knowledge of the probability density associated with the RF backscatter echo. The MMSE estimates, on the other hand, are computationally simple, yield unique closed form solutions, do not require a-priori knowledge of the probability distribution function of the backscatter echo, and result in accurate estimates in low SNR ratios. This paper also presents an unbiased decision rule to detect whether or not an RF echo exhibits any specular scattering relative to the wavelength of the interrogating ultrasonic pulse. The approach has been tried on simulations as well as on in-vivo scans of liver data, and appears to perform well.


Radical scavenging and anti-inflammatory effects of the halophyte Spergularia marina Griseb.
As a part of ongoing research to develop antioxidant and anti-inflammatory nutraceuticals, an ethanolic extract of Spergularia marina Griseb. was tested for its ability to scavenge radicals and suppress inflammation. The extract was able to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl, and superoxide radicals, respectively, in cell-free environments as well as intracellular radicals in H2O2-stimulated mouse macrophages. Inflammation in mouse macrophages induced by lipopolysaccharides was suppressed by S. marina according to the measurement of nitric oxide generation and expression of inflammatory cytokines, i.e. tumour necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6. The anti-inflammatory effect of S. marina was substantiated by the finding that the expression of the inflammatory modulators, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), was significantly decreased. The chemical composition of S. marina was evaluated by FT-IR analysis of the extract indicating the presence of polyphenols and flavonoids. In conclusion, S. marina is suggested as a novel source for antioxidant and anti-inflammatory agents.


[Intensity of the humoral immune response to herpesviruses as an indicator the body immune deficiency].
The state of the local immunity system of the oral cavity was studied by the level of saliva immunoglobulins in patients with different processes on their mucous membranes: herpetic infection, respiratory allergosis and malignant tumors of the mouth cavity and the laryngopharynx. The suppression of the production of sIgA, was accompanied by the enhanced production of antibodies to the most widespread herpesviruses (herpes simplex virus, cytomegalovirus and Epstein-Barr virus). The maximum levels of serum IgG to herpesviruses were determined in patients with malignant tumors. The role of herpesviruses in the pathogenesis of immunodeficient states is discussed.


Meckel's diverticula in an adult surgical unit eleven years experience.
A retrospective review of Meckel's diverticula over an 11-year period in a surgical unit, to which children were seldom admitted, revealed 28 diverticula, seven of which were symptomatic from inflammatory disease or obstruction. There was no morbidity nor mortality in this group. Twenty-one diverticula were removed as incidental findings, four patients dying from the cause of their symptoms. The complications of Meckel's diverticulum can be satisfactorily managed and are uncommon in the adult. Prophylactic diverticulectomy is difficult to justify.


Genome-wide DNA Methylation Profiling Reveals Methylation Markers Associated with 3q Gain for Detection of Cervical Precancer and Cancer.
Purpose: Epigenetic host cell changes involved in cervical cancer development following a persistent high-risk human papillomavirus (hrHPV) infection, provide promising markers for the management of hrHPV-positive women. In particular, markers based on DNA methylation of tumor suppressor gene promoters are valuable. These markers ideally identify hrHPV-positive women with precancer (CIN2/3) in need of treatment. Here, we set out to identify biologically relevant methylation markers by genome-wide methylation analysis of both hrHPV-transformed cell lines and cervical tissue specimens.Experimental Design and Results: Genome-wide discovery by next-generation sequencing (NGS) of methyl-binding domain-enriched DNA (MBD-Seq) yielded 20 candidate methylation target genes. Further verification and validation by multiplex-targeted bisulfite NGS and (quantitative) methylation-specific PCR (MSP) resulted in 3 genes (GHSR, SST, and ZIC1) that showed a significant increase in methylation with severity of disease in both tissue specimens and cervical scrapes (P < 0.005). The area under the ROC curve for CIN3 or worse varied between 0.86 and 0.89. Within the group of CIN2/3, methylation levels of all 3 genes increased with duration of lesion existence (P < 0.0005), characterized by duration of preceding hrHPV infection, and were significantly higher in the presence of a 3q gain (P < 0.05) in the corresponding tissue biopsy.Conclusions: By unbiased genome-wide DNA methylation profiling and comprehensive stepwise verification and validation studies using in vitro and patient-derived samples, we identified 3 promising methylation markers (GHSR, SST, and ZIC1) associated with a 3q gain for the detection of cervical (pre)cancer. Clin Cancer Res; 23(14); 3813-22. ©2017 AACR.


