CNS pericytes: concepts, misconceptions, and a way out.
Rouget, in 1873, was the first to describe a population of cells surrounding capillaries, which he regarded as contractile elements. Fifty years later, Zimmermann termed these cells "pericytes" and distinguished three subtypes along the vascular tree. Since then, the discussion concerning the contractile ability of pericytes has never ceased. Current concepts of pericyte biology rather suggest critical roles in the maintenance of homeostasis, blood-brain barrier (BBB) integrity, angiogenesis, and neovascularization. In addition, data from models of brain pathology suggest that novel pericytes are recruited from the bone marrow, but their respective precursor remains enigmatic. Recent data also suggest an important role in the regulation of cerebral blood flow, thus confirming Rouget's original idea. However, comparison of data from different studies is often constrained by the fact that pericytes were questionably identified. Although a clear-cut definition exists, defining pericytes as part of the vascular wall being enclosed in its basement membrane, pericytes are often mixed up with adjacent cell types of the vascular wall, the perivascular space, and the juxtavascular parenchyma. In fact, their identification is difficult-if not impossible-in standard histological sections. An unambiguous distinction, however, is possible at the ultrastructural level and in semi-thin sections, where their location within the vascular basement membrane can be displayed. Using these techniques in combination with immunological staining methods allows demarking their unique morphology and location. Here, we review original papers describing pericytes, briefly outline their topography within the vascular compartments, describe methods for their identification, and summarize current concepts of their function.


The digital rectal examination (DRE) remains important - outcomes from a contemporary cohort of men undergoing an initial 12-18 core prostate needle biopsy.
Indications for prostate needle biopsy (PNB) include elevated serum prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). We evaluated a contemporary cohort of men undergoing PNB to determine cancer detection rates when stratified by DRE status. The charts of 806 men who underwent a PNB were reviewed. Serum PSA was categorized as normal or abnormal according to age-specific criteria. A normal DRE was defined as a smooth, age-appropriate, asymmetric, or uniformly enlarged prostate. An abnormal DRE was defined by either a nodule or induration. Sensitivity, specificity, and predictive values were determined for an abnormal DRE and the diagnosis of prostate cancer. Within the cohort, 516 patients (64%) had a normal and 290 (36%) an abnormal DRE. Three hundred six (38%) men were diagnosed with prostate cancer of which 136 (44%) had an abnormal DRE. Fourteen percent of patients with prostate cancer had an isolated DRE abnormality. Furthermore, when specifically considering these 136 men with an abnormal DRE and prostate cancer, 43 (31%) had a normal age-specific PSA value. No differences in cancer detection rate were noted when stratifying by type of DRE abnormality. In this select cohort of patients undergoing prostate biopsy, an abnormal DRE had a sensitivity of 44%, specificity of 68%, positive predictive value (PPV) of 46%, and a negative predictive value (NPV) of 67% for detecting prostate cancer on biopsy. Almost 50% of men in our cohort diagnosed with prostate cancer had an abnormal DRE. While only 14% of all patients with prostate cancer had an isolated DRE abnormality, 31% of these men had normal age-specific PSA values. Such observations underscore the importance of the DRE for prostate cancer screening.


Relationship between D-Dimer to Lymphocyte Ratio and the Mortality in HBV-Associated Decompensated Cirrhosis.
HBV-associated decompensated cirrhosis (HBV-DC) is hallmarked by high short-term mortality. Accurate non-invasive prognostic tools for these patients are urgent clinical need. Thus, we aimed to explore the relationship between the plasma D-dimer to lymphocyte ratio (DLR) and mortality in HBV-DC patients. A retrospective analysis was conducted on 152 patients with HBV-DC. To estimate disease severity and outcomes, the Model for End-Stage Liver Disease (MELD) score was utilized. The predictive value of the DLR in assessing mortality risk was assessed using multivariate logistic regression analysis and receiver operating characteristic curve analysis. During the 30-day follow-up period, 20 patients died. The DLR was markedly different between non-survivors and survivors and higher DLR was found to be linked with adverse consequences. Furthermore, logistic regression demonstrated DLR as an independent predictive factor of 30-day mortality in HBV-DC patients and the prognostic value of DLR was very similar to that of MELD score, the combinations of DLR and MELD score show a better predictive value than that of a single index. The DLR was a reliable tool to predict 30-day mortality in HBV-DC patients.


