Acute stretch promotes endothelial cell proliferation in wounded healing mouse skin.
We have developed a novel in vivo model utilizing acute stretch to investigate endothelial cell proliferation as a marker of vascular growth in healing mouse skin. This study is a follow-up to ones revealing immediate stretch improves blood flow, decreases total tissue necrosis, and induces tissue insulin transcription. Dorsal distally based flaps of skin were stretched for 3 min using linear (skin hook) plus hemispherical load cycling (inflated subcutaneous silicone catheter). Unstretched, wounded skin along the back and sternum served as postoperative controls. Laser Doppler flowmetry demonstrated a threefold increase in flap perfusion at postoperative day 7. A stretch-induced sixfold increase in endothelial cell mitogenesis accompanied enhancements in blood flow and extracorporal wound healing over the sternum. Western blots revealed up-regulation/activation of insulin and mitogenic signaling intermediates in stretched skin. Activated insulin and insulin growth factor receptors (pIR/pIGFR), protein kinase B (Akt, pAkt), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (flk-1) were among the identified stretch-responsive intermediates. These results indicate the benefits of acute stretch are mediated through enhanced vascularity as evidenced by endothelial cell mitogenesis and up-regulation/activation of insulin and key angiogenic effectors in dorsal distally based skin flaps.


Acid-suppressive effects of rabeprazole: comparing 10mg and 20mg twice daily in Japanese Helicobacter pylori-negative and -positive CYP2C19 extensive metabolisers.
Rabeprazole 10mg b.i.d. is often administered as therapy for eradication of Helicobacter pylori (H. pylori) and is also proposed as therapy for refractory gastro-oesophageal reflux disease. However, there has not been a comprehensive assessment of its acid-suppressive effects. To compare the acid-suppressive effects of rabeprazole 10mg b.i.d. with 20mg b.i.d. considering H. pylori status. Thirteen H. pylori-negative and eleven H. pylori-positive Japanese CYP2C19 extensive metabolisers (<35 years). Intragastric pH was measured for 24h three times in a randomised manner; on day 7 of the repeated administration of rabeprazole 10mg b.i.d. or 20mg b.i.d., or a placebo. In median intragastric pH value and percent time of pH>3.0, >4.0, >5.0, >6.0, and >7.0 for 24h, no significant differences were observed between the two doses in either H. pylori-negative or H. pylori-positive subjects. At either dose, these parameters were significantly higher in H. pylori-positive subjects than in H. pylori-negative subjects. Nocturnal acid breakthrough occurred in seven and two of the thirteen H. pylori-negative subjects and one and two of the eleven H. pylori-positive subjects at each dose, respectively. The effects of rabeprazole 10mg b.i.d. were equal to those of 20mg b.i.d. in H. pylori-positive subjects; whereas in H. pylori-negative subjects, 20mg b.i.d. was superior for prevention of nocturnal acid breakthrough.


Do rat auditory event related potentials exhibit human mismatch negativity attributes related to predictive coding?
Rodent models play a significant role in understanding disease mechanisms and the screening of new treatments. With regard to psychiatric disorders such as schizophrenia, however, it is difficult to replicate the human symptoms in rodents because these symptoms are often either 'uniquely human' or are only conveyed via self-report. There is a growing interest in rodent mismatch responses (MMRs) as a translatable 'biomarker' for disorders such as schizophrenia. In this review, we will summarize the attributes of human MMN, and discuss the scope of exploring the attributes of human MMN in rodents. Here, we examine how reliably MMRs that are measured in rats mimic human attributes, and present original data examining whether manipulations of stimulus conditions known to modulate human MMN, do the same for rat MMRs. Using surgically-implanted epidural electroencephalographic electrodes and wireless telemetry in freely-moving rats, we observed human-like modulations of MMRs, namely that larger MMRs were elicited to unexpected (deviant) stimuli that a) had a larger change in pitch compared to the expected (standard) stimulus, b) were less frequently presented (lower probability), and c) had no jitter (stable stimulus onset asynchrony) compared to high jitter. Overall, these findings contribute to the mounting evidence for rat MMRs as a good analogue of human MMN, bolstering the development of a novel approach in future to validate the preclinical models based on a translatable biomarker, MMN.


Vaccination against hepatitis A and B in persons subject to homelessness in inner Sydney: vaccine acceptance, completion rates and immunogenicity.
To determine acceptance, completion rates and immunogenicity of the standard vaccination schedule for hepatitis A (HAV) and B (HBV) in persons subject to homelessness. A convenience sample of clients (n=201) attending a medical clinic for homeless and disadvantaged persons in Sydney was enrolled. Serological screening for HAV and HBV was undertaken. An appropriate vaccination program was instituted. Post-vaccination serology determined serological response. Although many clients had serological evidence of past infection, at least 138 (69%) clients had the potential to benefit from vaccination. For hepatitis A and B vaccinations, completion rates were 73% (73 of 100 clients) and 75% (69 of 92 clients), respectively; after vaccination, protective antibody was found in 98.2% (56 of 57) and 72% (36 of 50) of clients, respectively. A successful vaccination program can be mounted with a vulnerable population. We consider a clinic with a well-established history of acceptance and utilisation by the target group; a low staff turnover and regular clientele; inclusion of vaccination as part of routine client care; and counselling (part of pre- and post-serological testing) essential components in achieving good vaccination completion rates.


Optimized design of antisense oligomers for targeted rRNA depletion.
RNA sequencing (RNA-seq) is extensively used to quantify gene expression transcriptome-wide. Although often paired with polyadenylate (poly(A)) selection to enrich for messenger RNA (mRNA), many applications require alternate approaches to counteract the high proportion of ribosomal RNA (rRNA) in total RNA. Recently, digestion using RNaseH and antisense DNA oligomers tiling target rRNAs has emerged as an alternative to commercial rRNA depletion kits. Here, we present a streamlined, more economical RNaseH-mediated rRNA depletion with substantially lower up-front costs, using shorter antisense oligos only sparsely tiled along the target RNA in a 5-min digestion reaction. We introduce a novel Web tool, Oligo-ASST, that simplifies oligo design to target regions with optimal thermodynamic properties, and additionally can generate compact, common oligo pools that simultaneously target divergent RNAs, e.g. across different species. We demonstrate the efficacy of these strategies by generating rRNA-depletion oligos for Xenopus laevis and for zebrafish, which expresses two distinct versions of rRNAs during embryogenesis. The resulting RNA-seq libraries reduce rRNA to <5% of aligned reads, on par with poly(A) selection, and also reveal expression of many non-adenylated RNA species. Oligo-ASST is freely available at https://mtleelab.pitt.edu/oligo to design antisense oligos for any taxon or to target any abundant RNA for depletion.


Emerging Tacts and Selections from Previous Learned Skills: A Comparison between Two Types of Naming.
Naming consists of tacting an object and selecting it upon hearing its name as a result of emergence. After acquiring naming, children learn object-name relations more quickly and, hence, it is an important achievement in development. We studied the acquisition of the two skills that define naming, using two procedures, in seven typically developing 4-year-old children. The tact-selection procedure consisted of (a) teaching tacts of objects (or pictures) and probing for object selection upon hearing the objects' names, and (b) teaching object selection and probing tacts. The pairing procedure consisted of presenting objects (or pictures) at the same time that an adult said their names, without requiring from the child other response than attending. Of the seven children, five showed emergence of selection responses and tacts. Children showed more instances of emergence with the tact-selection procedure than with the pairing procedure and with three-dimensional (3-D) objects than with pictures. The results have important implications for teaching preschool children and children with learning disabilities.


Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis.
Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200-800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis. Clinicaltrials.gov: NCT01792115.


"Tinni" rice (Oryza rufipogon Griff.) production: an integrated sociocultural agroecosystem in eastern Uttar Pradesh of India.
This study reports how Traditional Ecological Knowledge (TEK) and informal cultural institutions have conserved key varieties of the wildgrowing rice, 'tinni' (red rice, or brownbeard rice, Oriza rufipogon Griff.), within the Bhar community of eastern Uttar Pradesh, India. The study was conducted, using conventional and participatory methods, in 10 purposively selected Bhar villages. Two distinct varieties of tinni ('tinni patali' and 'tinni moti') with differing habitats and phenotypic characters were identified. Seven microecosystems (Kari, Badaila, Chammo, Karmol, Bhainsiki, Bhainsala and Khodailia) were found to support these varieties in differing proportions. Tinni rice can withstand more extreme weather conditions (the highest as well as lowest temperatures and rainfall regimes) than the 'genetically improved' varieties of rice (Oriza sativa L.) grown in the region. Both tinni varieties are important bioresources for the Bhar's subsistence livelihoods, and they use distinctive conservation approaches in their maintenance. Bhar women are the main custodians of tinni rice agrobiodiversity, conserving tinni through an institution called Sajha. Democratic decision-making at meetings organized by village elders determines the market price of the tinni varieties. Overall, the indigenous institutions and women's participation seem to have provided safeguards from excessive exploitation of tinni rice varieties. The maintenance of tinni through cultural knowledge and institutions serves as an example of the importance of locally maintained crop varieties in contributing to people's resilience and food security in times of rapid social and environmental change.


An incremental regression method for graph structured data.
In this paper, we consider learning problems defined on graph-structured data. We propose an incremental supervised learning algorithm for network-based estimators using diffusion kernels. Diffusion kernel nodes are iteratively added in the training process. For each new node added, the kernel function center and the output connection weight are decided according to an empirical risk driven rule based on an extended chained version of the Nadaraja-Watson estimator. Then the diffusion parameters are determined by a genetic-like optimization technique.