Pseudomonas aeruginosa pleural empyema in a preterm infant.
Pleural empyema is defined as the pyogenic infection of the pleural space with purulent effusion. Although it is frequently seen in children and therapy protocols have been developed for it, there are only a few reports about pleural empyema in newborn infants. To our knowledge, just one preterm infant has been reported in the literature. In this article, we report an male infant born at 29 weeks of gestation who had pleural empyema on the 53rd day of life. Multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) was isolated from his pleural fluid culture. We suggest that this is the first preterm infant with P. aeruginosa empyema.


"Official" and "practical" kin: Inferring social and community structure from dental phenotype at Neolithic Çatalhöyük, Turkey.
The Neolithic site of Çatalhöyük, Turkey (7400-5600 cal BC) is widely acknowledged for its role in the study of early farming communities. To better understand the social and community structure of this setting, an intracemetery biological distance analysis was conducted. Metric and nonmetric observations were recorded in both deciduous and permanent dentitions (n = 266) to explore phenotypic patterning of individuals interred within individual buildings. Specifically, this study tests the hypothesis that individuals within houses and house groupings represent family units and the social structure of Çatalhöyük was largely biological-kin based. Multivariate and univariate statistical procedures were applied to phenotypic dental data. Results indicate that inclusion for interment within a house was only minimally related to biological affinity. Moreover, the site does not appear to be organized into larger, biologically related neighborhoods of houses. These findings suggest that Çatalhöyük may not have been a kin-based society, largely because membership within a house cemetery was not solely defined on the basis of biological affinity, such as in a family group. Rather, it appears that social structure was centered on the house as the unifying social principle. The choice for interment location may have transcended biological lines thereby creating an alternate and more fluid definition of "kin." These findings can be used to understand the transition to settled life and biological patterning in this Neolithic community.


Consequences of suppressing thoughts about tinnitus and the effects of cognitive distraction on brain activity in tinnitus patients.
Tinnitus is the perception of sound in the absence of any appropriate external stimulus. Based on the clinical observation that tinnitus patients may distract themselves from their sounds, we performed an experimental test on the effects of suppressing thoughts about tinnitus with 45 tinnitus patients, to systematically evaluate the immediate consequences of suppressing thought vs. attending to tinnitus. Suppression instructions tended to lead to a subsequent decrease in tinnitus-related thoughts, whereas attention to tinnitus resulted in an increase in such thoughts. No effects were seen in a control group who neither suppressed nor attended to their tinnitus. In an independent positron emission tomography study of cerebral blood flow with 8 patients we found that silent backward counting ('serial sevens test') led to a decrease in neural activity in auditory cortex, as well as perceived decrease of tinnitus loudness and annoyance. Thus, distraction that altered the tinnitus experience seemed to attenuate auditory cortex activity.


Materials management crucial to overall efficiency.
Because supplies are important to many departments, improved materials management may be an integral part of a hospital's productivity assessment. A successful program should encompass technical as well as managerial aspects of materials management. While looking at national performance statistics may provide a basis, each hospital should set its own standards in line with its strategic plan.


Streptomyces spp. From Ethiopia Producing Antimicrobial Compounds: Characterization via Bioassays, Genome Analyses, and Mass Spectrometry.
A total of 416 actinomycete cultures were isolated from various unique environments in Ethiopia and tested for bioactivity. Six isolates with pronounced antimicrobial activity were chosen for taxonomic identification and further investigation. Morphological and cultural properties of the isolates were found to be consistent with those of the genus Streptomyces, which was further confirmed by phylogenetic analysis based on 16S rRNA gene sequences. One of the isolates, designated Streptomyces sp. Go-475, which displayed potent activity against both pathogenic yeasts and Gram-positive bacteria, was chosen for further investigation. Metabolite profiles and bioactivity of Go-475 incubated on wheat bran-based solid and soya flour-based liquid media were compared using high-resolution LC-MS. This allowed identification of several known compounds, and suggested the ability of Go-475 to produce new secondary metabolites. Major anti-bacterial compounds were purified from liquid cultures of Go-475, and their structures elucidated by NMR and HRMS as 8-O-methyltetrangomycin and 8-O-methyltetrangulol. In addition, many potentially novel metabolites were detected, the majority of which were produced in solid media-based fermentation. The genome sequence of Streptomyces sp. Go-475 was obtained using a hybrid assembly approach of high quality Illumina short read and low quality Oxford Nanopore long read data. The complete linear chromosome of 8,570,609 bp, featuring a G+C content of 71.96%, contains 7,571 predicted coding sequences, 83 t(m)RNA genes, and six rrn operons. Analysis of the genome for secondary metabolite biosynthesis gene clusters further confirmed potential of this isolate to synthesize chemically diverse natural products, and allowed to connect certain clusters with experimentally confirmed molecules.