The relationship between structural brain imaging and histopathologic findings in schizophrenia research.
The suggestion that schizophrenia may involve a neurodegenerative process has emanated from the highly replicated finding of ventricular enlargement in brain images of patients with this disorder. These investigations have provided a direct impetus for recent histopathologic studies seeking evidence of a neurodegenerative process in the brains of subjects with schizophrenia. Whereas most postmortem studies have reported the presence of atrophy and/or neuronal loss in several corticolimbic regions of subjects with schizophrenia, no quantitative study, to date, has detected an increase in the number of glial cells. For this reason the changes observed in postmortem schizophrenic brain are not consistent with a typical adult pattern of neuronal degeneration, such as that seen in Huntington's disease. Because several studies have reported various changes in layer II of the anterior cingulate, prefrontal, and entorhinal cortices, the histopathologic findings described are compatible with the idea that schizophrenia involves a disturbance of the "inside-out" migration or differentiation of cortical neurons that normally occurs during ontogenesis. A neurodevelopmental perturbation early in life could result in discrete alterations of corticolimbic circuitry that eventually contribute to the appearance of schizophrenic symptoms during adolescence and adulthood.


Two subphenotypes of septic acute kidney injury are associated with different 90-day mortality and renal recovery.
The pathophysiology of septic acute kidney injury is inadequately understood. Recently, subphenotypes for sepsis and AKI have been derived. The objective of this study was to assess whether a combination of comorbidities, baseline clinical data, and biomarkers could classify meaningful subphenotypes in septic AKI with different outcomes. We performed a post hoc analysis of the prospective Finnish Acute Kidney Injury (FINNAKI) study cohort. We included patients admitted with sepsis and acute kidney injury during the first 48 h from admission to intensive care (according to Kidney Disease Improving Global Outcome criteria). Primary outcomes were 90-day mortality and renal recovery on day 5. We performed latent class analysis using 30 variables obtained on admission to classify subphenotypes. Second, we used logistic regression to assess the association of derived subphenotypes with 90-day mortality and renal recovery on day 5. In total, 301 patients with septic acute kidney injury were included. Based on the latent class analysis, a two-class model was chosen. Subphenotype 1 was assigned to 133 patients (44%) and subphenotype 2 to 168 patients (56%). Increased levels of inflammatory and endothelial injury markers characterized subphenotype 2. At 90 days, 29% of patients in subphenotype 1 and 41% of patients in subphenotype 2 had died. Subphenotype 2 was associated with a lower probability of short-term renal recovery and increased 90-day mortality. In this post hoc analysis, we identified two subphenotypes of septic acute kidney injury with different clinical outcomes. Future studies are warranted to validate the suggested subphenotypes of septic acute kidney injury.


Vibrations and static responses of asymmetric bimorph disks of piezoelectric ceramics.
In an earlier article, the flexural vibrations in bimorph disks and extensional vibrations in homogeneous disks of piezoelectric ceramics were studied. In the present paper, the coupled flexural and extensional vibrations and static responses in an asymmetric bimorph disk, which is formed by bonding together two piezoelectric ceramic disks of unequal thickness and opposite polarization, are investigated. Governing equations of coupled motions for asymmetric bimorphs are deduced from the recently derived 2-D, first-order equations for piezoelectric crystal plates with thickness-graded material properties. Then, closed form solutions of these equations for circular disks are obtained for free vibrations, piezoelectrically forced vibrations, and responses under static voltage difference. Resonance frequencies, distribution of displacements and surface charges, impedances, and static responses are calculated for asymmetric bimorph disks of various thickness ratios and diameter-to-thickness ratios. Experimental data on resonances and impedances are obtained for asymmetric bimorph disks of PZT-857 for different thickness ratios. Comparisons of predicted and measured results show that the agreements are close.