The diagnostic value of barium swallow in globus syndrome.
Serious lesions presenting as globus syndrome appear to be extremely rare, but many clinicians routinely request barium swallow to exclude these. No data yet exist on the diagnostic yield of contrast radiography. We reviewed 2854 barium swallows from one department over 7 years. The false-positive rate (37%) depended on presenting symptoms and differed between radiology departments, suggesting substantial subjectivity. No serious radiological abnormalities occurred in the estimated 2011 patients with globus syndrome. The 95% confidence interval for the likelihood of finding a significant abnormality on routine barium swallow in a patient with globus symptoms is 0-0.00145. The 2854 barium swallows cost an estimated pounds sterling 685,000 and 0.22-0.48 deaths. As the risk of missing a serious lesion in a patient with globus is very unlikely to exceed one in 700, we support the opinion that barium swallow should be reserved for those with risk factors or atypical features.


Psychological distress as a predictor of CHD events in men: the effect of persistence and components of risk.
This paper examines the role of psychological distress in the etiology of coronary heart disease (CHD), with particular reference to the persistence of distress symptoms, the contribution that undetected CHD at baseline makes to the observed associations and to the effect of separate components of psychological distress. 5449 men in an occupational cohort (79% of the total), with at least two prior measurements of the General Health Questionnaire (GHQ-30), were followed for CHD events (including CHD death, nonfatal myocardial infarction (MI), and angina) for (mean) 6.8 years. Psychological distress was measured using the GHQ-30, and general/anxiety, depression and sleep subscales were created based on a principal components analysis. Psychological distress increased the risk of CHD events, with the risk highest in men with recent onset of distress. Age-adjusted hazard ratios were 1.48 (1.03-2.13) for persistent and 1.77 (1.13-2.78) for new distress. Angina events accounted for much of the observed associations. This increased risk was independent of conventional CHD risk factors, markers of underlying CHD, or measures of reporting bias, and it was related to anxiety items and sleep disturbance rather than depressive symptoms. Psychological distress increases the risk of a future diagnosis of angina in men. This risk is not accounted for by the presence of underlying CHD. These results highlight the importance of identifying both the role of underlying atherosclerosis in the pathway linking distress to heart disease and the timing of action of the components of psychological distress.


Localization of the human dihydropteridine reductase gene to band p15.3 of chromosome 4 by in situ hybridization.
We report the localization of the gene for dihydropteridine reductase (DHPR) to the human chromosome region 4p15.3 by in situ hybridization using a cDNA probe to the enzyme. The distal end of the short arm of chromosome 4 is of considerable interest because the gene responsible for Huntington's disease is located in this region. Although this part of the chromosome is being extensively studied, DHPR is the first well-characterised gene to be assigned to the region. Restriction enzyme fragment length polymorphisms have been detected with a number of restriction endonucleases, including AvaII and MspI. These features may make the DHPR cDNA clone a useful probe not only for prenatal diagnosis of DHPR deficiency but also for linkage studies of Huntington's disease.


A qualitative investigation into nurses' perceptions of factors influencing staff injuries sustained during physical interventions employed in response to service user violence within one secure learning disability service.
The aim of the study was to examine learning disability nurses' perceptions of incidents involving physical intervention, particularly factors contributing to injuries sustained by this group. This article reports on a qualitative study undertaken within one secure NHS Trust to respond to concerns about staff injuries sustained during physical interventions to prevent incidents of service user violence from escalating out of control. The context of the study relates to increasing debate about the most effective approaches to incidents of violence and agression. A qualitative research design was utilized for the study. Semi-structured interviews were undertaken with 20 participants, two from each of the 10 incidents involving staff injury sustained during physical intervention. Four themes were produced by the analysis, the first, knowledge and understanding, contextualized the other three, which related to the physical intervention techniques employed, the interpretation of the incident and the impact on staff. Service user violence consistently poses nurses with the challenge of balancing the need to respond in order to maintain the safety of everyone whilst simultaneous supporting and caring for people with complex needs. This study highlights the need for further exploration of the contributory factors to the escalation of potentially violent situations. Services may have good systems in place for responding to and managing service user violence but appear less effective in understanding the reasons for and developing strategies to prevent violence occurring.


Chelidocystatin, a novel phytocystatin from Chelidonium majus.
Greater celandine (Chelidonium majus L.) has traditional uses in European and Chinese herbal medicine. In the plant sap significant inhibitory activity against papain was observed. A cysteine proteinase inhibitor, named chelidocystatin, was isolated from the plant using papain Sepharose affinity chromatography followed by gel filtration and ion-exchange chromatography. Chelidocystatin showed a M(r) of 10,000 on SDS-PAGE with the pI of 9.3, and was a strong inhibitor of cathepsin L (Ki = 5.6 x 10(-11) M), papain (Ki = 1.1 x 10(-10) M) and cathepsin H (Ki = 7.5 x 10(-9) M). The complete amino acid sequence of the protein was obtained with N-terminal sequencing and sequencing of the peptides after digestion of the protein. Moreover, a major part of the sequence was verified by molecular cloning. The conserved glycine residue at the N-terminal region and the QVVAG motif, which are both believed to be involved in the inhibitory activity, indicate that it is a member of the cystatin superfamily. The amino acid sequence of chelidocystatin shows a high degree of homology with cysteine proteinase inhibitors belonging to the phytocystatin group, especially with the recently described carrot and sunflower phytocystatins with which it shares 57% and 54% homology, respectively.


Effects of chlordecone and its alteration products on isolated rat liver mitochondria.
Partitioning of chlordecone, chlordecone alcohol, monohydrochlordecone, and dihydrochlordecone (2 to 100 microM) into isolated rat liver mitochondria altered the permeability properties of the inner membrane as evidenced by: inhibition of valinomycin-induced swelling, induction of passive swelling, oxidation of exogenous NADH, and induction of lysis. Associated with the increase in permeability were stimulation of state 4 and inhibition of state 3 respiration for the oxidation of both succinate and glutamate. Except for the inhibition of valinomycin-induced swelling, the following order of potency for all assays was obtained: chlordecone alcohol greater than or equal to chlordecone greater than monohydrochlordecone much greater than dihydrochlordecone. Mirex, a 12-chlorine analog of chlordecone, and a dioxolane-chlordecone adduct did not affect any of the reactions at saturating concentrations of 40 and 100 microM, respectively. The hydrated ketone, or a hydroxyl moiety, and a high chlorine content appear to be responsible for lytic and inhibitory activity. Lysis resulted in the leakage of water-soluble matrix enzymes from the mitochondria, but not in the solubilization of integral proteins.


Effect of Coffee Consumption on Risk of Coronary Heart Disease in a Systematic Review and Meta-Analysis of Prospective Cohort Studies.
Previous prospective studies have reported inconsistent findings on the association between coffee consumption and the risk of coronary heart disease (CHD). This study aimed to investigate their association using a meta-analysis of prospective studies. We searched PubMed and EMBASE for prospective cohort studies of the association between coffee consumption and the risk of CHD in the general population. We conducted a random-effects meta-analysis and also subgroup meta-analyses by various factors. Of 870 studies searched from databases, 32 prospective cohort studies were included in the final analysis. In the main meta-analysis of all studies, no significant association between coffee consumption and the risk of CHD was observed (relative risk [RR] 1.05, 95% confidence interval [CI] 0.97 to 1.14, I2 = 64.9%). In the subgroup meta-analyses by gender, coffee consumption significantly increased the risk of CHD in men (RR 1.19, 95% CI 1.05 to 1.35, n = 17), whereas a nonsignificantly decreased risk of CHD was observed in women (RR 0.91, 95% CI 0.77 to 1.08, n = 11). Also, in the subgroup meta-analyses by follow-up period, coffee consumption significantly increased the risk of CHD in the follow-up of 20 years or longer (RR 1.16, 95% CI 1.06 to 1.27, n = 4) regardless of gender. In conclusion, in the current meta-analysis of prospective studies, we found that, overall, no significant association between coffee consumption and the risk of CHD was observed. However, coffee consumption showed a differential effect by gender, with an increased risk of CHD in men and a potentially decreased risk in women.


Phosphorylation of caldesmon at sites between residues 627 and 642 attenuates inhibitory activity and contributes to a reduction in Ca2+-calmodulin affinity.
Caldesmon is an actin- and myosin-binding protein found in smooth muscle that inhibits actin activation of myosin ATPase activity. The activity of caldesmon is controlled by phosphorylation and by binding to Ca(2+)-calmodulin. We investigated the effects of phosphorylation by p(21)-activated kinase 3 (PAK) and calmodulin on the 22 kDa C-terminal fragment of caldesmon (CaD22). We substituted the major PAK sites, Ser-672 and Ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. The aspartic acid mutation of CaD22 weakened Ca(2+)-calmodulin binding but had no effect on inhibition of ATPase activity. Phosphorylation of the aspartic acid mutant with PAK resulted in the slow phosphorylation of Thr-627, Ser-631, Ser-635, and Ser-642. Phosphorylation at these sites weakened Ca(2+)-calmodulin binding further and reduced the inhibitory activity of CaD22 in the absence of Ca(2+)-calmodulin. Phosphorylation of these sites of the alanine mutant of CaD22 had no effect on Ca(2+)-calmodulin binding but did reduce inhibition of ATPase activity. Thus, the region between residues 627 and 642 may contribute to the overall regulation of caldesmon's activity.


Chronological change of renal pathological findings in the proliferative glomerulonephritis with monoclonal IgG deposits considered to have recurred early after kidney transplantation.
Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare disease that recently became recognized. Its pathological findings are characterized by the deposition of a single heavy chain subclass and a single light chain isotype. PGNMID has been proven to recur in renal allografts. Herein, the authors describe the case of a 46-year-old man who presented with nephrotic syndrome and progressive kidney injury following kidney transplantation. One month after transplantation, his clinical condition stabilized; however, the protocol biopsy showed depositions of IgG and complement on the glomeruli by immunofluorescence staining. Electron microscopy (EM) revealed granular electron-dense deposits (EDD) in the mesangium. Thereafter, renal biopsy was repeated because his proteinuria level increased. Proliferative glomerulonephritis, mainly in the mesangium, with IgG and complement deposits and mesangial and subendothelial EDD were observed; however, the pathological diagnosis was difficult. Renal dysfunction then became apparent, and renal biopsy was performed again 4 years and 10 months after kidney transplantation. Glomerular deposits on a single IgG subclass and a single light chain isotype (IgG3 kappa) with membranoproliferative features were observed. Abundant subendothelial EDD were detected on EM. Finally, the patient was diagnosed with PGNMID. Since it seemed that PGNMID had already developed at 1 month after transplantation, we considered recurrent PGNMID case in the allograft. The treatment for PGNMID has not been established yet, and even in this case, the graft function was eventually lost. For improving renal prognosis, early diagnosis and further investigation on the treatment are necessary.