A Case of Acute Necrotizing Myopathy in a Patient with Systemic Lupus Erythematosus.
BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple organ systems with a wide spectrum of clinical presentation and associated with positive serologies. Musculoskeletal involvement in patients with SLE is relatively uncommon, occurring in approximately 4% to 16% of cases. Some patients can develop necrotizing myopathy without myositis. MRI in patients with SLE-associated necrotizing myopathy usually shows interstitial edema, while muscle biopsy often shows type 2 muscle fiber atrophy. We herein report an unusual case of acute necrotizing myopathy in a patient recently diagnosed with SLE. This case report focuses on the pertinent features related to the diagnosis of this patient while highlighting the management of acute necrotizing myopathy. CASE REPORT A 30-year-old African American woman presented to the Emergency Department with skin rashes, myalgia, polyarthralgia, and muscle weakness resulting in the inability to walk, 2 weeks after being diagnosed with SLE. Laboratory analysis showed elevated creatine kinase and myoglobin. She was found to have both MRI and biopsy findings suggestive of necrotizing myopathy. She was treated with mycophenolate mofetil and steroids, with an improvement of muscle strength and decrease in creatine kinase over a 2-week period. CONCLUSIONS Immune-mediated necrotizing myopathies are a rare group of debilitating myopathies that can be associated with SLE. The diagnosis of necrotizing myopathy in patients with SLE requires a high index of suspicion and careful work-up to establish a diagnosis. Muscle biopsy often shows type 2 muscle fiber atrophy. Immunosuppressive therapy is the mainstay of treatment, and early initiation of immunotherapies is associated with an improvement in patient outcomes.


The stochastic dynamics of early epidemics: probability of establishment, initial growth rate, and infection cluster size at first detection.
Emerging epidemics and local infection clusters are initially prone to stochastic effects that can substantially impact the early epidemic trajectory. While numerous studies are devoted to the deterministic regime of an established epidemic, mathematical descriptions of the initial phase of epidemic growth are comparatively rarer. Here, we review existing mathematical results on the size of the epidemic over time, and derive new results to elucidate the early dynamics of an infection cluster started by a single infected individual. We show that the initial growth of epidemics that eventually take off is accelerated by stochasticity. As an application, we compute the distribution of the first detection time of an infected individual in an infection cluster depending on testing effort, and estimate that the SARS-CoV-2 variant of concern Alpha detected in September 2020 first appeared in the UK early August 2020. We also compute a minimal testing frequency to detect clusters before they exceed a given threshold size. These results improve our theoretical understanding of early epidemics and will be useful for the study and control of local infectious disease clusters.


Nucleotide sequence of the p21 transforming protein of Harvey murine sarcoma virus.
Harvey murine sarcoma virus is a retrovirus which transforms cells by means of a single virally encoded protein called p21 has. We have determined the nucleotide sequence of 1.0 kilobase in the 5' half of the viral genome which encompasses the has coding sequences and its associated regulatory signals. The nucleotide sequence has identified the amino acid sequence of two additional overlapping polypeptides which share their reading frames and the carboxyl termini with p21 but which contain additional NH2-terminal amino acids.


Optimization of the polarized Klein tunneling currents in a sub-lattice: pseudo-spin filters and latticetronics in graphene ribbons.
We found that with an increase of the potential barrier applied to metallic graphene ribbons, the Klein tunneling current decreases until it is totally destroyed and the pseudo-spin polarization increases until it reaches its maximum value when the current is zero. This inverse relation disfavors the generation of polarized currents in a sub-lattice. In this work we discuss the pseudo-spin control (polarization and inversion) of the Klein tunneling currents, as well as the optimization of these polarized currents in a sub-lattice, using potential barriers in metallic graphene ribbons. Using density of states maps, conductance results, and pseudo-spin polarization information (all of them as a function of the energy V and width of the barrier L), we found (V, L) intervals in which the polarized currents in a given sub-lattice are maximized. We also built parallel and series configurations with these barriers in order to further optimize the polarized currents. A systematic study of these maps and barrier configurations shows that the parallel configurations are good candidates for optimization of the polarized tunneling currents through the sub-lattice. Furthermore, we discuss the possibility of using an electrostatic potential as (i) a pseudo-spin filter or (ii) a pseudo-spin inversion manipulator, i.e. a possible latticetronic of electronic currents through metallic graphene ribbons. The results of this work can be extended to graphene nanostructures.


