Flavonol-cinnamate cycloadducts and diamide derivatives from Aglaia laxiflora.
Leaf extracts of the Malaysian plant Aglaia laxiflora provided two cytotoxic compounds, a new rocaglaol rhamnoside (1), a known rocaglaol (2), new (but inactive) flavonol-cinnamaminopyrrolidine adducts (3-6), and their probable biosynthetic precursors (7 and trimethoxyflavonol). All structures were elucidated primarily by 2D NMR spectroscopy. The structure and stereochemistry of aglaxiflorin A (3) were confirmed by single-crystal X-ray crystallography.


Childhood and adolescent depression: a review of the past 10 years. Part II.
To review the literature of the past decade covering the assessment, treatment, and prevention of early-onset major depressive disorder (MDD) and dysthymic disorder (DD). A computerized search for articles published during the past decade was made, and selected studies are presented. Diagnostic systems and standardized interviews have been developed to reliably assess and diagnose early-onset MDD and DD. To data, few controlled psychotherapeutic trials, in particular cognitive-behavioral therapy (CBT), and one study using fluoxetine have been shown to be efficacious in the acute management of early-onset MDD. While studies of tricyclic antidepressants have shown no difference between medication and placebo, these studies are inconclusive because of the inclusion of small samples and other methodological issues. CBT may also be useful for the prevention of MDD. No studies have been published on maintenance treatment of MDD or the treatment of early-onset DD. It appears that both pharmacological and psychotherapeutic interventions have a role in the acute treatment of MDD. However, further research on the separate and combined efficacy of these treatments for the acute treatment, maintenance, and prevention of early-onset MDD and DD is needed. The impact of comorbidity and psychosocial consequences of early-onset depression also emphasize the importance of utilizing a multimodal approach to treatment.


HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling.
The intratumoral microenvironment of head and neck squamous cell carcinoma (HNSC) is highly immunosuppressive. In this study, we explored the potential functional role of HSPA12B secreted by tumor-associated endothelial cells (TECs) in M2 polarization of macrophages. Bulk-seq data from TCGA-HNSC and single-cell RNA-seq data from GSE103322 (with over 5000 cells from 18 primary HNSC cases) were used for bioinformatic analysis. RAW264.7 cell line was used for in vitro studies. TECs in HNSC had significantly higher expression and secretion of HSPA12B, compared to normal human umbilical vein endothelial cells (HUVECs). Exogenous HSPA12B treatment increased the expression of M2 macrophage marker CD163 and CD206 on RAW264.7 cells in a dose-dependent manner but had no significant influence on CD86, an M1 macrophage marker. OLR1, a known receptor of HSP70 proteins, was specifically expressed in tumor-associated macrophages (TAMs) in HNSC. OLR1 knockdown significantly impaired HSPA12B uptake by RAW264.7 cells and weakened HSPA12B-induced CD163 and CD206 upregulation. HSPA12B treatment increased the expression of p-PI3K, p-Akt and p-mTOR in a dose-dependent manner in RAW264.7 cells. OLR1 inhibition and LY294002 treatment significantly weakened the effects HSPA12B on activating the PI3K/Akt/mTOR signaling and M2 marker expression. Based on these findings, we speculated that aberrantly expressed and secreted HSPA12B by TECs could be taken by macrophages partly via OLR1, leading to subsequent activation of the PI3K/Akt/mTOR signaling pathway and elevated expression of M2 markers. This mechanism shows a novel cross-talk between TECs and TAMs, which contributes to the intratumoral immunosuppressive microenvironment.


Isolation of Mitochondrial DNA from Single, Short Hairs without Roots Using Pressure Cycling Technology.
Hairs are commonly submitted as evidence to forensic laboratories, but standard nuclear DNA analysis is not always possible. Mitochondria (mt) provide another source of genetic material; however, manual isolation is laborious. In a proof-of-concept study, we assessed pressure cycling technology (PCT; an automated approach that subjects samples to varying cycles of high and low pressure) for extracting mtDNA from single, short hairs without roots. Using three microscopically similar donors, we determined the ideal PCT conditions and compared those yields to those obtained using the traditional manual micro-tissue grinder method. Higher yields were recovered from grinder extracts, but yields from PCT extracts exceeded the requirements for forensic analysis, with the DNA quality confirmed through sequencing. Automated extraction of mtDNA from hairs without roots using PCT could be useful for forensic laboratories processing numerous samples.


Faster ribosome synthesis induced by elevated aortic pressure in rat heart.
An increase in aortic pressure from 60 to 120 mmHg accelerated ribosomal protein synthesis in rat hearts during 1 or 2 h of labeling with 0.4 mM [3H]phenylalanine. When hearts were perfused with buffer that contained 20 mM glucose and normal plasma concentrations of 19 other amino acids without added insulin, ribosomal protein synthesis relative to the rate of total protein synthesis increased from approximately 0.22 to 0.36 and 0.30 as aortic pressure was raised from 60 to 120 mmHg during 1 or 2 h of labeling, respectively. With the addition of insulin, the relative rate of ribosomal protein synthesis averaged 0.33 at an aortic pressure of 60 mmHg and increased to 0.42 when aortic pressure was raised to 120 mmHg. These results indicate that elevation of aortic pressure has a preferential effect on synthesis of new ribosomes. This response appears to be an early and physiologically significant event in cardiac hypertrophy.


miR-145-5p: A Potential Biomarker in Predicting Gleason Upgrading of Prostate Biopsy Samples Scored 3+3=6.
The Gleason grading system is a major tool used for prediction of prostate cancer (PCa) behavior. Because of heterogeneity and sampling errors, prognosis is variable even among patients with the same Gleason score (GS). Therefore, more accurate biomarkers that complement the Gleason system are needed to improve the clinical management of PCa. Formalin-fixed, paraffin embedded tissue samples were obtained from radical prostatectomy (RP) (patient set 1, n=53) and needle biopsy (patient set 2, n=107; patient set 3, n=119). Cancer tissues from pure regions of each Gleason pattern (GP) were separately collected using laser-captured microdissection, followed by Real-time-PCR to determine the relative expression of miRNAs, including miR-1-5p, miR-21-5p, miR-30d-5p, miR-100-5p, miR-145-5p, miR-224-5p, and miR-708-5p. miRNA's association with Gleason upgrading (GU) was evaluated using receiver operator characteristics (ROC) curve and multivariate logistic regression analysis. The integrated miRNA targets prediction and enrichment analyses were performed to determine the potential functions of miRNA. It was found that miR-145-5p in GP3 from radical prostatectomy (RP) were overexpressed in patients with GS6 PCa compared with GS7 patients, which was further confirmed in a larger biopsy cohort. ROC curve analysis revealed that miR-145-5p in biopsy was significantly associated with GU upon RP. In multivariate analyses, miR-145-5p was an independent predictor of GU. Our study indicated that differential expression of miRNAs existed in GP3 from pure GS6 and GS7 PCa, highlighting a path toward the clinical use of miRNAs in predicting GU and assisting in treatment modality selection.


Open-label uridine for treatment of depressed adolescents with bipolar disorder.
This report is an open-label case series of seven depressed adolescents with bipolar disorder treated with uridine for 6 weeks. Treatment response was measured with the Children's Depression Rating Scale-Revised and the Clinical Global Impressions scale. Uridine was associated with decreased depressive symptoms, and was well tolerated by study participants. Further systematic studies of uridine are warranted.


Catalytic-site mutations in the MYST family histone Acetyltransferase Esa1.
Esa1 is the only essential histone acetyltransferase (HAT) in budding yeast. It is the catalytic subunit of at least two multiprotein complexes, NuA4 and Piccolo NuA4 (picNuA4), and its essential function is believed to be its catalytic HAT activity. To examine the role of Esa1 in DNA damage repair, we isolated viable esa1 mutants with a range of hypersensitivities to the toposide camptothecin. Here we show that the sensitivity of these mutants to a variety of stresses is inversely proportional to their level of histone H4 acetylation, demonstrating the importance of Esa1 catalytic activity for resistance to genotoxic stress. Surprisingly, individual mutations in two residues directly involved in catalysis were not lethal even though the mutant enzymes appear catalytically inactive both in vivo and in vitro. However, the double-point mutant is lethal, demonstrating that the essential function of Esa1 relies on residues within the catalytic pocket but not catalysis. We propose that the essential function of Esa1 may be to bind acetyl-CoA or lysine substrates and positively regulate the activities of NuA4 and Piccolo NuA4.


Comparing Calcium Alginate Dressings to Vacuum-assisted Closure: A Clinical Trial.
Several treatment modalities and protocols for arterial wound ulcers are available; however, little consensus exists on which treatment modality provides the best results. The present study sought to compare and evaluate the clinical efficacy of vacuum-assisted closure wound therapy to calcium alginate dressings in the treatment of neuroischemic diabetic foot ulceration. A single-center quasi-experimental matched subject clinical trial was conducted on 30 subjects living with type 2 diabetes and presenting with a newly diagnosed neuroischemic foot ulceration. Subjects were divided into 2 groups. Group A (n = 15) underwent negative pressure wound therapy and Group B (n =15) underwent treatment using calcium alginate dressings. Ulcer area and depth were measured during the trial. Both negative pressure therapy and calcium alginate dressings were effective in reducing the surface area and depth of ulcers (P = 0.0001). However, negative pressure was 3.2 times more effective in reducing surface area and 3.78 times more effective in reducing depth of ulcers when compared to calcium alginate (P = 0.0001). Vacuum-assisted closure should be considered as the treatment of choice for neuroischemic ulceration owing to its advantages in reducing surface area and depth when compared to calcium alginate dressings. Improved care could result in improved health outcomes, improved quality of life, and fewer diabetes-related foot complications.