Pathogenesis associated with philornid myiasis (Diptera: Muscidae) on nestling pearly-eyed thrashers (Aves: Mimidae) in the Luquillo Rain Forest, Puerto Rico.
Pathogenesis of myiasis due to the muscid fly Philornis deceptivus in nestling pearly-eyed thrashers (Margarops fuscatus) in the Luquillo Rain Forest, Puerto Rico was investigated. Philornid larvae penetrated the host integument, underwent a period of development and growth, and established, as third instar larvae, between the dermis and the body musculature. Movement into this location plus growth and development of the fly larva appeared to be linked to the ingestion of host tissues including red blood cells, mononuclear cells which infiltrated from focal accumulations adjacent to the lesion, and necrotic cellular debris which accumulated in the lesion. The resultant increase in size of the larvae greatly displaced the host integument. Following the evacuation of the larvae for the purpose of pupation, repair of the cavernous lesion was initiated with the production of an intense organized fibrinous exudate. Macrophages and plasma cells predominated with vascular congestion in surrounding tissues. Over the 21-day nest period, nestlings were subject to successive infestations of large numbers of larvae and host responses to these appeared to significantly debit an energy budget responsible for nestling development and growth. Nestling mortality and post fledging survivorship appeared linked to the impact of these energy demands.


Chondrosarcoma--55 unreported cases: epidemiology, surgical treatment and prognostic factors.
Fifty-five cases of chondrosarcoma, seen at the Istituto Nazionale Tumori of Milan, were reviewed to collect epidemiological data in order to verify therapeutic effects and the validity of possible prognostic factors. Epidemiological data according to sex and age distribution and skeletal location were in accordance with the literature (male:female ratio, 1.8; mean age, 37 years, 62% of lesions located in the pelvic or scapular girdle). Of 52 cases operated on with the intent of radicality, 5 were intralesional operations, 20 marginal and 27 radical. The local recurrence rate was dependent upon the degree of surgical radicality (60%, 35% and 11% respectively for intralesional, marginal and radical surgery). Age, site, type of first symptom and pathological grading were significant as prognostic factors. The type of the first symptom was directly correlated to the site of the tumour. Sex, tumour size and degree of surgical radicality were not relevant.


Changes in the risk management of Salmonella enterica subspecies diarizonae serovar 61:(k):1, 5, (7) in Swedish sheep herds and sheep meat due to the results of a prevalence study 2012.
The prevalence of Salmonella in food producing animals is very low in Sweden due to rigorous control programmes. However, no active surveillance is in place in sheep. The authorities decided to perform a prevalence study in sheep herds because findings at slaughter indicated that sheep associated S. diarizonae (S. enterica subspecies diarizonae serovar 61:(k):1, 5, (7)) might be common in sheep. Sampling was stratified by herd size in two groups, small herds with ≤ 30 animals and large herds with > 30 animals. In each stratum, 237 herds were selected at random. Faecal samples received from 244 out of the 474 randomly selected herds were analysed. A total of 40 of 100 (40%) of large herds and 17 of 144 (12%) of small herds were positive. The overall adjusted prevalence was 17.6% (95% CI, 12.9-22.2). Sheep associated S. diarizonae was detected in all counties (n = 21). Scientific opinions and an evaluation of on-farm control measures performed concluded that the impact of sheep associated S. diarizonae on human health is very low, and that risk management measures applied in response to findings of sheep associated S. diarizonae in sheep or sheep meat can be expected to have very little impact on reducing risks to human health. As a result, Swedish authorities decided to make an exemption for sheep associated Salmonella diarizonae in sheep and sheep meat in the current Salmonella control measures. Sheep associated S. diarizonae is endemic in Swedish sheep herds. It is more common in large herds and not limited to certain parts of the country. The responsible authorities concluded that current risk management actions regarding sheep associated S. diarizonae in sheep and sheep meat are not proportional to the risk. This is the first time in the history of the Swedish Salmonella control programme that an exemption from the legislation has been made for a specific serovar. If there is any future indication of an increasing risk, due to e.g. change in the pathogenicity or development of antimicrobial resistance, the risk assessment will be re-evaluated and control measures reinforced if needed.