Investigation of the Immunomodulatory effect of Berberis vulgaris on core-pulsed dendritic cell vaccine.
Virus-induced dendritic cells (DCs) functional deficiency leads to sub-optimal initiation of adaptive immune responses and consequently chronic infection establishment. The present study reports an advanced hepatitis C virus (HCV) therapeutic vaccine model based on In vivo enrichment of DCs with barberry ethanolic crude extract (BCE) then pulsing them with HCV core protein. DCs were enriched by BCE intravenous injection in BALB/c mice. Vaccine efficiency was assessed by flow cytometric analysis of splenocytes of immunized mice, cytokine profiling, cytotoxic T lymphocyte assay, and humoral immune response assessment. There was no significant difference in surface phenotypic characterization of splenocytes from mice immunized with non-BCE-enriched-core-pulsed DCs (iDcs-core) compared to those from mice injected with RPMI-1640 medium. However, splenocytes from mice immunized with BCE-enriched-core-pulsed DCs showed 197 % increase in CD16+ population, 33 % increase in MHCII(+) population, and 43 % decrease in CD3(+) population. In iDCs-core group, 57.9 % greater anti-core cytotoxic T lymphocyte activity, up-regulation in interferon gamma and interleukin (IL) -12 expression, and down-regulation in IL-4 and IL-10 were recorded. Moreover, sustained specific anti-core antibodies were detected only in sera of the same group. results indicate that BCE-enriched-core-transduced DCs may serve as a new model for immunotherapy of HCV chronic infection.


Functionally specific binding regions of microtubule-associated protein 2c exhibit distinct conformations and dynamics.
Microtubule-associated protein 2c (MAP2c) is a 49-kDa intrinsically disordered protein regulating the dynamics of microtubules in developing neurons. MAP2c differs from its sequence homologue Tau in the pattern and kinetics of phosphorylation by cAMP-dependent protein kinase (PKA). Moreover, the mechanisms through which MAP2c interacts with its binding partners and the conformational changes and dynamics associated with these interactions remain unclear. Here, we used NMR relaxation and paramagnetic relaxation enhancement techniques to determine the dynamics and long-range interactions within MAP2c. The relaxation rates revealed large differences in flexibility of individual regions of MAP2c, with the lowest flexibility observed in the known and proposed binding sites. Quantitative conformational analyses of chemical shifts, small-angle X-ray scattering (SAXS), and paramagnetic relaxation enhancement measurements disclosed that MAP2c regions interacting with important protein partners, including Fyn tyrosine kinase, plectin, and PKA, adopt specific conformations. High populations of polyproline II and α-helices were found in Fyn- and plectin-binding sites of MAP2c, respectively. The region binding the regulatory subunit of PKA consists of two helical motifs bridged by a more extended conformation. Of note, although MAP2c and Tau did not differ substantially in their conformations in regions of high sequence identity, we found that they differ significantly in long-range interactions, dynamics, and local conformation motifs in their N-terminal domains. These results highlight that the N-terminal regions of MAP2c provide important specificity to its regulatory roles and indicate a close relationship between MAP2c's biological functions and conformational behavior.


Cerebrospinal fluid monoamines in Down's syndrome adults at different ages.
Markers of monoamine metabolism in lumbar cerebrospinal fluid (CSF) and plasma were determined in nine young, healthy adults with trisomy 21 Down's syndrome (DS), 21-34-years-old, and in three DS subjects over 45 years, two of whom were demented, as well as in two groups of age-matched controls. Test scores of general intelligence, visuospatial ability, visual discrimination and verbal intelligence were reduced significantly in the old as compared to the young DS subjects. Dementia in DS was evident from a history of mental deterioration, disorientation and hallucinations. In the young DS adults, as compared to the controls, CSF 5-HIAA and norepinephrine were significantly elevated but plasma levels were unchanged. HVA, MHPG and biopterin did not differ between the DS groups and age-matched controls, or with relation to age in the DS or control subjects. These results suggest an increased turnover of monoamines in young adults with DS but that alterations in monoamine metabolism are unrelated to the cognitive decline with age in DS.


How Grids are perceived in healthcare and the public service sector.
Computational and data grids have been developed to manage large amounts of data produced in scientific collaborations. While the developed technologies could be employed to help the daily work in the public sector and in healthcare, their wide adaptation has not been seen, yet. In this paper we present a survey, which we conducted to find out how the decision makers and system specialists in the public service sector see the role of Grid technologies in their future work. The respondents of the survey work as decision makers and systems specialists in the healthcare and the public services domain in Switzerland.