Investigating the effect of changing ammunition on the composition of organic additives in gunshot residue (OGSR).
The measurement of the organic additives in smokeless gunpowder is an attractive approach for the detection of handgun use because it provides compositional information that can help associate residues and unfired gunpowder. We investigate several factors that will be required to advance the characterization of organic gunshot residue (OGSR) as a useful forensic tool, including evaluating residue contamination from previously fired ammunition, particle-to-particle compositional variability, and compositional features resulting from the type of firing primer used. Using ammunition loaded with known smokeless powders containing different stabilizers, a sequence of shots was fired from a .357 magnum revolver, and the muzzle exit residues were collected. Compositional analysis of the residues, both in bulk and as single particles, showed only a trace of the previously fired powder in the first shot and none in subsequent shots. In an additional experiment testing conventional leaded and the new lead-free firing primers, the OGSR composition was found not to depend on the primer type.


Effect of controlled cortical impact on the passage of pituitary adenylate cyclase activating polypeptide (PACAP) across the blood-brain barrier.
Injuries to the central nervous system can affect the blood-brain barrier (BBB), including disruption and influencing peptide transport across the BBB. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a potent neurotrophic and neuroprotective peptide currently being investigated for its therapeutic role following injury to the central nervous system and can cross the BBB in a saturable manner. The goal of the current study was to investigate for the first time PACAP38 uptake by the brain following traumatic brain injury (TBI). Using radioactively labeled PACAP38, we measured the levels of PACAP38 present in the injured, ipsilateral cortex in Sham-treated mice compared to mice receiving a controlled cortical impact (CCI), a model of TBI. Experiments were conducted at 6 different time points (from 2h up to 4 weeks) following CCI to determine temporal changes in PACAP38 transport. PACAP38 uptake was increased at 2 and 72h post-CCI compared to Sham. We did not detect changes in PACAP38 uptake in the contralateral cortex and cerebellum between Sham and CCI-treatment. The rate of PACAP38 transport into the ipsilateral cortex following CCI was increased 3.6-fold 72h after compared to 2h post-CCI. In addition, the rate of transport into the cerebellum was greater than that of the cortices. The data presented here shows PACAP38 transport is temporally altered following CCI-treatment and PACAP38 uptake is greater in the cerebellum compared to the cortices.


Ovine lentivirus lymphoid interstitial pneumonia. Rapid induction in neonatal lambs.
For examination of the characteristics of lentivirus-induced pulmonary disease in an animal model, neonatal lambs were given intratracheal injections of high-and low-passage ovine lentivirus (OvLV) isolates. In 6 of 6 lambs inoculated with low-passage OvLV or OvLV from lung lavage fluid, lesions of lymphoid interstitial pneumonia (LIP) developed. In none of 7 lambs inoculated with a high-passage OvLV or 4 control lambs inoculated with medium alone or ultrafiltered lung fluid did lung lesions develop. Systemic distribution of lentivirus was greater and development of lentivirus antibody was more rapid in lambs inoculated with low-passage OvLV, compared with lambs inoculated with high passage OvLV. The number of lymphocytes in bronchoalveolar lavage samples was increased in lambs with lymphoid interstitial pneumonia. The development of lymphoid interstitial pneumonia was markedly accelerated, in comparison with previous reports of experimentally induced lentivirus pneumonia in sheep. In lentivirus-inoculated lambs pulmonary lesions developed comparable to lymphoid interstitial pneumonia associated with the acquired immunodeficiency syndrome and other human benign lymphoid disorders of the lung. Similarities between the disease manifestations and virologic properties of OvLV and human T-cell lymphotropic virus III argue for the relevance of OvLV-induced disease as a model for human retrovirus diseases. The ability of OvLV to cause accelerated pulmonary disease in neonates may be due to age-related susceptibility factors that enhance the pathogenicity of lentiviruses.


Risankizumab to treat moderately to severely active Crohn's disease in adults: an evaluation of trials and data.
Risankizumab is a humanized monoclonal antibody that selectively inhibits interleukin (IL)-23. It is approved for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis, and more recently moderate-to-severe Crohn's disease (CD). After examining the current landscape of CD management including therapies which are currently approved and those in late stages of development, we will review the interleukin pathway and discuss the specific mechanism of targeted IL-23 inhibition, summarize available clinical trial data on efficacy and safety of Risankizumab, consider future positioning of Risankizumab in the therapeutic armamentarium, and ultimately discuss future needs for the field. Risankizumab represents the first and only targeted IL-23 inhibitor approved for the treatment of CD, providing a promising addition to the therapeutic armamentarium for CD, with a favorable safety profile and demonstrated efficacy in both biologic-naïve and exposed populations. It is possible that the targeted nature of Risankizumab may enhance efficacy and safety over combined IL-12/23 inhibition, with trials underway attempting to shed light on that hypothesis.


Twenty-four-hour analysis of elevated energy expenditure after physical activity in a metabolic chamber: models of daily total energy expenditure.
The Institute of Medicine proposed that 15% of energy expenditure (EE) as excess post-exercise oxygen consumption should be added to additional physical activity energy expenditure (DeltaPAEE) to estimate total EE. However, the magnitude of elevated post-physical activity energy expenditure (EPEE) under normal daily living conditions has not been examined. We examined the effects of EPEE on 24-h EE by modeling standard living conditions in a metabolic chamber. Eleven Japanese men completed three 24-h metabolic chamber measurements: a control day (C-day), a day with high-frequency moderate-intensity physical activity (M-day), and a day with high-frequency vigorous-intensity physical activity (V-day). Mean (+/- SD) 24-h EE for the C-day, the M-day, and the V-day was 2228 +/- 143 kcal, 2816 +/- 197 kcal, and 2813 +/- 163 kcal, respectively. No significant difference was observed in 24-h EE between an M-day and a V-day. Mean EPEEs on the M-day and the V-day did not significantly contribute to increasing 24-h EE. Relative EPEEs to DeltaPAEEs were 6.2 +/- 13.9% (M-day) and 5.1 +/- 9.2% (V-day). However, EPEE/24-h EE was negatively correlated with maximal oxygen uptake on the V-day (r = -0.68, P = 0.02), although no significant correlation between these variables was observed on the M-day (r = -0.41, P = 0.21). These results suggest that EPEE has a small effect on 24-h EE in the course of normal daily activities, findings that do not support the proposition by the Institute of Medicine for estimating TEE. However, persons with low physical fitness levels could enhance EE as EPEE by increasing vigorous-intensity daily physical activity.


Serum bicarbonate and long-term outcomes in CKD.
A low serum bicarbonate level is prevalent in chronic kidney disease (CKD); however, its relationship to long-term outcomes is unclear. Cohort study. The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 942 screened but non-randomized individuals and 839 randomized participants with baseline serum bicarbonate measurements with stage 2-4 CKD. Serum bicarbonate level categorized into quartiles. Kidney failure, all-cause mortality, and a composite outcome of mortality and kidney failure. Local laboratories at each participating site measured bicarbonate in fasting serum samples. Kidney failure outcomes were obtained from the US Renal Data System, and mortality data, from the National Death Index. Mean glomerular filtration rate (GFR) was 39 ± 21 (SD) mL/min/1.73 m(2) and serum bicarbonate level was 23.3 ± 3.8 mEq/L. Kidney failure rates were 72%, 64%, 50%, and 41%; mortality rates were 31%, 25%, 21%, and 25%, and rates of the composite outcome were 78%, 71%, 58%, and 54% in bicarbonate quartiles 1, 2, 3, and 4, respectively. In analyses adjusted for demographic and cardiovascular disease factors, serum albumin level, proteinuria, and cause of kidney disease, compared with quartile 4, quartile 1 was associated with a 2.22 HR (95% CI, 1.83-2.68) of kidney failure; 1.39 HR (95% CI, 1.07-1.18) of all-cause mortality; and 1.36 HR (95% CI, 1.15-1.62) of the composite outcome. These associations were rendered nonsignificant with adjustment for GFR (kidney failure HR, 1.05 [95% CI, 0.87-1.28]; all-cause mortality HR, 0.99 [95% CI, 0.75-1.13]; composite HR, 1.04 [95% CI, 0.87-1.24]). Single baseline measurement of serum bicarbonate. Low serum bicarbonate level was associated with increased risk of long-term outcomes in nondiabetic patients with CKD. However, this risk is not independent of baseline GFR. Clinical trials are necessary to evaluate whether bicarbonate supplementation slows the progression of CKD.


[Duplication of the bladder by a frontal septum. Apropos of a case].
The authors report a case of total bladder duplication by frontal septum. The anterior bladder was functional. The posterior bladder was non-functional, and drained a destroyed kidney. Analysis of the rare cases reported in the literature suggests that this malformation should be differentiated from other bladder duplications, because it may be a giant ureterocele. In conclusion, the authors stress the simplicity of the management, consisting of resection of the septum and nephrectomy of the non-functional kidney.


Preparation for the next major incident: are we ready? A 12-year update.
A major incident is any emergency that requires special arrangements by the emergency services and generally involves a large number of people. Recent such events in England have included the Manchester Arena bombing and the Grenfell Tower disaster. Hospitals are required by law to keep a major incident plan (MIP) outlining the response to such an event. In a survey conducted in 2006 we found a substantial knowledge gap among key individuals that would be expected to respond to the enactment of an MIP. We set out to repeat this survey study and assess any improvement since our original report. We identified NHS trusts in England that received more than 30 000 patients through the emergency department in the fourth quarter of the 2016/2017 period. We contacted the on-call anaesthetic, emergency, general surgery, and trauma and orthopaedic registrar at each location and asked each individual to answer a short verbal survey assessing their confidence in using their hospital's MIP. Of those eligible for the study, 62% were able to be contacted and consented to the study. In total 50% of respondents had read all or part of their hospital's MIP, 46.8% were confident that they knew where their plan was stored, and 36% knew the role they would play if a plan came into effect. These results show less confidence among middle-grade doctors compared with 2006. Confidence in using MIPs among specialty registrars in England is still low. In light of this, we make a number of recommendations designed to improve the education of hospital doctors in reacting to major incidents.