Minimalist hybrid ligand/receptor-based pharmacophore model for CXCR4 applied to a small-library of marine natural products led to the identification of phidianidine a as a new CXCR4 ligand exhibiting antagonist activity.
Here, we present a minimal hybrid ligand/receptor-based pharmacophore model (PM) for CXCR4, a chemokine receptor deeply involved in several pathologies, such as HIV infection, rheumatoid arthritis, cancer development/progression, and metastasization. This model, considerably simpler than those thus far proposed for this receptor, has been used to search for new CXCR4 inhibitors in a small marine natural product library available at ICB-CNR Institute (Pozzuoli, NA, Italy), since natural products, with their naturally selected chemical and functional diversity, represent a rich source of bioactive scaffolds; computational approaches allow searching for new scaffolds with a minimal waste of possibly precious natural product samples; and our "stripped-down" model substantially increases the probabilities of identifying potential hits even in small-sized libraries. This search, also validated by a systematic virtual screening of the same library, has led to the identification of a new CXCR4 ligand, phidianidine A (PHIA). Docking studies supported PHIA activity and suggested its possible binding modes to CXCR4. Using the CXCR4-expressing/CXCR7-negative GH4C1 cell line we show that PHIA inhibits CXCL12-induced DNA synthesis, cell migration, and ERK1/2 activation. The specificity of these effects was confirmed by the lack of PHIA activity in GH4C1 cells, in which siRNA highly reduces CXCR4 expression and the lack of cytoxicity of PHIA was also verified. Thus, PHIA represents a promising lead for a new family of CXCR4 modulators with wide margins of improvement in potency and specificity offered by the small and very simple underlying PM.


miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.
MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of beta-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.


P selectins and immunological profiles in HCV and Schistosoma mansoni induced chronic liver disease.
Hepatitis C virus (HCV) and Schistosoma mansoni are major causes of chronic liver disease (CLD) in which immune alteration is common. Recent studies suggested that certain platelets and lymphocytes activation markers may have an impact on progression of CLD. This study aimed to evaluate the potential of platelets and lymphocytes activation molecules expression on the pathogenesis of CLD in distinct or concomitant chronic HCV and schistosomiasis mansoni infections. The study populations were divided into group-I: patients with chronic schistosomiasis mansoni, group-II: HCV patients without cirrhosis, group-III: patients with combined liver diseases without cirrhosis, group-IV: patients with chronic HCV and liver cirrhosis and group-V: Age and sex matched healthy individuals as normal controls. All groups were subjected to full clinical evaluation, ELISA anti-HCV antibodies screening, parasitological examination for diagnosing S. mansoni and flow cytometry for lymphocyte (CD3, CD4, CD8, CD19, CD22, & CD56) and platelets activation (CD41, CD42 & CD62P (P- selectins)) markers. The platelet count was significantly decreased in HCV and/or S. mansoni patients. The total T-lymphocytes and T-helper cells were significantly reduced, while T-cytotoxics were increased. The patients possessed a significantly higher platelets activation marker; CD62P (P-selectins) and higher mean fluorescent intensity (MFI) positivity. There were considerable correlations between platelets count and both of CD62P and MFI. Our Findings suggest an increased expression of certain platelets and lymphocytes activation markers in chronic HCV and S. mansoni induced CLD that may have a role in disease progression.