Porcine DC-SIGN: molecular cloning, gene structure, tissue distribution and binding characteristics.
DC-SIGN, a human C-type lectin, is involved in the transmission of many enveloped viruses. Here we report the cloning and characterization of the cDNA and gene encoding porcine DC-SIGN (pDC-SIGN). The full-length pDC-SIGN cDNA encodes a type II transmembrane protein of 240 amino acids. Phylogenetic analysis revealed that pDC-SIGN, together with bovine, canis and equine DC-SIGN, are more closely related to mouse SIGNR7 and SIGNR8 than to human DC-SIGN. pDC-SIGN has the same gene structure as bovine, canis DC-SIGN and mouse SIGNR8 with eight exons. pDC-SIGN mRNA expression was detected in pig spleen, thymus, lymph node, lung, bone marrow and muscles. pDC-SIGN protein was found to express on the surface of monocyte-derived macrophages and dendritic cells, alveolar macrophages, lymph node sinusoidal macrophage-like, dendritic-like and endothelial cells but not of monocytes, peripheral blood lymphocytes or lymph node lymphocytes. A BHK cell line stably expressing pDC-SIGN binds to human ICAM-3 and ICAM-2 immunoadhesins in a calcium-dependent manner, and enhances the transmission of porcine reproductive and respiratory syndrome virus (PRRSV) to target cells in trans. The results will help better understand the biological role(s) of DC-SIGN family in innate immunity during the evolutionary process.


Transcription Factor Dynamics: One Molecule at a Time.
Cells must tightly regulate their gene expression programs and yet rapidly respond to acute biochemical and biophysical cues within their environment. This information is transmitted to the nucleus through various signaling cascades, culminating in the activation or repression of target genes. Transcription factors (TFs) are key mediators of these signals, binding to specific regulatory elements within chromatin. While live-cell imaging has conclusively proven that TF-chromatin interactions are highly dynamic, how such transient interactions can have long-term impacts on developmental trajectories and disease progression is still largely unclear. In this review, we summarize our current understanding of the dynamic nature of TF functions, starting with a historical overview of early live-cell experiments. We highlight key factors that govern TF dynamics and how TF dynamics, in turn, affect downstream transcriptional bursting. Finally, we conclude with open challenges and emerging technologies that will further our understanding of transcriptional regulation.


Persistent Dengue Infection in an Immunosuppressed Patient Reveals the Roles of Humoral and Cellular Immune Responses in Virus Clearance.
Detailed understanding of the roles of humoral and cellular immune responses in sterilizing dengue virus (DENV) infection in humans is required to inform effective vaccine development. We report an unusual case of persistent DENV infection in a lymphopenic renal transplant recipient who was therapeutically immunosuppressed to prevent organ rejection. Following resolution of symptomatic dengue, this patient remained positive for DENV3 RNA in the blood for 4 months and viruric up to 9 months post-infection despite demonstrable levels of serum neutralizing antibodies throughout this period. Full resolution of DENV infection instead coincided with recovery of CD8+ T cell counts during reversal from lymphopenia. Taken collectively, our observations suggest a role for cellular immunity in sterilizing DENV infection in humans. Any dengue vaccine should thus be able to induce both humoral and cellular immunity that respectively prevent symptomatic infection and enable effective viral clearance.


Synthesis of a Zr-Based Metal-Organic Framework with Spirobifluorenetetrabenzoic Acid for the Effective Removal of Nerve Agent Simulants.
A new microporous Zr(IV)-based metal-organic framework (MOF) containing 4,4',4″,4‴-(9,9'-spirobi[fluorene]-2,2',7,7'-tetrayl)tetrabenzoic acid (Spirof-MOF) was synthesized, characterized, and size-controlled for the adsorption and decomposition of a nerve agent simulant, dimethyl 4-nitrophenylphosphate (DMNP). Spirof-MOF showed a hydrolysis half-life (t1/2) of 7.5 min to DMNP, which was confirmed by using in situ 31P NMR spectroscopy. Additionally, size-controlled Spirof-MOFb (∼1 μm) exhibited a half-life of 1.8 min and 99% removal within 18 min for DMNP. The results show that Spirof-MOF is a new active material in removing nerve agent simulants by adsorption and hydrolytic decomposition.


Reversible inhibition of mitochondrial complex IV activity in PBMC following acute smoking.
Smoking causes a decrease of mitochondrial complex IV activity in chronic smokers. However, it is not known if this toxic effect is due to the acute effect of cigarette smoke itself or is a secondary phenomenon related to other smoking factors. The study assessed mitochondrial respiratory chain function in peripheral blood mononuclear cells of 15 healthy nonsmoker individuals before smoking (t0), immediately after smoking five cigarettes in 45 min (t1) and 24 h later (t2). Blood carboxyhaemoglobin (COHb) and carbon monoxide concentrations in exhaled air (COEA) were determined to ascertain smoke inhalation status. After acute smoking, COHb increased from 0.5 +/- 0.3% to 3.3 +/- 1.5%, and COEA from 2.9 +/- 2.5 to 26.1 +/- 9.9 ppm. Complex II and III enzyme activities did not change along the study. Complex IV activity showed a 23% inhibition at t1 but returned to initial (to) levels at t2. A decay in oxygen consumption was observed after the correction for mitochondrial content. Lipid peroxidation of cell membranes remained unchanged. Short-time smoking causes an acute and reversible mitochondrial complex IV inhibition in human mononuclear cells. These results suggest that smoke itself is one of the causes for the decrease of complex IV activity observed in chronic smokers.


Improving the remote estimation of soil organic carbon in complex ecosystems with Sentinel-2 and GIS using Gaussian processes regression.
The quantitative retrieval of soil organic carbon (SOC) storage, particularly for soils with a large potential for carbon sequestration, is of global interest due to its link with the carbon cycle and the mitigation of climate change. However, complex ecosystems with good soil qualities for SOC storage are poorly studied. The interrelation between SOC and various vegetation remote sensing drivers is understood to demonstrate the link between the carbon stored in the vegetation layer and SOC of the top soil layers. Based on the mapping of SOC in two horizons (0-30 cm and 30-60 cm) we predict SOC with high accuracy in the complex and mountainous heterogeneous páramo system in Ecuador. A large SOC database (in weight % and in Mg/ha) of 493 and 494 SOC sampling data points from 0-30 cm and 30-60 cm soil profiles, respectively, were used to calibrate GPR models using Sentinel-2 and GIS predictors (i.e., Temperature, Elevation, Soil Taxonomy, Geological Unit, Slope Length and Steepness (LS Factor), Orientation and Precipitation). In the 0-30 cm soil profile, the models achieved a R2 of 0.85 (SOC%) and a R2 of 0.79 (SOC Mg/ha). In the 30-60 cm soil profile, models achieved a R2 of 0.86 (SOC%), and a R2 of 0.79 (SOC Mg/ha). The used Sentinel-2 variables (FVC, CWC, LCC/Cab, band 5 (705 nm) and SeLI index) were able to improve the estimation accuracy between 3-21% compared to previous results of the same study area. CWC emerged as the most relevant biophysical variable for SOC prediction. The online version contains supplementary material available at 10.1007/s11104-022-05506-1.


Sonographic evaluation of umbilical cord thickness in monochorionic diamniotic twin pregnancies.
To develop a nomogram of the thickness of the umbilical cord (UC) and its components in monochorionic diamniotic (MCDA) twin pregnancies. This prospective longitudinal study involved 47 MCDA twin pregnancies (94 fetuses) between 18 and 33 weeks of gestation. Ultrasound assessments of UC cross-sections and measurements of the umbilical cord area (UCA), the umbilical vein area (UVA), the umbilical artery area (UAA), and the Wharton jelly area (WJA) were made. The UC measurements were correlated with gestational ages. Reference values for the gestational ages of MCDA pregnancies were determined and compared with those of dichorionic twins and singletons. The cases which developed selective intrauterine growth restriction were contrasted with normal cases. A positive correlation was found between all UC components and gestational age and fetal weight. The UCA of MCDA fetuses was significantly larger than that of DC fetuses (p < 0.001) at the expense of a larger WJA (p < 0.001) and similar to that of singleton pregnancies. The MCDA fetuses with an estimated fetal weight below the 10th percentile had a smaller UCA than fetuses with a normal estimated weight (p < 0.001). The MCDA twins exhibited a thicker UC than that of dichorionic twins.


Input strategy analysis for an air quality data modelling procedure at a local scale based on neural network.
In recent years, a significant part of the studies on air pollutants has been devoted to improve statistical techniques for forecasting the values of their concentrations in the atmosphere. Reliable predictions of pollutant trends are essential not only for setting up preventive measures able to avoid risks for human health but also for helping stakeholders to take decision about traffic limitations. In this paper, we present an operating procedure, including both pollutant concentration measurements (CO, SO₂, NO₂, O₃, PM10) and meteorological parameters (hourly data of atmospheric pressure, relative humidity, wind speed), which improves the simple use of neural network for the prediction of pollutant concentration trends by means of the integration of multivariate statistical analysis. In particular, we used principal component analysis in order to define an unconstrained mix of variables able to improve the performance of the model. The developed procedure is particularly suitable for characterizing the investigated phenomena at a local scale.