Incidence of cancer and mortality in patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial.
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) clinical trial, including 1,873 patients found an increased risk for cancer with lipid-lowering therapy with ezetimibe/simvastatin 10/40 mg/day, relative to placebo. In a registry-based follow-up study over 21 months from the conclusion of the SEAS trial, new incident cancer and total mortality were investigated in the SEAS study cohort from Denmark, Finland, Norway, Sweden, and the United Kingdom. Among 1,359 subjects eligible for follow-up (73% of the original total cohort), 1,194 had no history of cancer (primary follow-up cohort). New cancers and deaths were identified in the national cancer and mortality registries and classified by an Expert Review Committee. Data were analyzed using Cox proportional-hazards models of new cancers and mortality during follow-up according to treatment group assigned in the SEAS base study and with age, gender, smoking history, and previous cancers as covariates. The primary follow-up cohort had 12 patients with new cancers in the ezetimibe/simvastatin group and 22 in the placebo group (hazard ratio 0.55, 95% confidence interval 0.27 to 1.11), indicating no significant difference between the treatment groups. During follow-up, 43 patients assigned to ezetimibe/simvastatin and 33 assigned to placebo died (hazard ratio 1.29, 95% confidence interval 0.82 to 2.03). In conclusion, in this registry-based observational follow-up study of the original SEAS study patient population, treatment with ezetimibe/simvastatin was not associated with an increased risk for cancer or mortality in the 21-month period after the completion of the original SEAS study.


Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach.
It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. The PROGINS allele of the progesterone receptor (PGR) gene reduces the function of PGR and has been associated with increased risk of the endometrioid type ovarian cancer. We investigated whether genetic variation in PGR is also associated with endometrial cancer risk using a haplotype-based approach. We pooled data from two endometrial cancer case-control studies that were nested within two prospective cohorts, the Multiethnic Cohort Study and the California Teachers Study. Seventeen haplotype-tagging single nucleotide polymorphisms (SNPs) across four linkage disequilibrium (LD) blocks spanning the PGR locus were genotyped in 583 incident cases and 1936 control women. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each haplotype were estimated using conditional logistic regression, stratified by age and ethnicity. Genetic variation in LD block 3 of the PGR locus was associated with endometrial cancer risk (P(global test) = 0.002), with haplotypes 3C, 3D and 3F associated with 31-34% increased risk. Among whites (383 cases/840 controls), genetic variation in all four blocks was associated with increased endometrial cancer risk (P(global test) = 0.010, 0.013, 0.005 and 0.020). Haplotypes containing the PROGINS allele and several haplotypes in blocks 1, 3 and 4 were associated with 34-77% increased risk among whites. SNP analyses for whites suggested that rs608995, partially linked to the PROGINS allele (r(2) = 0.6), was associated with increased risk (OR = 1.30, 95% CI = 1.06-1.59). Our results suggest that genetic variation in the PGR region is associated with endometrial cancer risk.


Amoxicillin-induced immune hemolysis.
Severe hemolysis occurred in a 51-year-old female after a 17-day course of intravenous amoxicillin. A strongly positive direct antiglobulin test (anti-IgG titer 1:2,000) ensued which disappeared after withdrawal of the drug. Both the patient's serum and eluate obtained from the patient's red cells contained an IgG antibody which reacted with red blood cells coated in vitro with amoxicillin, but not with uncoated cells. In addition, high-titer antipenicillin, antiampicillin and antiamoxicillin IgG antibodies could be demonstrated in her serum by a RAST-based solid-phase radioimmunoassay. The patient's hemolysis gradually subsided within 1 week after discontinuing the drug. This is the first report of amoxicillin-induced immune hemolytic anemia.


Relation of age and self-reported chronic medical condition status with dietary nutrient intake in the US population.
To examine the association of nutrient intake with age and self-reported chronic medical condition status in a large, nationally representative sample. We used data from the Continuing Survey of Food Intakes by Individuals, 1989-1991. The analytic sample included subjects aged > or =25 years with 3 days of dietary data, and medical condition information (n=7,207). A positive response to having been informed by a doctor of having diabetes, heart disease, high blood pressure, cancer, osteoporosis, and stroke indicated the presence of chronic medical condition(s) (n=2,368). Sex-specific linear and logistic regression analyses adjusted for multiple covariates were used to examine the relation of age and morbidity status with nutrient intake. In men, age was associated with an increased risk of consuming <100% of the Recommended Dietary Allowance (RDA) of vitamin E, vitamin B12, calcium, zinc, and iron (p<0.05), and self-reported morbidity was associated with an increased risk of consuming <100% of the RDA of protein. Relative to men, women were more likely to report less than the RDA of most nutrients examined; however, neither age nor chronic disease status were associated with increased likelihood of reporting <100% of the RDA of any of the nutrients examined. In women, the probability of reporting <100% of the RDA of vitamin A, vitamin B6, folate, vitamin C, and iron, and in men, the probability of reporting <100% of the RDA of vitamin C, declined with age (p<0.05). No adverse effect of age and chronic disease interaction on intake of most nutrients was noted in men or women. Chronologic age and morbidity were associated with an increased risk of inadequate intake of several nutrients in free-living, independent men but not in women.