Cardiotoxicity of Anthracyclines.
Cardiotoxicity is a feared side effect that may limit the clinical use of anthracyclines. It may indeed affect the quality of life and survival of patients with cancer, regardless of oncological prognosis. This paper provides an overview of anthracycline-induced cardiotoxicity in terms of definition, classification, incidence, risk factors, possible mechanisms, diagnosis, and treatment. We also report effective strategies for preventing cardiotoxicity. In addition, we discuss limiting current approaches, the need for a new classification, and early cardiotoxicity detection and treatment. Probably, anthracycline-induced cardiotoxicity is a continuous phenomenon that starts from myocardial cell injury; it is followed by left ventricular ejection fraction (LVEF) and, if not diagnosed and cured early, progressively leads to symptomatic heart failure. Anthracycline-induced cardiotoxicity can be detected at a preclinical phase. The role of biomarkers, in particular troponins, in identifying subclinical cardiotoxicity and its therapy with angiotensin-converting enzyme inhibitors (mainly enalapril) to prevent LVEF reduction is a recognized and effective strategy. If cardiac dysfunction has already occurred, partial or complete LVEF recovery may still be obtained in case of early detection of cardiotoxicity and prompt heart failure treatment.


Incidence Rate of Advanced Chronic Kidney Disease Among Privately Insured Adults with Neurodevelopmental Disabilities.
Due to complex medical profiles, adults with neurodevelopmental disabilities (NDDs) may have a heightened risk for early development of chronic kidney disease (CKD) and accelerated CKD progression to advanced stages and kidney failure. The purpose of this study was to estimate the incidence rate of advanced CKD for adults with NDDs and compare the incidence rate to adults without NDDs. Data were used from the Optum Clinformatics® Data Mart to conduct this retrospective cohort study. The calendar year 2013 was used to identify eligible participants: individuals ≥18 years of age and without advanced CKD. Participants were followed from 01/01/2014 to advanced CKD, loss to follow-up, death, or end of the study period (12/31/2017), whichever came first. Diagnostic, procedure, and diagnosis-related group codes identified NDDs (intellectual disabilities, cerebral palsy, autism spectrum disorders), incident cases of advanced CKD (CKD stages 4+), diabetes, cardiovascular diseases, and hypertension present in the year 2013. Crude incidence rates (IR) of advanced CKD and IR ratios (IRR), comparing adults with vs without NDDs (with 95% CI) were estimated. Then, Cox regression estimated the hazard ratio (HR and 95% CI) for advanced CKD, comparing adults with NDDs to adults without NDDs while adjusting for covariates. Adults with NDDs (n=33,561) had greater crude IR of advanced CKD (IRR=1.32; 95% CI=1.24-1.42) compared to adults without NDDs (n=6.5M). The elevated rate of advanced CKD among adults with NDDs increased after adjusting for demographics (HR=2.19; 95% CI=2.04-2.34) and remained elevated with further adjustment for hypertension and diabetes (HR=2.01; 95% CI=1.87-2.15) plus cardiovascular disease (HR=1.84; 95% CI=1.72-1.97). Stratified analyses showed that the risk of advanced CKD was greater for all NDD subgroups. Study findings suggest that adults with NDDs have a greater risk of advanced CKD than do adults without NDDs, and that difference is not explained by covariates used in our analysis.


Oceanobacillus neutriphilus sp. nov., isolated from activated sludge in a bioreactor.
A Gram-stain-positive, neutrophilic, rod-shaped bacterium, strain A1g(T), was isolated from activated sludge of a bioreactor and was subjected to a polyphasic taxonomic characterization. The isolate grew in the presence of 0-17.0 % (w/v) NaCl and at pH 6.0-9.0; optimum growth was observed in the presence of 3.0-5.0 % (w/v) NaCl and at pH 7.0. Strain A1g(T) was motile, formed cream-coloured colonies, was catalase- and oxidase-positive and was able to hydrolyse aesculin, Tween 40 and Tween 60. Chemotaxonomic analysis revealed menaquinone-7 as the predominant respiratory quinone and anteiso-C₁₅:₀, anteiso-C₁₇:₀, iso-C₁₆:₀ and iso-C₁₅:₀ as major fatty acids. The genomic DNA G+C content of strain A1g(T) was 36.3 mol%. Comparative 16S rRNA gene sequence analysis revealed that the new isolate belonged to the genus Oceanobacillus and exhibited closest phylogenetic affinity to the type strains of Oceanobacillus oncorhynchi subsp. incaldanensis (97.9 % similarity) and O. oncorhynchi subsp. oncorhynchi (97.5 %), but less than 97 % sequence similarity with respect to the type strains of other recognized Oceanobacillus species. Levels of DNA-DNA relatedness between strain A1g(T) and reference strains O. oncorhynchi subsp. incaldanensis DSM 16557(T), O. oncorhynchi subsp. oncorhynchi JCM 12661(T) and Oceanobacillus iheyensis DSM 14371(T) were 29, 45 and 38 %, respectively. On the basis of phenotypic and genotypic data, strain A1g(T) is considered to represent a novel species of the genus Oceanobacillus, for which the name Oceanobacillus neutriphilus sp. nov. is proposed. The type strain is A1g(T) (=CGMCC 1.7693(T) =JCM 15776(T)).