Efficacy of Local Anesthetic Wound Infiltration in Temporomandibular Joint Ankylosis Surgery for Control of Postoperative Pain: A Prospective, Randomized Controlled, and Double-Blinded Trial.
This study aimed to compare the analgesic efficacy of wound infiltration with ropivacaine alone or with adjuvants clonidine or dexamethasone for postoperative pain in temporomandibular joint ankylosis (TMJA) surgery. The investigators implemented a randomized controlled trial with 3 parallel groups, among the patients of bilateral TMJA visiting the maxillofacial surgery unit between March 12, 2015 and February 5, 2017. At the completion of surgery, wound infiltration was done with 0.25% of ropivacaine (R group), 0.25% of ropivacaine with 0.5 mcg/kg of clonidine (RC group), 0.25% of ropivacaine with 0.1 mg/kg of dexamethasone (RD group), and 0.2 mL/kg of drug volume on each side. The primary outcome variables were total opioid consumption (fentanyl in micrograms/kilogram) and visual analog scale for pain at rest and movement for 24 hours after surgery. The secondary outcome variables were time (minutes) to first rescue analgesic requirement and patient satisfaction scores. The patients, surgeons, and anesthesiologists collecting the data were blinded to the group allocation. Continuous and qualitative data were summarized using mean (standard deviation) and frequency distribution, respectively. About 45 patients were randomized into 3 equal groups. Mean age of the sample was 17.6 ± 8.04 years (males = 24 [53%]; females = 21 [47%]). Surgery for TMJA included gap arthroplasty (n = 17), interpositional arthroplasty (n = 24), and total TMJ replacement (n = 4). Total fentanyl (micrograms) consumption during 24 hours was comparable between all the 3 groups and statistically not significant (P = .40). The pain scores (visual analog scale at rest and movement) were comparable at all time points. No significant difference was noted for time to first rescue analgesic requirement (P = .31). Patient satisfaction was higher in RC group as compared with R group (P = .009). No adverse effects were noted in any group. Within the confines of the sample size and the absence of power calculation, the study implies that wound infiltration with ropivacaine was as efficacious as when mixed with adjuvants, either clonidine or dexamethasone, for control of postoperative pain for 24 hours.


Conservation of the acetylation pattern of histones and the transcriptional activity in Ehrlich ascites tumor cells by sodium butyrate.
Histone deacetylases of Ehrlich ascites tumor cells are active at low temperatures (0-4 degrees C). The so-called hyperacetylated state of histones is the physiological state of histones in intact Ehrlich ascites tumor cells which is conserved by the continuous presence of 10 mM sodium butyrate during the preparation of nuclei and histones. Isolation of histones in the absence of butyrate causes an artificial decrease in histone acetylation. This artificial loss of histone acetylation produces a decrease of the elongation reaction in the RNA synthesis. The initiation of RNA synthesis is not affected.


Nickel-catalyzed coupling of isocyanates with 1,3-iodoesters and halobenzenes: a novel method for the synthesis of imide and amide derivatives.
Substituted imide and amide derivatives were conveniently prepared from the reaction of isocyanates with o-iodobenzoates and haloarenes catalyzed by the NiBr2(dppe)/dppe/Zn system in moderate to good yields with excellent tolerance of functional groups.


The efficacy and safety of Rhodiola formulation for the treatment of ischemic heart disease: A protocol for systematic review and meta-analysis.
Ischemic heart disease is the main cause of heart failure, which seriously endangers the health of people and puts a huge burden on health care resources all over the world. We propose the current protocol to evaluate the effectiveness and safety of Rhodiola on ischemic heart disease, providing a reference for clinical use. Two research members will electronically and independently search 4 English databases (EMBASE, PubMed, National Guideline Clearinghouse, and Cochrane Central Register of Controlled Trials) and 4 Chinese databases (Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Database) from their inception to October 2020. Quality assessment of the included randomized controlled trial was assessed using the Cochrane Collaboration's tool. All calculations were carried out with Stata 11.0 (The Cochrane Collaboration, Oxford, United Kingdom). A synthesis of current evidence of Rhodiola formulation for ischemic heart disease will be provided in this protocol. This study will provide a theoretical basis for the clinical use of Rhodiola formulation for treating ischemic heart disease.


Dynamic viscoelastic properties of silica alkoxide during the sol-gel transition.
The viscoelastic properties of silica alkoxide gel during the sol-gel transition (SGT) are analysed using an extended shear relaxation modulus expression with a functional form based on a product of power law and Debye-Maxwell relaxation kernels. The dynamic properties are probed by small-amplitude oscillatory shear measurements in three viscoelastic domains (pre-SGT, SGT, post-SGT). Using analytical expressions for the storage G'(omega) and loss G''(omega) moduli in these three domains, it is shown that the divergence of the mean characteristic relaxation time in the pre-SGT domain can be successfully described by a percolation with bond fluctuation dynamics. It is also shown that the equilibrium shear modulus in the post-SGT domain can be successfully described by a percolation model based on an analogy with an electrical network. The amplitude and the critical exponent of the power law relaxation at the gelation time first introduced by Winter and Chambon are estimated in the pre- and post-SGT domains.


Discovery of candesartan cilexetic as a novel neddylation inhibitor for suppressing tumor growth.
Protein neddylation is a posttranslational modification of conjugating the neuronal precursor cell-expressed developmentally down-regulated protein 8 (Nedd8) to substrates. Our previous work revealed that neddylation pathway is overactivated in various human lung cancers and correlates with the disease progression, whereas pharmacologically targeting this pathway has emerged as an attractive therapeutic strategy. As a follow-up research, 1331 approved drugs were investigated the inhibitory activities of cullin1 neddylation for screening the hit compounds via an improved enzyme-based assay. An antihypertensive agent, candesartan cilexetic (CDC), was identified as a novel neddylation inhibitor that ATP-competitively suppressing Nedd8-activating enzyme (NAE, E1) in mechanism, which inhibited the cullins neddylation superior than two representative non-covalent NAE inhibitors, M22 and mitoxantrone. Following with the findings such as apoptotic induction and tumor growth suppression in human lung cancer A549 in vitro and in vivo, CDC represents a potential anticancer lead compound with promising neddylation inhibitory activity.


Changes in tooth position in humans in relation to arterial blood pressure.
The three-dimensional physiological tooth movement synchronized with the heartbeat is called periodontal pulsation. This study utilized a computer-assisted amorphous sensor to evaluate the relation between tooth position and arterial blood pressure, and also between the amplitude of periodontal pulsation and arterial blood pressure. The measuring device consisted of a small magnet attached to the tooth and an amorphous sensor that was used to detect displacement of the tooth without actually contacting it. The sample consisted of the upper left central incisors of six healthy Japanese volunteers. The three measuring points for each tooth were on the labial surface. The cold-pressor test was used as an autonomic nerve stimulus that induces an increase in blood pressure and heart rate. Periodontal pulsation, electrocardiogram, blood pressure and heart rate were recorded simultaneously during a 1 min pre-test relaxation, a 2 min cold-pressor test and a 1 min recovery. The results showed significant correlations between tooth position and mean blood pressure in five of the six volunteers and between tooth position and pulse pressure in four. Moreover, it was confirmed that tooth position shifted in the labial direction in conjunction with an increase of the mean blood pressure induced by cold stimulation. Significant correlations were found between the amplitude of periodontal pulsation and pulse pressure in four of the volunteers. These findings suggest that in humans tooth position might be affected by the force of blood pressure transmitted through periodontal vessels and that the amplitude of periodontal pulsation tends to reflect changes of pulse pressure rather than changes in mean blood pressure.


P2 protein-induced experimental allergic neuritis. An ultrastructural study.
Experimental allergic neuritis (EAN) was induced in 2 groups of inbred Lewis rats by sensitization with P2 protein and peripheral nervous system (PNS) myelin, both purified from bovine intradural roots. Light- and electronmicroscopic study of P2-induced EAN revealed demyelinative lesions in spinal ganglia and root nerves and less frequently in peripheral nerves and root entry zones. Both small and large myelinated fibers were demyelinated, contradictory to the reported selective binding of anti-P2 antibodies to myelin of large fibers. The early lesions were characterised by perivenular lymphocytic infiltration, and subsequent "dissolution" of myelin sheath was associated with invasive of phagocytic cells. The distribution of demyelinative lesions and patterns of demyelination resembled those of PNS myelin-induced EAN except that the disease was milder and dissolution of myelin and intramyelinic edema were more frequently found in P2-induced EAN. The abundance of demyelination in P2-induced EAN strikes contrast to the scarcity of myelin change in experimental allergic encephalomyelitis (EAE) induced by myelin basic protein immunization.


Effects of ghrelin on gastric distention sensitive neurons in the arcuate nucleus of hypothalamus and gastric motility in diabetic rats.
This study was performed to observe the effects of ghrelin on the activity of gastric distention (GD) sensitive neurons in the arcuate nucleus of hypothalamus (Arc) and on gastric motility in vivo in streptozocin (STZ) induced diabetes mellitus (DM) rats. Electrophysiological results showed that ghrelin could excite GD-excitatory (GD-E) neurons and inhibit GD-inhibitory (GD-I) neurons in the Arc. However, fewer GD-E neurons were excited by ghrelin and the excitatory effect of ghrelin on GD-E neurons was much weaker in DM rats. Gastric motility research in vivo showed that microinjection of ghrelin into the Arc could significantly promote gastric motility and it showed a dose-dependent manner. The effect of ghrelin promoting gastric motility in DM rats was weaker than that in normal rats. The effects induced by ghrelin could be blocked by growth hormone secretagogue receptor (GHSR) antagonist [d-Lys-3]-GHRP-6 or BIM28163. RIA and real-time PCR data showed that the levels of ghrelin in the plasma, stomach and ghrelin mRNA in the Arc increased at first but decreased later and the expression of GHSR-1a mRNA in the Arc maintained a low level in DM rats. The present findings indicate that ghrelin could regulate the activity of GD sensitive neurons and gastric motility via ghrelin receptors in the Arc. The reduced effects of promoting gastric motility induced by ghrelin could be connected with the decreased expression of ghrelin receptors in the Arc in diabetes. Our data provide new experimental evidence for the role of ghrelin in gastric motility disorder in diabetes.