The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes.
Bacterial growth and cell division requires precise spatiotemporal regulation of the synthesis and remodelling of the peptidoglycan layer that surrounds the cytoplasmic membrane. GpsB is a cytosolic protein that affects cell wall synthesis by binding cytoplasmic mini-domains of peptidoglycan synthases to ensure their correct subcellular localisation. Here, we describe critical structural features for the interaction of GpsB with peptidoglycan synthases from three bacterial species (Bacillus subtilis, Listeria monocytogenes and Streptococcus pneumoniae) and suggest their importance for cell wall growth and viability in L. monocytogenes and S. pneumoniae. We use these structural motifs to identify novel partners of GpsB in B. subtilis and extend the members of the GpsB interactome in all three bacterial species. Our results support that GpsB functions as an adaptor protein that mediates the interaction between membrane proteins, scaffolding proteins, signalling proteins and enzymes to generate larger protein complexes at specific sites in a bacterial cell cycle-dependent manner.


Chlamydia trachomatis GlgA is secreted into host cell cytoplasm.
Glycogen has been localized both inside and outside Chlamydia trachomatis organisms. We now report that C. trachomatis glycogen synthase (GlgA) was detected in both chlamydial organism-associated and -free forms. The organism-free GlgA molecules were localized both in the lumen of chlamydial inclusions and in the cytosol of host cells. The cytosolic GlgA displayed a distribution pattern similar to that of a known C. trachomatis-secreted protease, CPAF. The detection of GlgA was specific since the anti-GlgA antibody labeling was only removed by preabsorption with GlgA but not CPAF fusion proteins. GlgA was detectable at 12h and its localization into host cell cytosol only became apparent at 24h after infection. The cytosolic localization of GlgA was conserved among all C. trachomatis serovars. However, the significance of the GlgA secretion into host cell cytoplasm remains unclear since, while expression of chlamydial GlgA in HeLa cells increased glycogen stores, it did not affect a subsequent infection with C. trachomatis. Similar to several other C. trachomatis-secreted proteins, GlgA is immunogenic in women urogenitally infected with C. trachomatis, suggesting that GlgA is expressed and may be secreted into host cell cytosol during C. trachomatis infection in humans. These findings have provided important information for further understanding C. trachomatis pathogenic mechanisms.


Transcervical Foley catheter with and without extraamniotic saline infusion for labor induction: a randomized controlled trial.
To compare the efficacy of transcervical Foley catheter alone (Foley) to transcervical Foley catheter with extraamniotic saline infusion for labor induction and cervical ripening in women with an unfavorable cervix. This was a multicenter, randomized, controlled trial of women presenting for labor induction with a singleton, cephalic fetus, intact membranes, and unfavorable cervix (Bishop score 6 or less). Eligible women were randomly assigned to receive either Foley catheter alone or Foley catheter with extraamniotic saline infusion. All women received concurrent oxytocin administration. The primary study outcome was the induction-to-delivery interval. Secondary outcomes included cesarean delivery, maternal infectious outcomes, and immediate neonatal outcomes. Analysis was by intent to treat. One hundred eighty-eight women met eligibility criteria and were randomly assigned (Foley plus extraamniotic saline infusion, n=97; Foley, n=91). Baseline demographic characteristics, including parity, gestational age, and Bishop score were similar between the study groups. The median induction-to-delivery interval in the extraamniotic saline infusion arm (12.6 hours, interquartile range 9.3-18.8 hours) was similar to that in the Foley arm (13.4 hours, interquartile range 9.6-17.5 hours) (P=. 70). The proportion of women delivered by 24 hours was comparable between groups (delivery 24 hours, extraamniotic saline infusion 89.7%, Foley 87.9%, P=.70), as was the rate of cesarean delivery (Foley 18.7%, extraamniotic saline infusion 27.8%, P=.14). No significant differences were noted between the study groups with respect to rate of chorioamnionitis, endometritis, or immediate birth outcomes. In women with an unfavorable cervix, the addition of extraamniotic saline infusion to a transcervical Foley catheter does not improve efficacy for labor induction. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00442663 I.