Unraveling Assemblage, Functions and Stability of the Gut Microbiota of Blattella germanica by Antibiotic Treatment.
Symbiosis between prokaryotes and eukaryotes is a widespread phenomenon that has contributed to the evolution of eukaryotes. In cockroaches, two types of symbionts coexist: an endosymbiont in the fat body (Blattabacterium), and a rich gut microbiota. The transmission mode of Blattabacterium is vertical, while the gut microbiota of a new generation is mainly formed by bacterial species present in feces. We have carried out a metagenomic analysis of Blattella germanica populations, treated and non-treated with two antibiotics (vancomycin and ampicillin) over two generations to (1) determine the core of bacterial communities and potential functions of the gut microbiota and (2) to gain insights into the mechanisms of resistance and resilience of the gut microbiota. Our results indicate that the composition and functions of the bacteria were affected by treatment, more severely in the case of vancomycin. Further results demonstrated that in an untreated second-generation population that comes from antibiotic-treated first-generation, the microbiota is not yet stabilized at nymphal stages but can fully recover in adults when feces of a control population were added to the diet. This signifies the existence of a stable core in either composition and functions in lab-reared populations. The high microbiota diversity as well as the observed functional redundancy point toward the microbiota of cockroach hindguts as a robust ecosystem that can recover from perturbations, with recovery being faster when feces are added to the diet.


[Mechanical effects on measuring displacement of the knee joint with the knee arthrometer KT1000 and KT2000].
The KT2000 knee ligament arthrometer manufactured by the MEDmetric Corporation is used in the field of orthopedics to establish quantitatively the size of the anterior and posterior draw phenomena of the knee joint. The basis for the measurement is the Lachman test in which a force is applied to the tibia relative to the femur. The resulting displacement is limited by the cruciate ligaments. The measurements obtained for a potentially injured knee are compared with those of the healthy knee and empirical threshold values, and serve as a basis for deciding whether to operate on patients with cruciate ligament insufficiency. The subject of the present study is a design shortcoming of the KT2000 that may falsify the measured results when the device is not correctly employed. A simple mechanical modification of the KT2000 can reduce this error. In the present study, the error is quantified and we show how the modification can keep it within tolerable limits.


Comparison-Based Image Quality Assessment for Selecting Image Restoration Parameters.
Image quality assessment (IQA) is traditionally classified into full-reference (FR) IQA, reduced-reference (RR) IQA, and no-reference (NR) IQA according to the amount of information required from the original image. Although NR-IQA and RR-IQA are widely used in practical applications, room for improvement still remains because of the lack of the reference image. Inspired by the fact that in many applications, such as parameter selection for image restoration algorithms, a series of distorted images are available, the authors propose a novel comparison-based IQA (C-IQA) framework. The new comparison-based framework parallels FR-IQA by requiring two input images and resembles NR-IQA by not using the original image. As a result, the new comparison-based approach has more application scenarios than FR-IQA does, and takes greater advantage of the accessible information than the traditional single-input NR-IQA does. Further, C-IQA is compared with other state-of-the-art NR-IQA methods and another RR-IQA method on two widely used IQA databases. Experimental results show that C-IQA outperforms the other methods for parameter selection, and the parameter trimming framework combined with C-IQA saves the computation of iterative image reconstruction up to 80%.


Tissue culture of human renal epithelial cells using a defined serum-free growth formulation.
Development of the culture of renal epithelial cells in a serum-free growth medium was driven by the need to examine the effects of hormones and other effector molecules on differentiated cell function without interference from the complex mixture of substances in serum. The present report details this laboratory's cumulative experience in the use of a defined growth medium for the propagation of epithelial cells from adult, fetal, and malignant human renal tissue. Routine cell culture technology was used to determine the capability of a defined growth medium to support the growth of renal epithelial cells isolated by collagenase dissociation of tissue from adult and fetal kidneys, renal cell carcinoma, and Wilms' tumors. The defined growth medium formulation consistently allows the isolation and growth of transporting renal epithelial cells from both normal adult and fetal kidneys. This growth medium only rarely supports the growth of epithelial cells from renal cell carcinomas and Wilms' tumors. The method developed for the culture of human proximal tubule cells requires minimal cell culture expertise and equipment, and results in the repeatable isolation of transporting epithelial cell cultures that retain features of differentiated proximal tubule cells.


Decentralization and health care prioritization process in Tanzania: from national rhetoric to local reality.
During the 1990s, Tanzania like many other developing countries adopted health sector reforms. The most common policy change under the health sector reforms has been decentralization, which involves the transfer of power and authority from the central level to local authorities. Based on the case study of Mbarali district in Tanzania, this paper uses a policy analysis approach to analyse the implementation of decentralized health care priority setting. Specifically, the paper examines the process, actors and contextual factors shaping decentralized health care priority setting processes. The analysis and conclusion are based on a review of documents, key informant interviews, focus group discussion, and notes from non-participant observation. The findings of the study indicate that local institutional contexts and power asymmetries among actors have a greater influence on the prioritization process at the local level than expected and intended. The paper underlines the essentially political character of the decentralization process and reiterates the need for policy analysts to pay attention to processes, institutional contexts, and the role of policy actors in shaping the implementation of the decentralization process at the district level.


Pilot study for forensic evaluations of the Precision ID GlobalFiler™ NGS STR Panel v2 with the Ion S5™ system.
With the continuous development of massively parallel sequencing (MPS), increasing numbers of laboratories have utilized this method for forensic genomic analyses. When sequencing common short tandem repeats (STRs), MPS does have many advantages over the length-based genotyping method that uses traditional capillary electrophoresis (CE) technology. The Precision ID GlobalFiler™ NGS STR Panel v2 was recently released to simultaneously target 31 autosomal STRs (20 expanded Combined DNA Index System (CODIS) core loci and 11 non-CODIS loci) and 4 gender determination loci (Amelogenin, DYS391, SRY and Y-indel (rs2032678)) with the Ion S5™ System. In the current study, we performed a preliminary validation for this novel MPS-STR panel that included the following analyses: repeatability, concordance, stutter and balance, sensitivity, case-type sample testing, stability, mixture and a population investigation. Complete and reliable profiles were obtained using 125 pg of positive control DNA. The commonly encountered types of case samples and artificial mixtures with ratios of 1:1, 1:3 and 3:1 were also fully genotyped. Additional allele sequence variations were detected in samples from 50 unrelated individuals, and subsequently, an increased power of discrimination and power of exclusion were achieved. However, the average depth of coverage (DoC) of the Penta D locus was detected to be dramatically lower than those of other loci, which caused an interlocus imbalance; this could be one of the reasons for the intralocus imbalance of this locus and the 0.18% inconsistent results in the concordance study. Although certain flaws were observed, the informative metrics, including the DoC, sequence coverage ratios (SCRs) and heterozygote balance (Hb), of the novel MPS multiplex in our study were sufficient for reliable sequencing results that were 99.61% in concordance with the capillary electrophoresis (CE) results. In general, the Precision ID GlobalFiler™ NGS STR Panel v2 was demonstrated to be sensitive, reliable and robust and could be a powerful tool for human identification and kinship analyses. Additionally, we look forward to its updated version.


Selective ionization of oxidized lipid species using different solvent additives in flow injection mass spectrometry.
Lipid oxidation in food products is a crucial problem that causes undesirable changes in the food's flavor, texture, and nutritional value. It should be carefully monitored as it can lead to the formation of potentially toxic compounds and in that way reduce the shelf life of the product. Liquid chromatography coupled to mass spectrometry is a powerful tool to monitor the formation of oxidized lipids. However, the presence of lipid species in both their non-oxidized and oxidized forms at distinctly different concentrations can hinder the detection and identification of the less abundant oxidized species, due to coelution. In this study, a flow injection mass spectrometry approach was used to selectively ionize oxidized triacylglycerols versus their non-oxidized precursors. Three mobile phase additives were investigated (ammonium formate, sodium acetate, and sodium iodide) at three different concentrations, and ion source settings (i.e., sheath gas temperature, capillary voltage, and nozzle voltage) were optimized. A fractional factorial design was conducted to examine not only the direct effect of the operating parameters on the selectivity of ionization for the oxidized lipid species, but also to assess their combined effect. Overall, selective ionization of oxidized versus non-oxidized lipid species was favored by the use of sodium-containing solvent additives. The application of specific ion source settings resulted in an increased ionization selectivity, with sheath gas temperature and capillary voltage having the most significant influence. A selectivity factor as high as 120 could be reached by combining 0.1 mg/mL sodium-containing additives, with 250 °C sheath gas temperature and 5000 V capillary voltage. These findings will contribute to future studies on fast detection and relative quantification of low abundant oxidized triacylglycerols and their possible impact on human health.


Water Networks Can Determine the Affinity of Ligand Binding to Proteins.
Solvent organization is a key but underexploited contributor to the thermodynamics of protein-ligand recognition, with implications for ligand discovery, drug resistance, and protein engineering. Here, we explore the contribution of solvent to ligand binding in the Haemophilus influenzae virulence protein SiaP. By introducing a single mutation without direct ligand contacts, we observed a >1000-fold change in sialic acid binding affinity. Crystallographic and calorimetric data of wild-type and mutant SiaP showed that this change results from an enthalpically unfavorable perturbation of the solvent network. This disruption is reflected by changes in the normalized atomic displacement parameters of crystallographic water molecules. In SiaP's enclosed cavity, relative differences in water-network dynamics serve as a simple predictor of changes in the free energy of binding upon changing protein, ligand, or both. This suggests that solvent structure is an evolutionary constraint on protein sequence that contributes to ligand affinity and selectivity.


Effects of rat visual, olfactory, or combined stimuli during cohousing on stress-related physiology and behavior in C57BL/6NCrl mice.
The Guide for the Care and Use of Laboratory Animals recommends housing rats and mice separately to reduce the potential for environmental stress to mice. The literature presents equivocal support for this practice, and housing practices vary widely. According to the existing literature, it is unclear whether visual, olfactory, or combined stimuli are responsible for stress-related changes in mouse physiology and behavior. To determine the extent to which exposure to visual, olfactory, or combined stimuli produce stress-related changes, measures of physiologic and behavioral stress were evaluated in mice after cohousing them in a room with rats. Adult, male C57BL/6NCrl mice (n = 8 per group) were randomly assigned to control, isolator cage, visual stimuli, olfactory stimuli, or visual+olfactory stimuli groups. After 15 d of exposure, body, and adrenal weights did not differ between groups. None of the groups of mice experienced significant increases in corticosterone or stress-related behavior in the open-field test after exposure to rat stimuli. These results suggest that the stress-related effects of cohousing with rats are negligible in mice and have implications for housing rats and mice in shared rooms, thereby al- lowing efficient use of research resources.