[Talking about death with young children].
Death has become a topic in our society and talking about it with young children is often the source of numerous questions on the part of adults, especially parents. How should we talk about death with young children? Does the migration process play a role in certain families? Do they draw on their culture of origin, their cultural or religious customs? Interviews carried out with ten parents provide some insights.


Prospective survey of percutaneous injuries in orthodontic assistants.
This prospective diary survey provides documentation concerning the occurrence of percutaneous injury among orthodontic chairside assistants in the United States and Canada. A 20-day period was used to collect data regarding exposure to injuries; 693 valid responses were received from orthodontic assistants. Most chairside assistants in this sample work in a solo practice and average 33 hours per week treating patients for 49 weeks per year. The study identified a percutaneous injury rate of 0.11 for chairside assistants during this period, a rate than can be extrapolated to 1.4 episodes of percutaneous injury per year per chairside assistant. The majority of these injuries occurred outside the mouth. Those assistants with longer orthodontic experience had a lower injury rate than those with less experience. The rate of percutaneous injury to dental assistants was slightly higher than the annual rate (0.99) for orthodontists monitored by means of a companion survey and slightly lower than the rate (1.9) for a smaller sample of orthodontists from the American Dental Association survey of 1995. The annual rate of percutaneous injury for orthodontic chairside assistants is less than half of that observed for dentists in general practice.


Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine.
Nocturnal hormone profiles were measured in patients with schizophrenia with predominantly negative symptoms both under drug-free baseline conditions and after subchronic administration of the atypical antipsychotic olanzapine, with the aim of characterizing its pharmacological properties on the neuroendocrine level. The following hormones were studied in the sleep laboratory under polysomnographic control: adrenocorticotrophic hormone, cortisol, growth hormone (GH), prolactin, testosterone, and melatonin. Blood samples were taken at regular time intervals over the night, and serum concentrations of the hormones were determined. Ten patients completed the study, two of them were excluded from analysis due to incomplete hormone profiles. The dynamics of baseline nocturnal hormone secretion were similar to the patterns known from healthy subjects. After the treatment period of about 4 weeks, hypothalamic-pituitary-adrenal axis activity was reduced with decreased cortisol plasma levels compared to baseline conditions. Olanzapine induced a moderate prolactin elevation. The characteristic GH peak around sleep onset, clearly present under baseline conditions, was markedly reduced after treatment. Testosterone and melatonin secretion were not significantly altered. In conclusion, although interpretation is difficult in some cases due to interference with indirect effects of olanzapine administration and the consequences of the clinical course of the underlying schizophrenic disorder, the neuroendocrine findings are consistent with the receptor-binding profile of olanzapine where, beside the D(2) antagonism, the antiserotonergic properties are most important.


Migration of cultured fetal spinal cord astrocytes into adult host cervical cord and medulla following transplantation into thoracic spinal cord.
Cell suspensions from 14-day-gestation rat spinal cord, which had previously been soaked for 1 hr in a 2 micrograms/ml solution of Phaseolus vulgaris leucoagglutinin (PHAL), were cultured on collagen gels containing laminin for 2 weeks. Pieces of the gel and attached cells were then transplanted into the dorsal column of adult host thoracic spinal cord. At 1, 2, and 3 months postimplantation (MPI), animals were sacrificed, and the spinal cords were removed, embedded in paraffin, and sectioned at 8 micron for immunohistochemistry at the light microscopic level. Sections were double labeled for PHAL and utilized as a marker for transplant-derived cells and glial fibrillary acidic protein (GFAP), a specific marker for astrocytes. Transplant-derived astrocytes (PHAL-GFAP positive cells) migrated from the transplantation site in both rostral and caudal directions and were observed within the host dorsal column ipsilateral to the transplantation site. At 2 months, lateral migration into the contralateral dorsal column and ipsilateral dorsal horn was observed. At 3 MPI transplant-derived astrocytes were observed in host medulla (nucleus gracilis). Transplant-derived astrocytes were also observed on the glial limitans as far as nucleus gracilis. A migration rate of 0.72 mm/day was calculated, assuming a 14-day delay in the initiation of migration. The ramifications of such extensive migration are discussed with regard to return of function and amelioration of lesion-induced deficits.


Ferrokinetics and erythropoiesis in man: red-cell production and destruction in normal and anaemic subjects.
Recent advances in the analysis of plasma 59Fe clearance have produced a unified method for measuring effective and ineffective erythropoiesis (Ricketts et al, 1975). We have used this method to investigate the balance between red-cell production and destruction in normal subjects and in patients with megaloblastic anaemia, iron deficiency anaemia, and refractory hypoplastic anaemia. The results show that the normal marrow can maintain an appropriate red-cell mass by altering red-cell production to match destruction. In the anaemias we have studied there is an increased rate of either intra- or extra-medullary red-cell destruction. The response of the marrow may be limited by iron supply, by defective nuclear maturation or by some intrinsic marrow defect.


Psychological Support Strategies for Adults With Type 2 Diabetes in a Very Low-Carbohydrate Web-Based Program: Randomized Controlled Trial.
A very low-carbohydrate (VLC) nutritional strategy may improve glycemic control and weight loss in adults with type 2 diabetes (T2D). However, the supplementary behavioral strategies that might be able to improve outcomes using this nutritional strategy are uncertain. This study aims to compare the impact of adding 3 different supplementary behavioral strategies to a web-based VLC diet intervention. To our knowledge, this is the first trial to randomize participants to different frequencies of dietary self-monitoring. The study included 112 overweight adults with T2D (hemoglobin A1c ≥6.5%) taking no antiglycemic medications or only metformin. They received a remotely delivered 12-month VLC diet intervention. Participants were randomly assigned through a full factorial 2×2×2 design to supplementary strategies: either daily or monthly dietary self-monitoring, either mindful eating training or not, and either positive affect skills training or not. Our research goal was to determine whether 3 different supplemental strategies had at least a medium effect size (Cohen d=0.5). Overall, the VLC intervention led to statistically significant improvements in glycemic control (-0.70%, 95% CI -1.04% to -0.35%; P<.001), weight loss (-6.82%, 95% CI -8.57% to -5.08%; P<.001), and depressive symptom severity (Cohen d -0.67, 95% CI -0.92 to -0.41; P<.001). Furthermore, 30% (25/83) of the participants taking metformin at baseline reduced or discontinued their metformin. Only 1 Cohen d point estimate reached 0.5; daily (vs monthly) dietary self-monitoring had a worse impact on depressive symptoms severity (Cohen d=0.47, 95% CI -0.02 to 0.95; P=.06). None of the strategies had a statistically significant effect on outcomes. For changes in our primary outcome, hemoglobin A1c, the daily (vs monthly) dietary self-monitoring impact was 0.42% (95% CI -0.28% to 1.12%); for mindful eating, it was -0.47% (95% CI -1.15% to 0.22%); and for positive affect, it was 0.12% (95% CI -0.57% to 0.82%). Other results for daily (vs monthly) dietary self-monitoring were mixed, suggesting an increase in weight (0.98%) and depressive symptoms (Cohen d=0.47), less intervention satisfaction (Cohen d=-0.20), more sessions viewed (3.02), and greater dietary adherence (Cohen d=0.24). For mindful eating, the results suggested a benefit for dietary adherence (Cohen d=0.24) and intervention satisfaction (Cohen d=0.30). For positive affect, the results suggested a benefit for depressive symptoms (Cohen d=-0.32), the number of sessions viewed (3.68), dietary adherence (Cohen d=0.16), and intervention satisfaction (Cohen d=0.25). Overall, our results support the use of a VLC diet intervention in adults with T2D. The addition of monthly (not daily) dietary self-monitoring, mindful eating, and positive affect skills training did not show a definitive benefit, but it is worth further testing. ClinicalTrials.gov NCT03037528; https://clinicaltrials.gov/ct2/show/NCT03037528.


A new electrochemical HPLC method for analysis of enkephalins and endomorphins.
Endogenous opioid peptides, enkephalins and endomorphins, are located in key regions involved in pain transmission and analgesia, including the spinal cord. These endogenous peptides activate opioid receptors to produce analgesia and reduce pain. We describe a new method to measure enkephalin and endomorphins by high performance liquid chromatography with electrochemical detection. This method allows use of a small sample volume to measure met-enkephalin, leu-enkephalin, endomorphin-1 and endomorphin-2 simultaneously. Using push-pull perfusion of the spinal cord, there were detectable concentrations of met-enkephalin, leu-enkephalin, and endomorphin-2. Further infusion of 100mM potassium chloride evoked release of met-enkephalin and endomorphin-2 but not leu-enkephalin. Thus, we have developed a method to simultaneously measure enkephalins and endomorphins in small sample volume that allows measurement of these opioid peptides in vivo.


Disparity curvature and the perception of three-dimensional surfaces.
BINOCULAR stereopsis provides information about the relative distance of objects from the differences in the horizontal position of their images on the two retinas. Because the size of the disparity between two points is inversely related to the square of the viewing distance, it is usually assumed that disparities have to be scaled according to distance using the vergence angle of the eyes, or by using the small vertical disparities that also exist between corresponding points of the two images. Here we present evidence that the visual system could extract information about the shapes of surfaces (without the need for scaling) by using the second spatial derivative of disparity--disparity curvature--which remains invariant with viewing distance. Rather than computing the second derivative, we suggest that an approximation to disparity curvature could be derived from the differences in curvature of corresponding line elements in the two eyes.