Meta-analysis of the role of statin therapy in reducing myocardial infarction following elective percutaneous coronary intervention.
Statin medications initiated during percutaneous coronary intervention have been evaluated in clinical trials mainly to assess if this therapy reduces subsequent restenosis. The benefit of statin therapy on individual cardiovascular outcomes other than restenosis is largely unknown. Hence, a meta-analysis of the available randomized trials was conducted to evaluate individual cardiovascular outcomes with statin therapy compared with placebo after elective percutaneous coronary intervention. In all, there were 6 studies available for analysis (Prevention of Restenosis by Elisor After Transluminal Coronary Angioplasty [PREDICT], Fluvastatin Angioplasty Restenosis [FLARE], the Lescol Intervention Prevention Study [LIPS], German Atorvastatin Intravascular Ultrasound [GAIN], Atorvastatin for Reduction of Myocardial Damage During Angioplasty [ARMYDA], and a study by Briguori et al) that randomized 3,941 patients (1,967 to statins and 1,974 to placebos). Clinical follow-up ranged from 1 day to 45 months. The incidence of myocardial infarction was 3.0% in the statin group and 5.2% in the placebo group (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.42 to 0.78, p<0.0001). The incidence of all-cause mortality was 2.3% versus 3.0% (OR 0.74, 95% CI 0.50 to 1.1, p=0.14), that of cardiovascular mortality was 0.71% versus 1.2% (OR 0.58, 95% CI 0.30 to 1.11, p=0.10), and that of repeat surgical or percutaneous revascularization was 19.6% versus 21.9% (OR 0.89, 95% CI 0.78 to 1.02, p=0.098) in the statin arm versus the placebo arm, respectively. The incidence of stroke was 0.4% in the statin arm and 0.08% in the placebo arm (OR 3.00, 95% CI 0.60 to 14.77, p=0.18). In conclusion, statin therapy initiated at the time of elective percutaneous coronary intervention significantly reduces myocardial infarction.


Thoracic juxtafacet cyst (JFC): a cause of spinal myelopathy.
Spinal cord compression due to synovial facet cyst in thoracolumbar spine is rare. Several etiologies of juxtafacet cysts (JFCs) in this location have been discussed, particularly overload of the arthritic facet joints. Due to the narrow caliber of the thoracic spine, JFC in this location can present with radicular pain or progressive myelopathy. We report an interesting case of a 67 year-old woman who presented with the signs and symptoms of thoracic myelopathy. A left-sided T11/12 JFC was identified on MRI and CT scans correlating with her myelopathy. She experienced a substantial improvement in her myelopathic symptoms after surgical excision of the JFC. The presentation, etiology, and therapeutic aspects of JFC are discussed in detail.


Administrative audits of professional services: effective residency training experience.
The development of a structured method of providing administrative experience for hospital pharmacy residents, using internal audit techniques, is described. Residents were assigned topics to investigate in the administrative area of hospital pharmacy early during their two-year, academically affiliated residency. They were expected to review and evaluate the topic critically using internal audit techniques; written and oral reports were presented to the administrative staff. Residents were able to complete the audits while attending classes as part of their academic experience. As a result of performing the audits, residents have learned administrative skills in problem identification, assessed their personal competency by reviewing major components of contemporary practice, learned accepted standards of pharmacy practice, and developed skills in making improvements in conformity with quality assurance standards. This program has been incorporated as an integral part of the residency program.


Epilepsy: new advances.
Epilepsy affects 65 million people worldwide and entails a major burden in seizure-related disability, mortality, comorbidities, stigma, and costs. In the past decade, important advances have been made in the understanding of the pathophysiological mechanisms of the disease and factors affecting its prognosis. These advances have translated into new conceptual and operational definitions of epilepsy in addition to revised criteria and terminology for its diagnosis and classification. Although the number of available antiepileptic drugs has increased substantially during the past 20 years, about a third of patients remain resistant to medical treatment. Despite improved effectiveness of surgical procedures, with more than half of operated patients achieving long-term freedom from seizures, epilepsy surgery is still done in a small subset of drug-resistant patients. The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research. Concerted actions to address these challenges are urgently needed.


Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention.
Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae.


Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions.
The TGF-beta superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell fate specification in development to immune suppression. Activins define a major subgroup of TGF-beta ligands that regulate cellular differentiation, proliferation, activation and apoptosis. Activins signal through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. ActRIIB binds to the outer edges of the activin finger regions, with the two receptors juxtaposed in close proximity, in a mode that differs from TGF-beta3 binding to type II receptors. The dimeric activin A structure differs from other known TGF-beta ligand structures, adopting a compact folded-back conformation. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface and suggests that diversity in the conformational arrangements of TGF-beta ligand dimers could influence cellular signaling processes.


Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice.
Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID. We used conditional Slc6a3DTR/+ mice to model progressive DA deficiency and the β-adrenergic receptor (β-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of β-AR ligands on striatal ChIs. LID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that β-ARs can effectively modulate ChI firing. The work suggests that pharmacological modulation of ChIs by β-ARs might provide a therapeutic option for managing LID.