Topical treatment of herpes labialis with chloroform.
The efficacy of topical chloroform treatment of herpes labialis (HL) was evaluated in 50 patients with culture-verified HL. Treatment was begun within 48 hours of lesion onset, with either chloroform or camphor-in-oil placebo applied locally once a day for three days. Patients were observed daily by one investigator who also cultured and photographed the lesions. The photographs were evaluated by two other investigators. By direct observation, the time for scab formation was significantly less in the group treated with chloroform (P less than .01). No difference in time to healing was noted. Blind evaluation of the serial photographs showed a trend for more rapid scab formation and healing in patients treated with chloroform, but the differences were not significant. The minimal benefit derived from topical chloroform therapy of HL does not appear sufficient to recommend its routine use.


A Comparison of Control Strategies in Commercial and Research Knee Prostheses.
To provide an overview of control strategies in commercial and research microprocessor-controlled prosthetic knees (MPKs). Five commercially available MPKs described in patents, and five research MPKs reported in scientific literature were compared. Their working principles, intent recognition, and walking controller were analyzed. Speed and slope adaptability of the walking controller was considered as well. Whereas commercial MPKs are mostly passive, i.e., do not inject energy in the system, and employ heuristic rule-based intent classifiers, research MPKs are all powered and often utilize machine learning algorithms for intention detection. Both commercial and research MPKs rely on finite state machine impedance controllers for walking. Yet while commercial MPKs require a prosthetist to adjust impedance settings, scientific research is focused on reducing the tunable parameter space and developing unified controllers, independent of subject anthropometrics, walking speed, and ground slope. The main challenges in the field of powered, active MPKs (A-MPKs) to boost commercial viability are first to demonstrate the benefit of A-MPKs compared to passive MPKs or mechanical non-microprocessor knees using biomechanical, performance-based and patient-reported metrics. Second, to evaluate control strategies and intent recognition in an uncontrolled environment, preferably outside the laboratory setting. And third, even though research MPKs favor sophisticated algorithms, to maintain the possibility of practical and comprehensible tuning of control parameters, considering optimal control cannot be known a priori. This review identifies main challenges in the development of A-MPKs, which have thus far hindered their broad availability on the market.


Elucidating the impact of bacterial lipases, human serum albumin, and FASII inhibition on the utilization of exogenous fatty acids by Staphylococcus aureus.
Incorporation of host-derived exogenous fatty acids (eFAs), particularly unsaturated fatty acids (UFAs), by Staphylococcus aureus could affect the bacterial membrane fluidity and susceptibility to antimicrobials. In this work, we found that glycerol ester hydrolase (Geh) is the primary lipase hydrolyzing cholesteryl esters and, to a lesser extent, triglycerides and that human serum albumin (HSA) could serve as a buffer of eFAs, where low levels of HSA facilitate the utilization of eFAs but high levels of HSA inhibit it. The fact that the type II fatty acid synthesis (FASII) inhibitor, AFN-1252, leads to an increase in UFA content even in the absence of eFA suggests that membrane property modulation is part of its mechanism of action. Thus, Geh and/or the FASII system look to be promising targets to enhance S. aureus killing in a host environment by restricting eFA utilization or modulating membrane properties, respectively.


Signature changes in the expressions of protein-coding genes, lncRNAs, and repeat elements in early and late cellular senescence.
Replicative cellular senescence is the main cause of aging. It is important to note that early senescence is linked to tissue regeneration, whereas late senescence is known to trigger a chronically inflammatory phenotype. Despite the presence of various genome-wide studies, there is a lack of information on distinguishing early and late senescent phenotypes at the transcriptome level. Particularly, the changes in the noncoding RNA portion of the aging cell have not been fully elucidated. By utilising RNA sequencing data of fibroblasts, hereby, we are not only reporting changes in gene expression profiles and relevant biological processes in the early and late senescent phenotypes but also presenting significant differences in the expressions of many unravelled long noncoding RNAs (lncRNAs) and transcripts arisen from repetitive DNA. Our results indicate that, in addition to previously reported L1 elements, various LTR and DNA transposons, as well as members of the classical satellites including HSAT5 and α-satellites (ALR/Alpha), are expressed at higher levels in late senescence. Moreover, we revealed finer links between the expression levels of repeats with the genes located near them and known to be involved in cell cycle and senescence. Noncoding elements reported here provide a new perspective to be explored in further experimental studies.


Ontogeny of in vitro-differentiated mouse mast cells.
Rat and mouse heparin-containing connective tissue mast cells (CTMC) are stained by both alcian blue and safranin, whereas the chondroitin sulfate-containing mucosal mast cells (MMC) are stained by alcian blue but not by safranin. Mouse bone marrow-derived mast cells (BMMC) (the presumptive in vitro counterpart of the in vivo-differentiated MMC) were derived by culture of progenitors in the presence of 50% WEHI-3-conditioned medium and 10% fetal calf serum and were then cultured for up to 14 days with confluent skin-derived mouse 3T3 fibroblasts in the same culture medium. Although the BMMC adhered to the fibroblast monolayer, they continued to divide, probably because of the presence of interleukin 3 in the conditioned medium. After 14 days of coculture, their cellular histamine content increased approximately 15-fold, and greater than 50% of the BMMC changed histochemically from safranin negative to safranin positive. At this time 30-50% of the glycosaminoglycans of the proteoglycans synthesized by these cocultured mast cells were heparin, whereas the initial BMMC synthesized proteoglycans containing chondroitin sulfate E. When activated immunologically, the cocultured mast cells generated approximately fivefold more prostaglandin D2 than did the activated starting BMMC. Thus, interleukin 3-dependent mouse BMMC can be induced to undergo phenotypic changes in staining characteristics, histamine content, glycosaminoglycan structure, and metabolism of arachidonic acid to resemble heparin-containing CTMC. These findings suggest that the tissue microenvironment determines the phenotypic characteristics of mast cells. This demonstration of the functional diversity of different populations of mast cells adds an important dimension to the understanding of the role of mast cells in biological processes.


Second-line treatment efficacy and toxicity in older vs. non-older patients with advanced gastric cancer: A multicentre real-world study.
Although gastric cancer (GC) incidence rises with age, older patients are poorly represented in clinical trials, whose results are therefore difficult to translate into standard management of older patients. Purpose of this study was to compare clinico-pathological features and survival outcomes between older and non-older patients with advanced GC treated with at least two chemotherapy lines. Clinico-pathological characteristics, basal values, and treatment data of older (≥70 years at second-line start) and non-older patients were compared using chi-square test or 2-tailed Fisher exact test. The Kaplan-Meier estimation was used to calculate progression-free survival (PFS) and overall survival (OS), which were examined by log-rank test. Older patients represented 31.8% of the population (N = 868). Intestinal type was more frequent in older patients (P = .02). Poorly differentiated tumours were more often observed in non-older patients (P = .009). At stage IV diagnosis, the rate of liver metastases was higher in older patients (P = .02), while peritoneal spread was more represented in non-older patients (P = .002). Although older patients were more often treated with monotherapy (P = .001), they had similar PFS (HR 0.86, 95%CI 0.71-1.03, P = .102) and OS (HR 0.82, 95%CI 0.65-1.02, P = .08) compared to the non-older counterpart. No statistical differences were observed in treatment-related adverse events, hospital admissions, or further treatment lines between age groups. In our large cohort study, despite some differences in tumour characteristics and treatment intensity, no survival difference was found between older and non-older patients with advanced GC treated with at least two chemotherapy lines. Incidence of adverse events was similar between age groups.


The management of eyelid neoplasms.
The results of 377 patients treated for eyelid neoplasms are reported. A definitive histological diagnosis is essential before commencing treatment. Basal cell carcinomata were the commonest lesions encountered in this series. The various indications for radiotherapy, surgery and cryotherapy are discussed and their respective advantages and disadvantages considered. The aim of treatment is a cure of the primary condition and a satisfactory cosmetic result with the minimum of complications. In this Unit surgery is reserved for a simple excision biopsy or diathermy excision and Wolfe graft as radiotherapy appears to offer the best form of treatment in most cases.


A transfected L-myc gene can substitute for c-myc in blocking murine erythroleukemia differentiation.
We investigated the ability of the proto-oncogene L-myc to substitute for c-myc in blocking murine erythroleukemia differentiation. Murine erythroleukemia cells (line C19) were transfected with recombinant plasmids containing genomic and cDNA fragments of the L-myc gene driven by a Moloney murine leukemia virus long terminal repeat. Clones expressing constitutive high levels of L-myc failed to differentiate in response to the chemical inducer N,N'-hexamethylene bisacetamide (HMBA). The block to differentiation correlated with the level of L-myc expression. Furthermore, transfected clones grown in the presence of inducer for an extended period of time showed an increased level of L-myc expression. These results suggest that functional domains of the c-myc gene involved in differentiation are located in the discrete regions of homology between the c- and L-myc genes.


Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models.
N-Methyl-d-aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000nmol) and Ro25-6981 (20, 50, 100, 200nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25-6981 increased the mechanical nociceptive threshold in a dose-dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1-2 and L4-5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain.