'The mosquitoes are preparing to attack us': knowledge and perceptions of communities in south-eastern Tanzania regarding mosquito swarms.
Targeting swarms of male Anopheles mosquitoes with techniques such as aerosol spraying could potentially suppress malaria vector populations and parasite transmission. Unfortunately, research on Anopheles swarming behaviours is limited, particularly in East Africa where only a handful of studies have been done. New evidence has recently emerged that such swarms are common even in Tanzania, where they could be readily identified and characterized by community-based volunteers, and potentially targeted for control. However, improved understanding of public knowledge and perceptions will be crucial for successful uptake of any interventions targeting swarms. Explanatory sequential mixed methods approach was used to assess knowledge and perceptions regarding mosquito swarms among community members in Ulanga and Kilombero districts, south-eastern Tanzania. A survey questionnaire was administered to 307 respondents, after which focus group discussions were conducted to clarify responses regarding mosquito swarms and malaria transmission. Findings from both study components were used to draw qualitative inferences. Most community members (83%) had previously seen mosquito swarms, predominantly in farms, over long grasses or bushes, above ponds and over roofs of houses and pit-latrines. However, there was little evidence that community members could distinguish between mosquito swarms and those of other insects. Neither were they aware that swarms consisted mostly of male mosquitoes. Swarming was associated with mosquitoes preparing to attack people, foraging for food, playing or resting. Very few respondents associated swarming with mosquito mating. Nearly all community members were willing to accept interventions targeting mosquito swarms; and approximately three quarters would pay for such interventions, between 0.9 and 2.3 USD/year. Majority of the community members recognized presence of mosquito swarms in their communities but did not associate these swarms with mosquito mating. Instead, swarming was associated with mosquitoes seeking food or planning to attack people, and thus were generally considered dangerous. This understanding created the basis for wide-acceptance of interventions targeting swarming mosquitoes. Although the likelihood of actual interventions targeting swarms is still low, such community knowledge will be crucial in future field studies of mosquito swarms and possible inclusion of community members in mosquito control efforts.


Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential.
The glycoprotein hormones, luteinizing hormone, follicle-stimulating hormone and thyroid stimulating hormone, are important regulators of reproductive and metabolic processes. However, because of the nature of their ligand-receptor interactions that contain multiple contact sites, classical small molecule drug discovery strategies have not been successful. However, recent advances in screening and combinatorial chemistry strategies have identified chemical series that act allosterically as positive, negative or mixed modulators of the glycoprotein hormone receptors. This review will discuss the discovery and highlight the currently known series of allosteric modulators to this therapeutically important family of G-protein coupled receptors. Lastly, we will present potential mechanisms whereby the different series could modulate receptor function in the context of currently held theory and known structure of G protein-coupled receptors.


Pro-inflammatory immune profile mediated by TNF and IFN-γ and regulated by IL-10 is associated to IgG anti-SARS-CoV-2 in asymptomatic blood donors.
The SARS-CoV-2 virus has infected and killed millions of people, but little is known about the risk factors that lead to the development of severe, mild or asymptomatic conditions after infection. The individual immune response and the balance of cytokines and chemokines have been shown to be important for the prognosis of patients. Additionally, it is essential to understand how the production of specific antibodies with viral neutralizing capacity is established. In this context, this study aimed to identify positive individuals for IgG anti-SARS-CoV-2 in a large population of blood donors (n = 7837) to establish their immune response profile and to evaluate its viral neutralization capacity. The prevalence found for IgG anti-SARS-CoV-2 was 5.6% (n = 441), with male blood donors (61.9%) being more prevalent among the positive ones. The results showed that positive individuals for IgG anti-SARS-CoV-2 have high serum concentrations of chemokines, TNF, IFN-γ and IL-10. The analyses showed that the positivity index for IgG anti-SARS-CoV-2 is associated with the neutralizing capacity of the antibodies, which, in turn, is significantly related to lower serum concentrations of CCL5 and CXCL10. The results allow us to hypothesize that the development and maintenance of IgG anti-SARS-CoV-2 antibodies in infected individuals occurs in a pro-inflammatory microenvironment well regulated by IL-10 with great capacity for recruiting cells from the innate and adaptive immune systems.


Family caregiver perspectives on symptoms and treatments for patients dying from complications of cystic fibrosis.
Most patients with advanced cystic fibrosis (CF) die from respiratory failure and experience distressing symptoms as lung disease progresses. Little has been reported about symptom management and the continuation of disease-specific treatments near the end of life for patients with CF. We aimed to describe symptom prevalence, symptom management, and frequency of use of disease-specific treatments for patients dying from complications of CF. We conducted semistructured interviews about end-of-life care in CF with bereaved family caregivers and asked questions about symptoms and treatments. Twenty-seven caregivers answered questions about symptoms and treatments. Caregivers reported that distressing symptoms were common during the last week of life, including dyspnea (100%), fatigue (96%), anorexia (85%), anxiety (74%), pain (67%), and cough (56%). Most caregivers felt that symptom control was "somewhat good." Many reported that medical providers "did the best they could" to manage symptoms but four (15%) recalled no physician inquiry about symptoms. Caregivers expressed beliefs that symptoms could not be controlled and described concerns about side effects and potential for hastening death with the use of opioids and anxiolytics. Patients received numerous disease-specific treatments, and caregivers described many of them as uncomfortable but necessary. Distressing symptoms are common in dying CF patients, and disease-specific treatments also cause discomfort. Many family caregivers have low expectations for symptom control. This exploratory research can be used to inform clinical interventions to improve symptom management for patients with advanced CF.


Rotational dynamics in motor cortex are consistent with a feedback controller.
Recent studies have identified rotational dynamics in motor cortex (MC), which many assume arise from intrinsic connections in MC. However, behavioral and neurophysiological studies suggest that MC behaves like a feedback controller where continuous sensory feedback and interactions with other brain areas contribute substantially to MC processing. We investigated these apparently conflicting theories by building recurrent neural networks that controlled a model arm and received sensory feedback from the limb. Networks were trained to counteract perturbations to the limb and to reach toward spatial targets. Network activities and sensory feedback signals to the network exhibited rotational structure even when the recurrent connections were removed. Furthermore, neural recordings in monkeys performing similar tasks also exhibited rotational structure not only in MC but also in somatosensory cortex. Our results argue that rotational structure may also reflect dynamics throughout the voluntary motor system involved in online control of motor actions.


On the specificity of healing functions: a study of diagnosis in three faith healing institutions in Feira (Bahia, Brazil).
This essay examines three popular ethnomedical institutions in Brazil: faith healers, Protestant evangelicals, and the practitioners of one of the Japanese new religions. In particular, I compare the relative degrees of diagnostic specificity in their practices. Medical anthropologists have neglected the analysis of this aspect of practice, although I show in the present paper its utility for comparative work. Also, I show that diagnostic specificity is congruent with an ontological view of illness and an active role for the healer, while lack of diagnostic specificity is congruent with a very general form of therapy, such as is found in the Seicho-no-Ie religion. Traditional rezadores, in contrast, use a high degree of diagnostic specificity.


Alterations of molecular architectures in skeletal muscle plasma membranes of dehydrated and water-loaded mice.
It is likely that orthogonal arrays (OAs) and caveolae seen on the replicas of freeze-fractured muscle plasma membranes are involved in maintaining osmotic homeostasis. Therefore, using the freeze-fracture technique, we examined the ultrastructural changes in OAs and caveolae of the skeletal muscle plasma membrane of dehydrated and water-loaded mice. In the muscle plasma membranes of 6 dehydrated and 6 water-loaded mice, caveolar distribution was not altered, and the densities of caveolae and OAs did not show statistically significant differences when compared with those in 6 control mice, although the skeletal muscles of water-loaded mice sometimes had muscle plasma membranes with extremely numerous OAs. In contrast, the muscle plasma membranes of dehydrated mice often revealed changes in the distribution of OAs, which existed in a group at the confined area of the muscle plasma membranes and were frequently accompanied by the aggregations of intramembranous particles (IMPs) around OAs. Thus, on the basis of the present study, we suggest that OAs in skeletal muscles as well as those in brain may play an important role in maintaining osmotic homeostasis of these organs under abnormal water balance.


Exploring Oxidovanadium(IV) Complexes as YopH Inhibitors: Mechanism of Action and Modeling Studies.
YopH tyrosine phosphatase, a virulence factor produced by pathogenic species of Yersinia, is an attractive drug target. In this work, three oxidovanadium(IV) complexes were assayed against recombinant YopH and showed strong inhibition of the enzyme in the nanomolar range. Molecular modeling indicated that their binding is reinforced by H-bond, cation-π, and π-π interactions conferring specificity toward YopH. These complexes are thus interesting lead molecules for phosphatase inhibitor drug discovery.


Like parent, like child: a cross-sectional study of intra-household consumption patterns of non-alcoholic beverages among British households with children.
Most research investigating sugar-sweetened beverages (SSB) and health, conducted at the individual or household level, ignores potentially important intra-household dynamics. We analysed self-reported consumption relationships between children and adults, and between children of different ages, as well as the associations between intra-household consumption, BMI and sociodemographic characteristics. A cross-sectional analysis of survey data from Kantar Fast Moving Consumer Goods panellists in September 2017. Great Britain. Random sample of 603 households with children under 18 years who regularly purchase non-alcoholic beverages. Low- or no-sugar/diet beverages dominate consumption across all age categories, particularly children under 12 years. SSB consumption increased as children became older. Children's reported consumption of SSB and low- or no-sugar/diet beverages was positively associated with consumption by adults; a child in adolescence had over nine times the odds of consuming SSB (adjusted OR 9·55, (95 % CI 5·38, 17·00), P < 0·001), and eight times the odds of consuming low- or no-sugar/diet drinks (adjusted OR 8·12, (95 % CI 4·71, 13·97), P < 0·001), if adults did so. In households with multiple children, consumption patterns of older siblings were associated with those of the younger; notably a perfect correlation between children aged 0 and 6 years consuming SSB if siblings 13-18 years did so, and children aged 7-12 years had 22 times the odds of consuming SSB if siblings aged 13-18 years did so (OR 22·33, (95 % CI 8·60, 58·01), P < 0·001). Multiple policies, targeting children as well as adults, such as fiscal levers and advertisement restrictions, are needed to reduce and prevent the consumption of SSB.