Automated two-column purification of iminobiotin and BrdU-labeled PCR products for rapid cloning: application to genes synthesized by polymerase chain assembly.
Polymerase chain assembly (PCA) is a powerful tool for basic biological research and biotechnology applications. During the last several years, major advances have been made in de novo gene synthesis. However, there is still a need for fast and reproducible methods to automatically purify the synthesized genes. Upon completion of PCA, the subsequent PCR-amplified product mixture still contains undesired shorter DNA fragments that hinder cloning efforts. To avoid tedious gel purification, an automated two-column purification has been developed and used in conjunction with rapid PCA. The system enables fast synthesis and isolation of the full-length DNA of interest, important for facile cloning of desired DNA fragments. During the PCR amplification step, forward and reverse primers tagged with iminobiotin and bromodeoxyuridine labels, respectively, were used. The automated purification was then performed on the PCR mixture using two affinity/immunocapture columns in series to isolate only the desired full-length product. The procedure has been applied to the pUC19 beta-lactamase gene (929 bp). Follow-up PCR of the purified product, cloning, and sequencing demonstrated the technique's effectiveness in obtaining the pure full-length gene. The purification has also been performed on other synthesized genes, indicating its utility as a general approach.


'It all depends!': A qualitative study of preferences for place of care and place of death in terminally ill patients and their family caregivers.
It is often suggested that terminally ill patients favour end-of-life care at home. Yet, it is unclear how these preferences are formed, if the process is similar for patients and family caregivers, and if there are discrepancies between preferences for place of care and place of death. Understanding these nuances is essential to support people in their decision-making and ultimately provide better care at the end-of-life. To gain an in-depth understanding of how terminally ill patients and their family caregivers make decisions about preferred place of care and place of death. Semi-structured interviews with patients and family caregivers, which were analysed thematically using qualitative description. A total of 17 participants (8 patients and 9 caregivers) recruited from an acute palliative care hospital ward, a sub-acute hospice unit, and a palliative homecare organisation in Melbourne, Australia. The process of forming location preferences was shaped by uncertainty relating to the illness, the caregiver and the services. Patients and caregivers dealt with this uncertainty on a level of thoughts, emotions, and actions. At the end of this process, patients and caregivers expressed their choices as contextual, personal, relational, conditional and flexible preferences. These findings suggest that in many cases end-of-life decision-making does not conclude with a clear and stable choice. Understanding the reasons for the malleability of preferences and the process of how they are formed has implications for both clinicians and researchers.