Chronic norepinephrine infusion and insulin and glucagon secretion in the dog.
The effect of epinephrine on glucose homeostasis has been studied extensively in many species, but there is little data on the effects of another catecholamine, norepinephrine. This study was designed to examine the alterations that occur in insulin and glucagon secretion during a chronic low-dose infusion of norepinephrine in free-roaming dogs. A total of four intravenous glucose tolerance tests and insulin-induced hypoglycemia tests were performed on each of five dogs infused with norepinephrine (1.4 g/min) for 3 mo and on each of eight control dogs. The infusion resulted in a threefold increase in plasma norepinephrine without a significant effect on blood pressure. Fasting serum glucose was elevated significantly in the norepinephrine-infused dogs [102.4 +/- 2.1 vs. 92.8 +/- 1.7 (SE) mg/100 ml]. Fasting plasma glucagon was elevated by the norepinephrine infusion (58.4 +/- 7.6 vs. 31.3 +/- 3.1 pg/ml), whereas fasting serum insulin was inhibited (12.3 +/- 1.3 vs 16.8 +/- 1.7 U/ml). Glucagon secretion in response to hypoglycemia was markedly enhanced in the infused dogs compared with controls. It has been reported that the infusion of norepinephrine in humans will inhibit insulin secretion and increase serum glucose concentrations but have no effect on serum glucagon concentrations. The stimulation of glucagon by norepinephrine has been demonstrated in the isolated, perfused canine pancreas but has not been reported previously in the free-roaming dog.


Parietal tumor recurrence of lung metastasis after radiofrequency ablation.
Metastasis is the most common form of malignant lung tumor. Radiofrequency ablation (RFA) is a new treatment for single pulmonary tumors. However, RFA can be complicated by iatrogenic and parietal recurrence. We report the case of a 67-year-old man with a single pulmonary metastasis from colorectal cancer diagnosed two years previously and locally controlled by left hemi-colectomy. The metastasis was treated by RFA. Four months after the procedure, a positron emission tomography scan revealed parietal chest contamination. Surgical resection enabled the diagnosis of parietal tumor expansion and confirmed successful treatment of the initial metastasis. This case highlights the risk of iatrogenic parietal contamination after RFA. To our knowledge no similar case has been published to date. The most appropriate steps to prevent this type of complication still have to be defined.


Genetic variation of cholesterol ester content in mouse adrenals.
Total cholesterol concentrations in muscle, liver, and plasma do not differ significantly between adult male C57BL/10J and DBA/2J mice. In the adrenal glands of these two strains, of their hybrids, and of AC mice, concentrations of free cholesterol vary by 5 percent. Adrenals from C57 mice, however, contain six times as much esterified cholesterol as adrenals from AC or DBA mice. The intermediate concentrations of cholesterol esters in F(1) hybrids suggest that the difference in this measure is inherited additively. The finding of variation in adrenal cholesterol within a species is useful for the further study of the role of cholesterol in steroidogenesis by means of genetic analysis.


[Value of electromyography in diagnosis of incontinence].
Electromyography (EMG) of the pelvic floor musculature is only carried out as a routine method in few clinics. There is a lack of standard patient groups and, correspondingly, standardized values do not exist. Close cooperation between proctologists and neurologists is the exception. Some surgeons use the EMG to evaluate muscular defects (mapping), however sonography is a less invasive method to detect these lesions. It is the real domain of the EMG to provide qualitative and quantitative evidence of neurogenic lesions, which means that it allows to differentiate between central and peripheral as well as between acute and chronic lesions. It also enables the experienced neurophysiologist to estimate the prognosis and to give an expert opinion. Optimum utilization of the method is only possible with interdisciplinary cooperation.


Philadelphia chromosome-positive blastic leukaemia: ultrastructural and ultracytochemical evidence of basophil and mast cell differentiation.
Ultrastructural, ultracytochemical, immunologic and biochemical studies were performed on leukaemic cells from 41 patients with Philadelphia chromosome-positive blastic leukaemia; 28 patients were in blast transformation of chronic myelogenous leukaemia and 13 patients presented with 'acute' leukaemia. The patients were divided into two morphologic groups, lymphoid (16 cases) and myeloid (25 cases), on the basis of light microscopy and cytochemistry. All lymphoid cases studied for the presence of CALLA (10 patients) and TdT (11 patients) were positive. Two of 13 myeloid cases studied were TdT positive. The blasts from 10 of 16 lymphoid cases contained immature basophil/mast cell granules on ultrastructural examination. Peroxidase-positive 'lymphoid' blasts were noted in three of seven patients studied by ultracytochemical techniques. The reactivity was primarily confined to granular structures. Of the 25 cases in the myeloid group, blasts from 14 cases showed basophil/mast cell differentiation, nine cases showed neutrophil/monocyte features, and two cases were megakaryoblastic. Distinct patterns of ultrastructural peroxidase positivity were seen in the seven myeloid cases studied. In basophil/mast cell precursors the reactivity was primarily confined to granules; neutrophil precursors showed reactivity in the nuclear envelope, rough endoplasmic reticulum (RER), golgi and granules; in megakaryoblasts, only the nuclear envelope and RER were positive while the granules were consistently negative.


How to identify epistemic injustice in global health research funding practices: a decolonial guide.
Epistemic injustice is a growing area of study for researchers and practitioners working in the field of global health. Theoretical development and empirical research on epistemic injustice are crucial for providing more nuanced understandings of the mechanisms and structures leading to the exclusion of local and marginalised groups in research and other knowledge practices. Explicit analysis of the potential role of epistemic injustice in policies and practices is currently limited with the absence of methodological starting points. This paper aims to fill this gap in the literature by providing a guide for individuals involved in the design and review of funding schemes wishing to conduct epistemic injustice analysis of their processes using a decolonial lens. Placing contemporary concerns in a wider historical, political and social context and building from the intertwined issues of coloniality of power, coloniality of knowledge and coloniality of being that systematically exclude non-Western epistemic groups, this practice paper presents a three-step decolonial approach for understanding the role and impact of epistemic injustices in global health research funding. It starts with an understanding of how power operates in setting the aim of a call for research proposals. Then, the influence of pose and gaze in the review process is analysed to highlight the presence of epistemological colonisation before discussing methods to address the current funding asymmetries by supporting new ways of being and doing focused on knowledge plurality. Expanding research on how epistemic wrongs manifest in global health funding practices will generate key insights needed to address underlying drivers of inequities within global health project conception and delivery.


Use of a vital capacity maneuver to prevent atelectasis after cardiopulmonary bypass: an experimental study.
Respiratory failure secondary to cardiopulmonary bypass (CPB) remains a major complication after cardiac surgery. The authors previously found that the increase in intrapulmonary shunt was well correlated with the amount of atelectasis. They tested the hypothesis that post-CPB atelectasis can be prevented by a vital capacity maneuver (VCM) performed before termination of the bypass. Eighteen pigs received standard hypothermic CPB (no ventilation during bypass). The VCM was performed in two groups and consisted of inflating the lungs during 15 s to 40 cmH2O at the end of the bypass. In one group, the inspired oxygen fraction (FIO2) was then increased to 1.0. In the second group, the FIO2 was left at 0.4. In the third group, no VCM was performed (control group). Ventilation-perfusion distribution was measured with the inert gas technique and atelectasis by computed tomographic scanning. Intrapulmonary shunt increased after bypass in the control group (from 4.9 +/- 4% to 20.8 +/- 11.7%; P < 0.05) and was also increased in the vital capacity group ventilated with 100% oxygen (from 2.2 +/- 1.3% to 6.9 +/- 2.9%; P < 0.01) but was unaffected in the vital capacity group ventilated with 40% oxygen. The control pigs showed extensive atelectasis (21.3 +/- 15.8% of total lung area), which was significantly larger (P < 0.01) than the proportion of atelectasis found in the two vital capacity groups (5.7 +/- 5.7% for the vital capacity group ventilated with 100% oxygen and 2.3 +/- 2.1% for the vital capacity group ventilated with 40% oxygen. In this pig model, postcardiopulmonary bypass atelectasis was effectively prevented by a VCM.


Multimodality Monitoring: Toward Improved Outcomes.
Multimodality monitoring provides insights into the critically ill brain-injured patient through the assessment of biochemical, physiological, and electrical data that provides insight into a patient's condition and what strategies may be available to limit further damage and improve the odds for recovery. Modalities utilized include evaluation of intracranial pressure along with cerebral perfusion pressure to determine adequate blood flow; continuous electroencephalography to protect the patient from seizures and to identify early functional manifestations of ischemia and toxicity; transcranial Doppler evaluation for bedside review of circulatory adequacy; tissue oxygen monitoring to establish that brain tissue is receiving adequate oxygen from blood flow; and microdialysis to evaluate the metabolic function of the tissue in areas of concern. These monitors provide insights regarding specific aspects of brain tissue and overall brain function in the critically ill patient. Although recommendations continue to evolve for therapeutic targets for each of these modalities, an effective clinician may use each of these modalities to evaluate patients on an individual basis to improve the outcome of each patient, tailoring management to provide the care needed for any unique clinical presentation.


The synergy of 6-O-sulfation and N- or 3-O-sulfation of chitosan is required for efficient inhibition of P-selectin-mediated human melanoma A375 cell adhesion.
We prepared chitosan sulfated derivatives to address the common structural requirement of the sulfate pattern to block P-selectin-mediated tumor cell adhesion. Our results indicate that 6-O-sulfation of chitosan is indispensable for inhibition of P-selectin binding to human melanoma A375 cells. Furthermore, additional N-sulfation or 3-O-sulfation dramatically enhanced the inhibitory activity of 6-O-sulfated chitosan, suggesting that efficient anti-P-selectin adhesion activity of sulfated saccharides requires the synergy of 6-O-sulation and N- or 3-O-sulfation in glucosamine units.


Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.
We examined the effect of intravenously infused glucagon-like peptide 1 (GLP-1) on subjective appetite sensations after an energy-fixed breakfast, and on spontaneous energy intake at an ad libitum lunch. 20 young, healthy, normal-weight men participated in a placebo-controlled, randomized, blinded, crossover study. Infusion (GLP-1, 50 pmol/ kg.h or saline) was started simultaneously with initiation of the test meals. Visual analogue scales were used to assess appetite sensations throughout the experiment and the palatability of the test meals. Blood was sampled throughout the day for analysis of plasma hormone and substrate levels. After the energy-fixed breakfast, GLP-1 infusion enhanced satiety and fullness compared with placebo (treatment effect: P < 0.03). Furthermore, spontaneous energy intake at the ad libitum lunch was reduced by 12% by GLP-1 infusion compared with saline (P = 0.002). Plasma GLP-1, insulin, glucagon, and blood glucose profiles were affected significantly by the treatment (P < 0.002). In conclusion, the results show that GLP-1 enhanced satiety and reduced energy intake and thus may play a physiological regulatory role in controlling appetite and energy intake in humans.