Actions of cadmium on basolateral plasma membrane proteins involved in calcium uptake by fish intestine.
The inhibition of Ca(2+)-ATPase, (Na+ + K+)-ATPase and Na+/Ca2+ exchange by Cd2+ was studied in fish intestinal basolateral plasma membrane preparations. ATP driven 45Ca2+ uptake into inside-out membrane vesicles displayed a Km for Ca2+ of 88 +/- 17 nM, and was extremely sensitive to Cd2+ with an IC50 of 8.2 +/- 3.0 pM Cd2+, indicating an inhibition via the Ca2+ site. (Na+ + K+)-ATPase activity was half-maximally inhibited by micromolar amounts of Cd2+, displaying an IC50 of 2.6 +/- 0.6 microM Cd2+. Cd2+ ions apparently compete for the Mg2+ site of the (Na+ + K+)-ATPase. The Na+/Ca2+ exchanger was inhibited by Cd2+ with an IC50 of 73 +/- 11 nM. Cd2+ is a competitive inhibitor of the exchanger via an interaction with the Ca2+ site (Ki = 11 nM). Bepridil, a Na+ site specific inhibitor of Na+/Ca2+ exchange, induced an additional inhibition, but did not change the Ki of Cd2+. Also, Cd2+ is exchanged against Ca2+, albeit to a lesser extent than Ca2+. The exchanger is only partly blocked by the binding of Cd2+. In vivo cadmium that has entered the enterocyte may be shuttled across the basolateral plasma membrane by the Na+/Ca2+ exchanger. We conclude that intracellular Cd2+ ions will inhibit plasma membrane proteins predominantly via a specific interaction with divalent metal ion sites.


How useful is cerebrospinal fluid lactate estimation in differential diagnosis of meningitis?
Cerebrospinal fluid lactate (CSF) was measured by a rapid enzymatic method in 230 patients admitted with a suspected diagnosis of central nervous system infection. In all untreated cases of bacterial meningitis the levels exceeded 4.3 mmol/l and fell below 3.9 mmol/l in most patients with virus meningitis. We believe values of 3.9-4.3 mmol/l should be considered borderline as occasional CSF samples in cases of virus meningitis yield values in this range. However, distinction between untreated pyogenic meningitis and virus meningitis is rarely problematic in clinical practice, so routine use of the test as an emergency procedure offers no extra advantage. The test is unlikely to be of much help in differentiating partly treated bacterial meningitis from virus meningitis, but it is a valuable additional procedure for differentiating tuberculous meningitis from virus meningitis, highly modified bacterial meningitis and parameningeal septic states.


Fluorofenidone attenuates renal fibrosis by inhibiting the mtROS-NLRP3 pathway in a murine model of folic acid nephropathy.
Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-β (TGF-β), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1β, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.


Measurement of cell numbers by means of the endogenous enzyme hexosaminidase. Applications to detection of lymphokines and cell surface antigens.
By using a chromogenic substrate for an ubiquitous lysosomal enzyme, hexosaminidase to estimate cell numbers, a sensitive and simple procedure has been developed in which microtiter reaction wells are directly scanned in a spectrophotometer. This method has been adapted to several cell biological assays. Quantitation of the biological activities of T cell growth factor and interferon can be performed on large numbers of samples. Adhesion of dispersed solid tissue cells to fibronectin coated substrates may be quantitated with little expenditure of reagents. By use of a panning procedure in microtiter plates a sensitive and very simple assay for the binding of monoclonal antibodies to cell surface antigens has been developed.


Binding of dihydroxynaphthyl aryl ketones to tubulin colchicine site inhibits microtubule assembly.
Dihydroxynaphthyl aryl ketones 1-5 have been evaluated for their abilities to inhibit microtubule assembly and the binding to tubulin. Compounds 3, 4 and 5 displayed competitive inhibition against colchicine binding, and docking analysis showed that they bind to the tubulin colchicine-binding pocket inducing sheets instead of microtubules. Remarkable differences in biological activity observed among the assayed compounds seem to be related to the structure and position of the aryl substituent bonded to the carbonyl group. Compounds 2, 3 and 4, which contain a heterocyclic ring, presented higher affinity for tubulin compared to the carbocyclic analogue 5. Compound 4 showed the best affinity of the series, with an IC50 value of 2.1 μM for microtubule polymerization inhibition and a tubulin dissociation constant of 1.0 ± 0.2 μM, as determined by thermophoresis. Compound 4 was more efficacious in disrupting microtubule assembly in vitro than compound 5 although it contains the trimethoxyphenyl ring present in colchicine. Hydrogen bonds with Asn101 of α-tubulin seem to be responsible for the higher affinity of compound 4 respects to the others.


Quantitative CT analysis to predict esophageal fistula in patients with advanced esophageal cancer treated by chemotherapy or chemoradiotherapy.
Esophageal fistula is one of the most serious complications of chemotherapy or chemoradiotherapy (CRT) for advanced esophageal cancer. This study aimed to evaluate the performance of quantitative computed tomography (CT) analysis and to establish a practical imaging model for predicting esophageal fistula in esophageal cancer patients treated with chemotherapy or chemoradiotherapy. This study retrospectively enrolled 204 esophageal cancer patients (54 patients with fistula, 150 patients without fistula) and all patients were allocated to the primary and validation cohorts according to the time of inclusion in a 1:1 ratio. Ulcer depth, tumor thickness and length, and minimum and maximum enhanced CT values of esophageal cancer were measured in pretreatment CT imaging. Logistic regression analysis was used to evaluate the associations of CT quantitative measurements with esophageal fistula. Receiver operating characteristic curve (ROC) analysis was also used. Logistic regression analysis showed that independent predictors of esophageal fistula included tumor thickness [odds ratio (OR) = 1.167; p = 0.037], the ratio of ulcer depth to adjacent tumor thickness (OR = 164.947; p < 0.001), and the ratio of minimum to maximum enhanced CT value (OR = 0.006; p = 0.039) in the primary cohort at baseline CT imaging. These predictors were used to establish a predictive model for predicting esophageal fistula, with areas under the receiver operating characteristic curves (AUCs) of 0.946 and 0.841 in the primary and validation cohorts, respectively. The quantitative analysis combined with T stage for predicting esophageal fistula had AUCs of 0.953 and 0.917 in primary and validation cohorts, respectively. Quantitative pretreatment CT analysis has excellent performance for predicting fistula formation in esophageal cancer patients who treated by chemotherapy or chemoradiotherapy.


Quality of Life Differences for Primary Immunodeficiency Patients on Home SCIG versus IVIG.
Patients with primary immunodeficiency disease (PIDD) and antibody deficiency require lifelong immunoglobulin replacement therapy. While both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) replacement therapy are effective in preventing infection, patients with PIDD still experience worse health-related quality of life (hrQOL) outcomes. Assess differences in hrQOL for PIDD patients receiving home SCIG versus IVIG. SF-36 surveys were administered by a specialty pharmacy to 630 PIDD patients receiving home SCIG and IVIG at baseline and then every 3 months between 2014 and 2016. Results were analyzed using two-sample t tests and linear mixed effects model. Analysis was repeated for different age categories and trended over time. Patients receiving SCIG reported statistically significant higher energy fatigue scores (+ 9 points, p < 0.001) but lower perceived role limitations due to physical health scores (- 14 points, p < 0.001). These differences were only observed in patients > 36 years of age. There were no differences in the composite SF-36 score for patients receiving SCIG versus IVIG (+ 1, p = 0.66). Immunoglobulin-naïve patients all improved their hrQOL, but a larger improvement was seen in those initiating SCIG versus IVIG. Patients with PIDD on home IVIG versus SCIG have similar composite hrQOL scores as measured by the SF-36. In the adult population, initiating immunoglobulin replacement with SCIG may result in more hrQOL improvement compared with IVIG, although personal preferences should also be considered. Patients with PIDD on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Patients with primary immune-deficiency on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Personal preferences are important in deciding whether to treat with IVIG or SCIG.


Control of replication of bacterial plasmids: genetics, molecular biology, and physiology of the plasmid R1 system.
Plasmids are autonomously replicating DNA molecules that are present in defined copy numbers in bacteria. This number may for some plasmids be very low (2-5 per average cell). In order to be stably inherited, replication and partitioning of the plasmid have to be strictly controlled. Plasmids carry genetic information for both processes. In the present paper we summarize what is known about the replication control system of one low-copy-number plasmid, R1, belonging to the FII incompatibility group. We do so because the FII group seems to be one of the best understood examples with respect to genetics, molecular biology, and physiology of the replication control system. The paper is not a classical review, but rather an essay in which we discuss the aspects of replication control that we regard as being important.


The influence of angiotensin II and RAAS blockers on lipolytic and glycolytic activity in isolated adipocytes from Wistar, Wistar-Kyoto and Spontaneously Hypertensive Rats.
The renin-angiotensin-aldosterone system (RAAS) is related to dysfunctional adipose tissue, but the actions of angiotensin II (AII) in adipocytes remains unclear. This study aimed to investigate the effects of RAAS blockers and AII in lipolysis and glycolysis from isolated adipocytes in Wistar (WIS), Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR). Adipocytes from 15-weeks-old WIS, WKY and SHR were incubated with AII (10-17 M to 10-6 M) and noradrenaline (NOR - 10-10 M to 10-4 M) in presence or not of antagonists (Losartan Potassium 10-4 M, PD 123319 5.6 nM or co-incubation). Glycerol and lactate production in WIS and WKY were not affected by the RAAS blockade. SHR glycerol was attenuated by the blockers but lactate was not affected. NOR induced increase in glycerol from 10-7 M for all strains. Normotensive rats are not affected by blockers but decreased lipolytic activity ins SHR. The SHR hypolipodistrophy cannot be related to any disturbance in lipolytic or glycolytic upstream pathways.