Pooling as a strategy for the timely diagnosis of soil-transmitted helminths in stool: value and reproducibility.
The strategy of pooling stool specimens has been extensively used in the field of parasitology in order to facilitate the screening of large numbers of samples whilst minimizing the prohibitive cost of single sample analysis. The aim of this study was to develop a standardized reproducible pooling protocol for stool samples, validated between two different laboratories, without jeopardizing the sensitivity of the quantitative polymerase chain reaction (qPCR) assays employed for the detection of soil-transmitted helminths (STHs). Two distinct experimental phases were recruited. First, the sensitivity and specificity of the established protocol was assessed by real-time PCR for each one of the STHs. Secondly, agreement and reproducibility of the protocol between the two different laboratories were tested. The need for multiple stool sampling to avoid false negative results was also assessed. Finally, a cost exercise was conducted which included labour cost in low- and high-wage settings, consumable cost, prevalence of a single STH species, and a simple distribution pattern of the positive samples in pools to estimate time and money savings suggested by the strategy. The sensitivity of the pooling method was variable among the STH species but consistent between the two laboratories. Estimates of specificity indicate a 'pooling approach' can yield a low frequency of 'missed' infections. There were no significant differences regarding the execution of the protocol and the subsequent STH detection between the two laboratories, which suggests in most cases the protocol is reproducible by adequately trained staff. Finally, given the high degree of agreement, there appears to be little or no need for multiple sampling of either individuals or pools. Our results suggest that the pooling protocol developed herein is a robust and efficient strategy for the detection of STHs in 'pools-of-five'. There is notable complexity of the pool preparation to ensure even distribution of helminth DNA throughout. Therefore, at a given setting, cost of labour among other logistical and epidemiological factors, is the more concerning and determining factor when choosing pooling strategies, rather than losing sensitivity and/or specificity of the molecular assay or the method.


Maternal Attitudes and Other Factors Associated with Infant Vaccination Status in the United States, 2011-2014.
To assess the role of maternal attitudes and other factors associated with infant vaccination status. Data on reported vaccination status were analyzed from a nationally representative prospective survey of mothers of 2- to 6-month-old infants. Weighted univariate and multiple logistic regression analyses were conducted. Latent profile analysis of mothers reporting nonimmunized infants identified distinct groups, RESULTS: Of 3268 mothers, 2820 (weighted 86.2%), 311 (9.1%), and 137 (4.7%), respectively, reported their infant had received all, some, or no recommended vaccinations for age. Younger infants and infants with younger mothers were more likely to have received no vaccinations. Mothers with neutral and negative attitudes toward vaccination were >3 (aOR 3.66, 95% CI 1.80-7.46) and 43 times (aOR 43.23, 95% CI 20.28-92.16), respectively, more likely than mothers with positive attitudes to report their infants had received no vaccinations. Two subgroups of mothers reporting that their infants had received no vaccinations were identified: group A (52.5%) had less than positive attitudes and less than positive subjective norms about vaccination (ie, perceived social pressure from others); group B (47.5%) had positive attitudes and positive subjective norms. Group A mothers were more likely to be white (76.1% vs 48.3%, P?=?.002), more educated (43.5% vs 35.4% college or higher, P?=?.02), and to exclusively breastfeed (74.9% vs. 27.3%, P?<?.001). Although access barriers can result in nonvaccination, less than positive maternal attitude toward vaccination was the strongest predictor. Strategies to improve vaccination rates must focus on both improved access and better understanding of factors underlying maternal attitudes.


[Diagnosis and treatment of syncope].
Syncope is associated with considerable costs to society as well as to the patient. Syncope may arise on a neurological, cardiac, or neurovascular background. Cardiac and neurological causes are evaluated by standard methods. Neurovascular syncope is diagnosed by tilt table testing and carotid massage. The treatment of neurological or cardiac syncope aims at the underlying cause, whereas the treatment of neurovascular syncope consists of information and instruction in reasonable precautions. In persisting cases, medical treatment or pacemaker implantation may be necessary.


Characterization of Lignin Compounds at the Molecular Level: Mass Spectrometry Analysis and Raw Data Processing.
Lignin is the second most abundant natural biopolymer, which is a potential alternative to conventional fossil fuels. It is also a promising material for the recovery of valuable chemicals such as aromatic compounds as well as an important biomarker for terrestrial organic matter. Lignin is currently produced in large quantities as a by-product of chemical pulping and cellulosic ethanol processes. Consequently, analytical methods are required to assess the content of valuable chemicals contained in these complex lignin wastes. This review is devoted to the application of mass spectrometry, including data analysis strategies, for the elemental and structural elucidation of lignin products. We describe and critically evaluate how these methods have contributed to progress and trends in the utilization of lignin in chemical synthesis, materials, energy, and geochemistry.