Practical issues in the management of the long QT syndrome: focus on diagnosis and therapy.
The long QT syndrome (LQTS) is a leading cause of sudden death in the young. It is not as rare as previously assumed, given its established prevalence of 1:2,000 live births. It is characterised by prolongation of the QT interval and by the occurrence of syncope, due to torsades-des-pointes ventricular tachycardia, cardiac arrest and sudden death; these life-threatening cardiac events are usually, but not always, associated with physical or emotional stress. It is a genetic disorder, and knowledge of the genotype impacts significantly on management. Extremely effective therapies are available, which makes the existence of undiagnosed affected and symptomatic patients inexcusable. Indeed, mortality for properly treated patients has now declined to around 1% over a 10-year period. This review, aimed at the clinical cardiologist, discusses briefly the essential genetic information and focuses primarily on the main issues of diagnosis and therapy. One special point of interest is in the impact of genetics on clinical management and the potential medicolegal consequences of not pursuing genetic screening in the proband and hence in the family members.


Paradigm Shifts in Voluntary Force Control and Motor Unit Behaviors with the Manipulated Size of Visual Error Perception.
The detection of error information is an essential prerequisite of a feedback-based movement. This study investigated the differential behavior and neurophysiological mechanisms of a cyclic force-tracking task using error-reducing and error-enhancing feedback. The discharge patterns of a relatively large number of motor units (MUs) were assessed with custom-designed multi-channel surface electromyography following mathematical decomposition of the experimentally-measured signals. Force characteristics, force-discharge relation, and phase-locking cortical activities in the contralateral motor cortex to individual MUs were contrasted among the low (LSF), normal (NSF), and high scaling factor (HSF) conditions, in which the sizes of online execution errors were displayed with various amplification ratios. Along with a spectral shift of the force output toward a lower band, force output with a more phase-lead became less irregular, and tracking accuracy was worse in the LSF condition than in the HSF condition. The coherent discharge of high phasic (HP) MUs with the target signal was greater, and inter-spike intervals were larger, in the LSF condition than in the HSF condition. Force-tracking in the LSF condition manifested with stronger phase-locked EEG activity in the contralateral motor cortex to discharge of the (HP) MUs (LSF > NSF, HSF). The coherent discharge of the (HP) MUs during the cyclic force-tracking predominated the force-discharge relation, which increased inversely to the error scaling factor. In conclusion, the size of visualized error gates motor unit discharge, force-discharge relation, and the relative influences of the feedback and feedforward processes on force control. A smaller visualized error size favors voluntary force control using a feedforward process, in relation to a selective central modulation that enhance the coherent discharge of (HP) MUs.


The outer membrane localization of the Neisseria gonorrhoeae MsrA/B is involved in survival against reactive oxygen species.
The PilB protein of Neisseria gonorrhoeae has been reported to be involved in the regulation of pilin gene transcription, but it also possesses significant homology to the peptide methionine sulfoxide reductase family of enzymes, specifically MsrA and MsrB from Escherichia coli. MsrA and MsrB in E. coli are able to reduce methionine sulfoxide residues in proteins to methionines. In addition, the gonococcal PilB protein encodes for both MsrA and MsrB activity associated with the repair of oxidative damage to proteins. In this work, we demonstrate that the PilB protein of Neisseria gonorrhoeae is not involved in pilus expression. Additionally, we show that wild-type N. gonorrhoeae produces two forms of this polypeptide, one of which contains a signal sequence and is secreted from the bacterial cytoplasm to the outer membrane; the other lacks a signal sequence and is cytoplasmic. Furthermore, we show that the secreted form of the PilB protein is involved in survival in the presence of oxidative damage.


Dynamics of aggregation and emergence of cooperation.
Aggregation is one of the most basic social phenomena, and many activities of social insects are linked to it. For instance, the selection of a valuable site and the spatial organization of the population are very often by-products of amplifications based on the local density of nestmates. The patterns of aggregation are very diverse, ranging from the gathering of all animals in a unique site to their splitting between several ones. One might question how these multiple patterns emerge. Do ants actively initiate the formation of such patterns by modulating the emission of an attracting signal such as the trail pheromone? Alternatively, do patterns result from quantitative changes in the duration of interaction between animals once they have reached the gathering site, without any active modulation of the communications? To discuss these questions, we present two empirical studies: the gregarious behavior of cockroaches (Blatella) and self-assembly in the weaver ant (Oecophylla). Through experimental and theoretical studies, we show how a single behavior-the resting time-leads to a collective choice in both species. This behavior is a response to the density of conspecifics and can also be modulated by heterogeneities in the environment. In weaver ants, it allows the colony to focus the formation of chains in a given area among several potential sites. In cockroaches, it allows the gathering of individuals in particular shelters, depending on the proximity between strains. These results are discussed with emphasis on the role of aggregation processes in the emergence of cooperativity and task allocation.


[Pedicled thoraco-abdominal skin flap applied in early repair of deep ulcer of upper extremity resulting from snake-bite injury].
The ulcer resulting from snake-bite injury was characterized by deep and wide tissue necrosis and secondary infection. The patient was at high risk of loss of function of his extremity. From 1989 to 1996, 16 cases with deep ulcer of the upper extremity resulting from snake-bite injury were treated with different types of axial thoraco-abdominal skin flaps, depending on the location of the ulcer. Thoraco-umbilical skin flap was used in 2 cases, lateral thoracoabdominal skin flap in 1 case, iliolumbar skin flaps in 5 cases, lower abdominal skin flaps in 6 cases, lower abdominal divided foliated skin flap in 1 case and Y-shaped hypogastric skin flap in 1 case. Reparative operation was carried out within 3 weeks after injury and primary repair were undertaken in 6 of them. The pedicles were divided in 17 to 24 days after operation. Twelve flaps survived. Three of the 6 flaps had mild signs of inflammation which disappeared after administration of antibiotics. One had necrosis of the distal part of the flap, and was healed with split skin graft. This type of skin flap was an ideal method for the treatment of snake-bite injury of the upper extremity.


Sound attenuation in two-dimensional glasses at finite temperatures.
The thermal conductivity of glasses exhibits an unusual temperature dependence compared to their crystalline counterparts. Sound attenuation due to disorder in glasses was proposed to be important in rationalizing this special behavior. Simulation studies suggest that in the harmonic approximation, the sound attenuation follows Rayleigh scattering scaling at small wave vector in both two-dimensional (2D) and 3D glasses. The influence of the anharmonicity on sound attenuation has very recently been investigated numerically, but only in 3D glasses. Hence, it remains unknown in simulations how sound attenuation changes with the wave vector in 2D glasses when the anharmonicity comes into play. Here, we address this issue by performing computer simulations in low-temperature 2D glasses over a large range of glass stabilities. We find that the way the anharmonicity affects sound attenuation in 2D glasses is the same as that in 3D, thus revealing that numerically the influence of the anharmonicity on sound attenuation does not rely on the spatial dimension.


Nitric oxide production induced by herpes simplex virus type 1 does not alter the course of the infection in human monocytic cells.
Undifferentiated U937 cells were not susceptible to herpes simplex virus type 1 (HSV-1) infection, but after differentiation with phorbol 12-myristate 13-acetate an increase in the permissivity to the virus was observed accompanied by the production of significant levels of viral particles. High levels of nitric oxide (NO) were produced in differentiated U937 cells infected with HSV-1. This production was comparable to that observed after addition of the NO donor glycerine trinitrate. The levels of NO drastically decreased when the cells were incubated with L-monomethyl arginine (L-NMA), an inhibitor of NO synthase. Although similar levels of NO were sufficient to decrease susceptibility of U937 cells to other viruses, neither incubation with NO donors nor addition of L-NMA altered the permissiveness to HSV-1 infection. Thus, these results suggest that NO does not interfere with the replication of HSV-1 in U937 cells.


Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews.
Background: The higher risk of pancreatic cancer in Ashkenazi Jews compared with non-Jews is only partially explained by the increased frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews.Methods: We evaluated the impact of 16 established pancreatic cancer susceptibility loci in a case-control sample of American Jews, largely Ashkenazi, including 406 full-Jewish pancreatic cancer patients and 2,332 full-Jewish controls, genotyped as part of the Pancreatic Cancer Cohort and Case-Control Consortium I/II (PanScan I/II), Pancreatic Cancer Case-Control Consortium (PanC4), and Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) datasets. We compared risk in full-Jewish subjects with risk in part-Jewish; non-Jewish Southern European; and in the combined non-Jewish Eastern, Northern, Southern, and Western European (non-Jewish white European) subjects from the same datasets. Jewish ancestries were genetically identified using seeded Fast principal component analysis. Data were analyzed by unconditional logistic regression, and adjusted for age, sex, and principal components.Results: One SNP on chromosome 13q22.1 (rs9543325; OR, 1.36; 95% confidence interval, 1.16-1.58; P = 10-4.1) was significant in full-Jews. Individual ORs and minor allele frequencies were similar between Jewish and non-Jewish white European subjects. The average ORs across the 16 pancreatic cancer susceptibility loci for full-Jewish, full- plus part-Jewish, non-Jewish Southern European, and non-Jewish white European subjects were 1.25, 1.30, 1.31, and 1.26, respectively.Conclusions: The 16 pancreatic cancer susceptibility loci similarly impact Jewish and non-Jewish white European subjects, both individually and as summary odds.Impact: These 16 pancreatic cancer susceptibility loci likely do not explain the higher risk seen in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev; 26(10); 1540-8. ©2017 AACR.