Women's knowledge of new regulations about publicly funded medications for osteoporosis.
To provide adequate and updated information regarding changes in health care regulations or policies can be a challenging task for policy makers. The aim of the present study was to examine knowledge about new regulations regarding publicly funded drugs for the treatment of osteoporosis in a group of 109 Israeli women. Participants were interviewed between 3 and 6 months after the new regulations were enacted. Although participants were aware of their eligibility, moderate levels of knowledge were found regarding the content of the regulations. Especially low levels of knowledge were found regarding the scope of services and the definition of osteoporosis according to the regulations. High-risk participants (i.e. older participants and those with lower T score or who had suffered a fracture) had no better knowledge of the regulations. The development of multifaceted information programs aimed at disseminating the content of policy changes is encouraged.


Transmission of hormonal stimulation by cell-to-cell communication.
Rat ovarian granulosa cells and mouse myocardial cells respond to cell-specific hormones by cyclic AMP-dependent mechanisms. In coculture, these heterologous cells communicate by means of gap junctions. Exposure of the cocultures to a hormone specific for one cell type causes the heterologous cells to respond through a cell contact-dependent mechanism. These studies suggest that this cross-stimulation results from the intercellular communication of a mediator that is common to both cell types. The communicated mediator may be cyclic AMP.


Hyaluronan and its catabolic products in tissue injury and repair.
Hyaluronan is an unbiquitous glycosaminoglycan present in most tissues. Under homeostatic conditions hyaluronan exists as a high molecular mass polymer that has important roles in tissue structural integrity. Under conditions of stress such as following tissue injury, hyaluronan becomes depolymerized and lower molecular mass polymers are generated. The biological properties of these hyaluronan fragments appear to be distinct from the larger precursor molecules. This review examines the biological role of hyaluronan fragments in tissue injury and repair.


HoxD expression in the fin-fold compartment of basal gnathostomes and implications for paired appendage evolution.
The role of Homeobox transcription factors during fin and limb development have been the focus of recent work investigating the evolutionary origin of limb-specific morphologies. Here we characterize the expression of HoxD genes, as well as the cluster-associated genes Evx2 and LNP, in the paddlefish Polyodon spathula, a basal ray-finned fish. Our results demonstrate a collinear pattern of nesting in early fin buds that includes HoxD14, a gene previously thought to be isolated from global Hox regulation. We also show that in both Polyodon and the catshark Scyliorhinus canicula (a representative chondrichthyan) late phase HoxD transcripts are present in cells of the fin-fold and co-localize with And1, a component of the dermal skeleton. These new data support an ancestral role for HoxD genes in patterning the fin-folds of jawed vertebrates, and fuel new hypotheses about the evolution of cluster regulation and the potential downstream differentiation outcomes of distinct HoxD-regulated compartments.


Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice.
Repeated social defeat (RSD) activates neuroendocrine pathways that have a significant influence on immunity and behavior. Previous studies from our lab indicate that RSD enhances the inflammatory capacity of CD11b⁺ cells in the brain and promotes anxiety-like behavior in an interleukin (IL)-1 and β-adrenergic receptor-dependent manner. The purpose of this study was to determine the degree to which mice subjected to RSD were more responsive to a secondary immune challenge. Therefore, RSD or control (HCC) mice were injected with saline or lipopolysaccharide (LPS) and activation of brain CD11b⁺ cells and behavioral responses were determined. Peripheral LPS (0.5 mg/kg) injection caused an extended sickness response with exaggerated weight loss and prolonged social withdrawal in socially defeated mice. LPS injection also amplified mRNA expression of IL-1β, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and CD14 in enriched CD11b⁺ cells isolated from socially defeated mice. In addition, IL-1β mRNA levels in enriched CD11b⁺ cells remained elevated in socially defeated mice 24 h and 72 h after LPS. Moreover, microglia and CNS macrophages isolated from socially defeated mice had the highest CD14 expression after LPS injection. Both social defeat and LPS injection increased the percentage of CD11b⁺/CD45(high) macrophages in the brain and the number of inflammatory macrophages (CD11b⁺/CD45(high)/CCR2⁺) was highest in RSD-LPS mice. Anxiety-like behavior was increased by social defeat, but was not exacerbated by the LPS challenge. Nonetheless, reduced locomotor activity and increased social withdrawal were still present in socially defeated mice 72 h after LPS. Last, LPS-induced microglia activation was most evident in the hippocampus of socially defeated mice. Taken together, these findings demonstrate that repeated social defeat enhanced the neuroinflammatory response and caused prolonged sickness following innate immune challenge.


Quality of integrated community case management services at public health posts, Southwest Ethiopia.
The purpose of this study is to assess the quality of an integrated community case management service (ICCM) and associated factors at health posts in Ethiopia. Institution-based cross-sectional study design was conducted in the health posts of Jimma zone. Data were collected using a structured questionnaire and in-depth interviews. Binary logistic regression was used to identify independent predictors of client satisfaction on services and the qualitative data were presented by triangulating with quantitative findings. This study indicated that 80%, 65% and 55% of health extension workers (HEW) correctly assessed cases, classified cases and prescribed drugs of ICCM cases respectively. Some caregivers (40.2%) knew about danger signs which they heard from HEWs (81.9%). More than one-fourth (29.01%) of caregivers reported that their children were exposed to illness like diarrhea (39.1%) in the last two weeks. HEWs have demonstrated to a large number of caregivers (66%) how to give medications. Being a housewife [AOR = 0.17(0.05,0.56)], having a farmer husband[AOR = 3.77(1.09,12.98)] and having a government employed husband [AOR = 5.32(1.03,27.48)] were significantly associated with ICCM services. More than half of health extension workers correctly assessed, classified and prescribed drugs for ICCM cases. Some caregivers knew about danger signs which the majority of them heard from health extension workers. Being a housewife and paternal occupation were significantly associated with clients' satisfaction in ICCM services. Findings of this study can be used to guide the development of programs to improve integrated community case management service in Ethiopia by informing policymakers and other stakeholders about challenges of ICCM services.


Prevalence of Hepatitis B Virus (HBV) Among Blood Donors in Eastern Saudi Arabia: Results From a Five-Year Retrospective Study of HBV Seromarkers.
Transfusion-transmissible hepatitis B virus (HBV) infection is a major problem worldwide. Recently, confirmatory nucleic acid tests (NATs) for HBV DNA have been employed in several countries. We assessed the prevalence and yearly trends of HBV infection in blood donors in the Eastern Province of Saudi Arabia, screening for HBV surface antigen (HBsAg), antibody against HBV core antigen (anti-HBc), and HBV DNA. Between 2011 and 2015, a total of 22,842 donors were screenedfor HBsAg, anti-HBc, and HBV DNA using the HBsAg Qualitative II kit (Abbott, Ireland Diagnostics Division, Sligo, Ireland), ARCHITECT Anti-hepatitis B core antigen antibody (HBc) II Assay kit (Abbott GmbH & Co. KG, Wiesbaden, Germany), and NAT Procleix Ultrio Elite Assay kit (Grifols Diagnostic Solutions Inc., Los Angeles, CA, USA), respectively. A total of 739 (3.24%) donors were HbsAg(+), anti-HBc(+), or HBV DNA(+); 63 (0.28%) were HbsAg(+), anti-HBc(+), and HBV DNA(+). Twelve (0.05%) were anti-HBc(+) and HBV DNA(+) but HBsAg(-); they were considered to have occult infection. Further, 664 (2.91%) were HBsAg(-) but anti-HBc(+), indicating chronic or resolving infection. HBV prevalence increased significantly from 2011 to 2012, increased marginally till 2013, and showed a decreasing trend from 2013 (P>0.05). The five-year prevalence of HBV infection among blood donors in the Eastern Province of Saudi Arabia (3.24%) is lower than that reported for other regions in the country. The occult HBV infection rate of 0.05% emphasizes the importance of NATs in isolating potential infectious blood units.


Beta-alanine potentiation of [3H]flunitrazepam binding to rat spinal cord homogenates.
The effect of beta-alanine, gamma-aminobutyric acid (GABA), and other functionally related amino acids on [3H]flunitrazepam binding to rat spinal cord homogenates was studied. beta-Alanine potentiated [3H]flunitrazepam binding by 40% and GABA by 88%. Taurine increased the binding by 19%. Hypotaurine produced an 11% increase. No significant effect was seen in glycine, alanine, serine, valine or the dipeptide carnosine. The beta-alanine increase in [3H]flunitrazepam binding was completely inhibited by 10 microM strychnine, whereas the GABA increase required 0.1 mM strychnine to be fully suppressed. Results suggest that beta-alanine specifically potentiates binding of [3H]flunitrazepam in rat spinal cord homogenates.


MAGED4B Promotes Glioma Progression via Inactivation of the TNF-α-induced Apoptotic Pathway by Down-regulating TRIM27 Expression.
MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.


Bridge to transplant with the HeartMate device.
The incidence and prevalence of chronic heart failure continues to increase, with an estimated 400,000 new cases per year in the United States. Cardiac transplantation is an effective therapy but is severely limited to approximately 2300 patients per year due to the donor shortage. With ever increasing waiting times, a significant number of patients become severely debilitated or expire prior to transplantation. A mechanical circulatory support device was first used as a "bridge to transplantation" in 1969. Since then, mechanical devices have increased tremendously in reliability and efficaciousness. The HeartMate left ventricular assist device (LVAD) has been utilized extensively in a bridge to transplant application with excellent results. Patients refractory to aggressive medical management can be sustained reliably until transplantation. In addition, bridging allows for the correction of physiologic and metabolic dearrangements often seen in these severely ill patients prior to transplantation. Nutritional, economic, and quality-of-life issues also favor earlier LVAD placement in refractory patients. This reportsummarizes the overall bridging experience with the HeartMate LVAD and focuses on our experience with this device at Rush-Presbyterian-St. Luke's Medical Center.


Immunofluorescence imaging diagnosis of Fabry heterozygotes using confocal laser scanning microscopy.
An immunofluorometric method was developed for the semiquantitative determination of trihexosylceramide in cultured fibroblasts from Fabry disease patients, using a laser scanning confocal imaging system. The accumulated glycolipid was detected as granular inclusions in the cells. Heterozygote identification was achieved both by counting of immunoreactive cells and by measuring the relative fluorescence intensity with a digital imaging system.