Stigma, discrimination, and sexual (dis)satisfaction among people living with HIV: results from the "AIDES et toi" survey.
The effects of HIV-related stigma and discrimination have been studied in several areas, such as access to testing, quality of care quality, and access to work. Nevertheless, the effects of stigma and discrimination on the sexual life of people living with HIV/AIDS (PLWHA) have not been studied enough. AIDES, a French community-based organization, has developed a biannual survey which assesses several socioeconomical and psychosocial dimensions of the people in contact with this organization. A focus on the results concerning sexual (dis)satisfaction and the factors associated are presented here. A convenience sample of 521 HIV-positive men having sex with men, heterosexual men and women was analyzed. A logistic regression was performed to examine which factors were significantly associated with sexual dissatisfaction. Results showed that being older, not having a full-time job, not having a steady sexual partner, lower frequency of sexual intercourse, discrimination in the sexual relationship setting, and the perception of loneliness were independently associated with sexual dissatisfaction. A quality health approach must include the aspects linked to sexual life and sexual satisfaction. Given the potentially harmful effects that HIV-related stigma and discrimination have on PLWHA's well-being, more specific actions and advocacy in this direction should be developed and implemented.


[The wandering gastrostomy tube].
A case is described in which a patient with a gastrostomy tube (PEG) was admitted to hospital with chronic and severe diarrhoea and signs of cachexia. The gastrostomy tube had been inserted by percutaneous endoscopic procedure two months before, and the patient had been suffering from diarrhoea ever since. X-ray investigation by contrast documented that the PEG ended inside the colon, at the left colic flexure. The case emphasizes the need to control the position of a PEG, should unexpected gastrointestinal symptoms occur.


Direct effects of elevated dissolved CO2 can alter the life history of freshwater zooplankton.
Dissolved CO2 levels (pCO2) are increasing in lentic freshwaters across the globe. Recent studies have shown that this will impact the nutritional quality of phytoplankton as primary producers. However, the extent to which freshwater zooplankton may also be directly affected remains unclear. We test this in three model species representative of the main functional groups of primary consumers in freshwaters; the water flea Daphnia magna, the seed shrimp Heterocypris incongruens and the rotifer Brachionus calyciflorus. We experimentally exposed individuals to three pCO2 levels (1,500; 25,500 and 83,000 ppm) to monitor changes in life history in response to current, elevated and extreme future pCO2 conditions in ponds and shallow lakes. All species had reduced survival under the extreme pCO2 treatment, but the water flea was most sensitive. Body size and reproduction were reduced at 25,500 ppm in the water flea and the seed shrimp and population growth was delayed in the rotifer. Overall, our results show that direct effects of pCO2 could impact the population dynamics of freshwater zooplankton. By differentially modulating the life history of functional groups of primary consumers, elevated pCO2 has the potential to change the evolutionary trajectories of populations as well as the ecological functioning of freshwater communities.


Peripheral Blood T-Cell Populations in COPD, Asymptomatic Smokers and Healthy Non-Smokers in Indian subpopulation- A Pilot Study.
COPD is a major global health problem affecting 4-10% of Indian adult male population. Immunological processes have been implicated in the pathogenesis of COPD. As compared to healthy smokers, COPD patients have airway inflammation indicated by the presence of CD8+ T cells in the lung. This predominant increase in CD8+ T cells in the lung may be reflected in the peripheral blood. In an attempt to understand why only some smokers develop COPD, we compared the peripheral T-cell markers in COPD patients with that of asymptomatic smokers, and healthy nonsmokers. Twenty healthy non-smokers (HNS), 19 asymptomatic smokers (AS) and 21 COPD male patients (age and pack year-matched) were identified after clinical evaluation and spirometry. Blood CD3+, CD4+, CD8+ T-cell populations were measured. Smokers with COPD had severe airflow limitation (FVC, 69.8+16.7%; FEV1, 47.47+16.9%; FEV1/FVC, 53.1+13.3%). The BMI was found to be significantly lower among patients with COPD (19.1+4.8kg/m(2)) as compared to AS (23+4.3kg/m(2)) and HNS (23.7+4.0kg/m(2)) (p value = 0.003 HS). The mean CD3+T-cell absolute count in COPD patients (1154.3+582.2), showed a marked decline as compared to that of AS (1251.9+491.6) and HNS (1424.9+352.2). The mean CD4+T-cell counts in COPD patients (652.7+340.5) were also lower when compared to AS (745.7+313.8) and HNS (832.5+220.7). The mean CD8+T-cell counts among COPD patients (424.7+264.3) were, similar to the counts observed among AS (426.9+193.2) and HNS (500.4+191). Though not statistically significant, the absolute counts of CD3+, CD4+ and CD8+ lymphocytes among COPD patients tended to be lower. No significant difference in the CD4+/CD8+ lymphocyte ratio between the patient groups was observed. Our study indicates that BMI is related to the severity of COPD, hence proving a systemic component to its pathogenesis. However, we found similar percentages of CD8+Tcells in all the study groups suggesting that predominant CD8+ T cells in the airways may be due to its de novo origin rather than recruitment from blood. However, larger studies are needed to clarify the effect of disease severity, beedi smoking and ethnicity.


Skin and liver diseases induced in flounder (Platichthys flesus) after long-term exposure to contaminated sediments in large-scale mesocosms.
Disease development in flounder (Platichthys flesus) was studied over a period of 3 years in three large mesocosms (40 m x 40 m x 3 m). Two of the mesocosms contained clean sand and the third, sharing a common water circulation with one of the clean-sand mesocosms, was stocked with contaminated dredged spoil. In this way, one of the clean-sand mesocosms was indirectly polluted via the water phase, and analysis of contaminant concentrations in sediments and flounder tissues showed that it had a status intermediate between the other two. Random samples of the flounder populations from the indirectly polluted and reference mesocosms were examined every 2 months for epidermal diseases (lymphocystis, skin ulcers, fin rot) and then released. In addition, every 6 months, random samples of fish from all three mesocosms were sacrificed for histological and chemical investigation. With regard to the development of epidermal disease, the results showed little difference between the reference mesocosm and the indirectly polluted mesocosm, with the exception that lymphocystis was significantly elevated in the indirectly polluted mesocosm. Although pollution may be a risk factor in the etiology of this disease, such a relationship would probably be obscured under field conditions due to variation arising from other factors. Histopathological analysis of the livers revealed in total four cases of hepatocellular adenoma (1.5% of sampled population) in fish from the polluted mesocosms, the first occurring after 2.5 years of exposure in fish from the indirectly polluted mesocosm. Furthermore, several other liver lesions, including foci of cellular alteration and hydropic vacuolated lesions, developed during the course of the experiment before tumor formation was apparent. Prevalences of these conditions were very much lower in the reference mesocosm than in the two polluted mesocosms. Densities of melanomacrophage centers in the liver showed a similar trend. The findings clearly indicate that long-term exposure to chemically contaminated dredged spoil can induce liver neoplasia and other liver lesions in flounder at contaminant levels comparable to those found in the natural environment.


Tuberculin reactivity in bacille Calmette-Guérin vaccinated populations: a compilation of international data.
The effect of previously administered bacille Calmette-Guérin (BCG) vaccine on subsequent tuberculin skin tests (TSTs) complicates screening for latent tuberculosis infection (LTBI) in foreign-born persons. To determine the usefulness of the TST as a screening test for LTBI in foreign-born persons. A literature search was performed of published studies that compared tuberculin reactivity amongst BCG-vaccinated and non-vaccinated groups. The percentages of positive reactors in the two groups were then used to calculate a prevalence ratio. The prevalence ratio varied with the age of the groups tested and the incidence of TB in their countries of origin. The TST performed poorly in vaccinated persons of all ages from countries of low TB incidence, but was a useful screen for LTBI in vaccinated adults from countries of high and intermediate incidence. The test performed poorly as a screening method for vaccinated children under 2 years of age. Its usefulness in vaccinated children aged 2-14 years varied considerably. The usefulness of the TST as a screening method for LTBI depends on the age of the patient and the incidence of TB in their country of origin.


Origin of storm footprints on the sea seen by synthetic aperture radar.
Spaceborne synthetic aperture radar can detect storm footprints on the sea. Coastal weather radar from Cape Hatteras provides evidence that the echo-free hole at the footprint core is the result of wave damping by rain. The increased radar cross section of the sea surrounding the echo-free hole results from the divergence of the precipitation-forced downdraft impacting the sea. The footprint boundary is the gust front; its oriention is aligned with the direction of the winds aloft, which are transported down with the downdraft, and its length implies downdraft impact 1 hour earlier at a quasi-stationary impact spot. The steady, localized nature of the storm remains a mystery.


Recent advances in managing overactive bladder.
Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. In this review, we focus on recent advances in the management of OAB. We examine the evidence on the effect of anticholinergic load on OAB patients. Advances in medical treatment include a new beta-3 agonist, vibegron, which is thought to have fewer drug interactions than mirabegron. Treatment of genitourinary syndrome of the menopause with oestrogens and ospemifene have also shown promise for OAB. Botulinum toxin has been shown to be an effective treatment option. We discuss the new implantable neuromodulators that are on the market as well as selective bladder denervation and laser technology.


PET/CT and renal pathology: a blind spot for radiologists? Part 1, primary pathology.
PET/CT with (18)F-FDG shows metabolically active disease and is widely used for the diagnosis and follow-up of patients with cancer. Nonmetabolically active renal pathology may be missed without close attention to the CT portion of the study, whereas metabolically active pathology may be missed on PET because of physiologic tracer excretion in the kidneys. This article illustrates primary lesions of the kidney on FDG PET/CT with emphasis on key anatomic features and the appearance of tracer uptake. Close attention to both the FDG PET and CT portions of the study is essential to interpret renal pathology correctly on FDG PET/CT examinations.


Diet, genetic susceptibility and human cancer etiology.
There is evidence that high penetrance hereditary genes cause a number of relatively uncommon tumors in the familial setting, whereas common cancers are influenced by multiple loci that alter susceptibility to cancer and other conditions. The latter category of genes are involved in the metabolism of carcinogens (activation, detoxification) as well as those that interact with dietary exposure. This paper will consider some of the basic principles in studying susceptibility genes and provide a few examples in which they interact with dietary components.


Model-based Assessment of the Effect of Contact Precautions Applied to Surveillance-detected Carriers of Carbapenemase-producing Enterobacteriaceae in Long-term Acute Care Hospitals.
An intervention that successfully reduced colonization and infection with carbapenemase-producing Enterobacteriaceae (CPE) in Chicago-area long-term acute-care hospitals included active surveillance and contact precautions. However, the specific effects of contact precautions applied to surveillance-detected carriers on patient-to-patient transmission are unknown, as other, concurrent intervention components or changes in facility patient dynamics also could have affected the observed outcomes. Using previously published data from before and after the CPE intervention, we designed a mathematical model with an explicit representation of postintervention surveillance. We estimated preintervention to postintervention changes of 3 parameters: β, the baseline transmission rate excluding contact precaution effects; δb, the rate of a CPE carrier progressing to bacteremia; and δc, the progression rate to nonbacteremia clinical detection. Assuming that CPE carriers under contact precautions transmit carriage to other patients at half the rate of undetected carriers, the model produced no convincing evidence for a postintervention change in the baseline transmission rate β (+2.1% [95% confidence interval {CI}, -18% to +28%]). The model did find evidence of a postintervention decrease for δb (-41% [95% CI, -60% to -18%]), but not for δc (-7% [95% CI, -28% to +19%]). Our results suggest that contact precautions for surveillance-detected CPE carriers could potentially explain the observed decrease in colonization by itself, even under conservative assumptions for the effectiveness of those precautions for reducing cross-transmission. Other intervention components such as daily chlorhexidine gluconate bathing of all patients and hand-hygiene education and adherence monitoring may have contributed primarily to reducing rates of colonized patients progressing to bacteremia.


Heritable Differences in Catecholamine Signaling Modulate Susceptibility to Trauma and Response to Methylphenidate Treatment: Relevance for PTSD.
Alterations in cortical catecholamine signaling pathways can modulate acute and enduring responses to trauma. Heritable variation in catecholamine signaling is produced by a common functional polymorphism in the catechol-O-methyltransferase (COMT), with Val carriers exhibiting greater degradation of catecholamines than Met carriers. Furthermore, it has recently been suggested that drugs enhancing cortical catecholamine signaling may be a new therapeutic approach for posttraumatic stress disorder (PTSD) patients. We hypothesized that heritable differences in catecholamine signaling regulate the behavioral response to trauma, and that methylphenidate (MPD), a drug that preferentially blocks catecholamine reuptake in the prefrontal cortex (PFC), exerts COMT-dependent effects on trauma-induced behaviors. We first examined the contribution of the functional mutation COMTval158met to modulate enduring behavioral responses to predator stress in a unique "humanized" COMTval158met mouse line. Animals were exposed to a predator (cat) for 10 min and enduring avoidance behaviors were examined in the open field, light-dark box, and "trauma-reminder" tests 1-2 weeks later. Second, we examined the efficacy of chronic methylphenidate to reverse predator stress effects and if these effects were modulated by COMTval158met genotype. Mice were exposed to predator stress and began treatment with either saline or methylphenidate (3 mg/kg/day) 1 week after stress until the end of the testing [avoidance behaviors, working memory, and social preference (SP)]. In males, predator stress and COMTval158met had an additive effect on enduring anxiety-like behavior, with Val stressed mice showing the strongest avoidance behavior after stress compared to Met carriers. No effect of COMT genotype was observed in females. Therefore methylphenidate effects were investigated only in males. Chronic methylphenidate treatment reversed the stress-induced avoidance behavior and increased social investigation independently of genotype. Methylphenidate effects on working memory, however, were genotype-dependent, decreasing working memory in non-stressed Met carriers, and improving stress-induced working memory deficit in Val carriers. These results suggest that heritable variance in catecholamine signaling modulates the avoidance response to an acute trauma. This work supports recent human findings that methylphenidate might be a therapeutic alternative for PTSD patients and suggests that methylphenidate effects on anxiety (generalized avoidance, social withdrawal) vs. cognitive (working memory) symptoms may be modulated through COMT-independent and dependent mechanisms, respectively.


Determining patient utility following coronary revascularization.
The observation of the primary endpoints of a clinical trial is only one part of what goes into determining the flow of benefits an individual receives from the treatments under consideration. An optimal comparison of CABG and PTCA requires a consideration of the varying time paths of patient "utility" associated with each procedure because these procedures differ in that CABG will have a higher initial morbidity and mortality while PTCA involves more frequent recurrent angina pectoris resulting in more repeat procedures or crossovers. This paper introduces a survey which can be used to estimate the patient's utility associated with two alternative forms of therapy, CABG and PTCA, for the treatment of multivessel coronary artery disease. Once these estimates of utility are determined, they can be combined with expected years of survival to create Quality Adjusted Life Years (QALYs).


[Characteristics of Fc IgG receptors on the surface of formalinized sheep erythrocytes].
The binding of IgG molecules with sheep red blood cells (SRBC) was evaluated by a decrease in the serological activity of hyperimmune horse serum towards Pasteurella pestis capsular antigen. As in serological tests based on passive hemagglutination, low concentrations of red blood cells are commonly used, there was no danger of obtaining distorted results due to the nonspecific adsorption of IgG on the surface of SRBC. But for the objective evaluation of the results obtained in the determination of antibody affinity by the suspension method the use of an adequate control was necessary. Fab-fragments, in contrast to IgG, could not be extracted by red blood cells from the solution. The average number of Fc IgG receptors on the surface of one formalinized SRBC was about 60,000, and the affinity of these receptors somewhat varied, the average association constant being KO=10(6), (03) L/M.


Platelet-active drugs in the secondary prevention of cardiovascular events: an overview.
Experimental and clinical evidence strongly suggests that platelets play an important role in a variety of acute cardiovascular events, as well as in the vascular disease with which they are frequently associated. Hence, there is considerable interest in the use of platelet-active drugs in the prevention of these events. A sound pharmacologic basis for the use of platelet-active agents will require further advances in our understanding of the pathophysiology of cardiovascular events and the pharmacology of these drugs.


Expression of the Na(+)/Ca(2+) exchanger ameliorates ionomycin-induced cell death.
PC12 cells were stably transfected with cDNA encoding the Na(+)/Ca(2+) exchanger (NCX1.4). A robust Na(+)-dependent Ca(2+) uptake confirmed the functional expression of the protein. When NCX1. 4 expressing cells (NO) and vector transfected control cells (VC) were exposed to 0.5-20 microM ionomycin for 6 h, a dose-dependent increase in LDH release was observed. LDH release was significantly reduced in NO when compared with VC. When either VC and NO were treated with 3 microM ionomycin and 1.1 mM EGTA, the increase in LDH release was nearly abolished. However, when VC and NO were treated with ionomycin and then EGTA was added 2 min later, LDH release remained elevated. These data suggest ionomycin-induced cell death was Ca(2+) dependent and expressing NCX1.4 may have ameliorated cell death by reducing elevated [Ca(2+)](I).


Bromocriptine administration lowers serum prolactin and disrupts parental responsiveness in common marmosets (Callithrix j. jacchus).
The influence of prolactin on parental responsiveness was investigated in eight unpaired, parentally inexperienced common marmosets (Callithrix jacchus; 6 female, 2 male). The marmosets were prescreened with infants (1-10 days of age) and required to exhibit short latency retrieval and infant carrying in at least three consecutive pretests as criterion for inclusion in this study. The marmosets were then administered the dopamine agonist bromocriptine (0.5 mg/0.5ml vehicle subcutaneously) and the vehicle alone (0.5 ml 10% ethanol solution) twice daily for 3 consecutive days in random order. Bromocriptine treatment reduced circulating prolactin to nondetectable levels. Bromocriptine treatment eliminated infant retrieval in four of the eight marmosets and was associated with significantly increased retrieval latencies and significantly reduced carrying durations in the four monkeys that continued to retrieve following bromocriptine treatment. When given the vehicle alone, the marmosets retrieved infants significantly faster than during pretests, suggesting a handling effect of the injection series. Bromocriptine treatments were associated with significantly increased movement during the tests. The results of this study indicate that prolactin and/or its regulatory neurotransmitters are involved in the control of the spontaneous display of parental responsiveness in common marmosets.


Government plan for nurses to tackle obesity.
Nurses should be prepared to have difficult conversations with parents about diet in a bid to tackle child obesity, the government has said.


Establishment of a human TLR4 compound heterozygous knockout hESC line (WAe009-A-N) to model toll-like receptor 4 deficiency by CRISPR/Cas9 system.
Toll-like receptor 4 (TLR4) is a pattern recognition receptor (PRRS) and an important protective immune receptor. TLR4 deficiency can lead to Inflammatory bowel disease. To explore the role of TLR4, we used CRISPR/Cas9 system to produce TLR4 compound heterozygous knockout embryonic stem cells in H9 cell line. The WAe009-A-N has a compound heterozygous 7 bp deletion/8 bp deletion in TLR4 exon 3, which resulted in a frameshift in the translation of TLR4, and TLR4 protein wasn't detectable in this cell line. In addition, the WAe009-A-N with normal karyotype can express pluripotent markers and differentiate into three germ layers in vitro.


Dual oxidase/oxygenase reactivity and resonance Raman spectra of {Cu3O2} moiety with perfluoro-t-butoxide ligands.
A Cu(i) fully fluorinated O-donor monodentate alkoxide complex, K[Cu(OC4F9)2], was previously shown to form a trinuclear copper-dioxygen species with a {Cu3(μ3-O)2} core, TOC4F9, upon reactivity with O2 at low temperature. Herein is reported a significantly expanded kinetic and mechanistic study of TOC4F9 formation using stopped-flow spectroscopy. The TOC4F9 complex performs catalytic oxidase conversion of hydroquinone (H2Q) to benzoquinone (Q). TOC4F9 also demonstrated hydroxylation of 2,4-di-tert-butylphenolate (DBP) to catecholate, making TOC4F9 the first trinuclear species to perform tyrosinase (both monooxygenase and oxidase) chemistry. Resonance Raman spectra were also obtained for TOC4F9, to our knowledge, the first such spectra for any T species. The mechanism and substrate reactivity of TOC4F9 are compared to those of its bidentate counterpart, TpinF, formed from K[Cu(pinF)(PR3)]. The monodentate derivative has both faster initial formation and more diverse substrate reactivity.