Epithelialization of a synthetic polymer in the feline cornea: a preliminary study.
This study examined the potential of a synthetic polymer to support stable epithelial growth when implanted in the feline cornea. A perfluoropolyether-based polymer was cast into lenticules that were coated with collagen I and implanted in four feline corneas. Epithelial growth onto the lenticules was monitored clinically for 6 weeks, after which time the animals were killed, and three corneas were evaluated histologically. Immunohistochemistry was used to identify proteins associated with the formation of a basement membrane (laminin) and adhesion complexes (bullous pemphigoid antigen and collagen VII). Electron microscopy was used to examine the tissue-polymer interface for evidence of the assembly of these adhesive structures. Postoperative epithelial growth began on days 2 to 3, and lenticules were fully epithelialized by days 5 to 9. Lenticules were clinically well tolerated and histology showed epithelium consisting of multiple layers adherent to the lenticule's surface. Laminin, bullous pemphigoid antigen and collagen VII were identified at the tissue-polymer interface using immunohistochemistry. Ultrastructural examination showed evidence of assembly of these proteins into a recognizable basement membrane and hemidesmosomal plaques. A perfluoropolyether-based polymer coated with collagen I was implanted in the feline cornea and supported epithelial growth that showed signs of persistent adhesion, both clinically and histologically. This polymer shows potential for ophthalmic applications that require sustained epithelialization.


Adaptive image region-growing.
Proposes a simple, yet general and powerful, region-growing framework for image segmentation. The region-growing process is guided by regional feature analysis; no parameter tuning or a priori knowledge about the image is required. To decide if two regions should be merged, instead of comparing the difference of region feature means with a predefined threshold, the authors adaptively assess region homogeneity from region feature distributions. This results in an algorithm that is robust with respect to various image characteristics. The merge criterion also minimizes the number of merge rejections and results in a fast region-growing process that is amenable to parallelization.


Single central nervous system lesions can simulate multiple sclerosis.
Three cases are reported in which an initial misdiagnosis of multiple sclerosis was made. In each of these a single central nervous system lesion with space occupying effect was present. These lesions caused confusion because multiple closely running neurological tracts were affected, and there was relapse and remission in the neurological signs and symptoms produced. We conclude that such cases need careful assessment to determine whether a single structural lesion could explain the presentation. Early imaging may show remediable lesions or prevent unnecessary steroid therapy.


Endoscopic endonasal surgical management of chondrosarcomas with cerebellopontine angle extension.
Skull base chondrosarcomas are slow-growing, locally invasive tumors that arise from the petroclival synchondrosis. These characteristics allow them to erode the clivus and petrous bone and slowly compress the contents of the posterior fossa progressively until the patient becomes symptomatic, typically from cranial neuropathies. Given the site of their genesis, surrounded by the petrous apex and the clival recess, these tumors can project to the middle fossa, cervical area, and posteriorly, toward the cerebellopontine angle (CPA). Expanded endoscopic endonasal approaches are versatile techniques that grant access to the petroclival synchondrosis, the core of these lesions. The ability to access multiple compartments, remove infiltrated bone, and achieve tumor resection without the need for neural retraction makes these techniques particularly appealing in the management of these complex lesions. Analysis of the authors' database yielded 19 cases of skull base chondrosarcomas; among these were 5 cases with predominant CPA involvement. The electronic medical records of the 5 patients were retrospectively reviewed for age, sex, presentation, pre- and postoperative imaging, surgical technique, pathology, and follow-up. These cases were used to illustrate the surgical nuances involved in the endonasal resection of CPA chondrosarcomas. The male/female ratio was 1:4, and the patients' mean age was 55.2 ±11.2 years. All cases involved petrous bone and apex, with variable extensions to the posterior fossa and parapharyngeal space. The main clinical scenario was cranial nerve (CN) palsy, evidenced by diplopia (20%), ptosis (20%), CN VI palsy (20%), dysphagia (40%), impaired phonation (40%), hearing loss (20%), tinnitus (20%), and vertigo/dizziness (40%). Gross-total resection of the CPA component of the tumor was achieved in 4 cases (80%); near-total resection of the CPA component was performed in 1 case (20%). Two patients (40%) harbored high-grade chondrosarcomas. No patient experienced worsening neurological symptoms postoperatively. In 2 cases (40%), the symptoms were completely normalized after surgery. Expanded endoscopic endonasal approaches appear to be safe and effective in the resection of select skull base chondrosarcomas; those with predominant CPA involvement seem particularly amenable to resection through this technique. Further studies with larger cohorts are necessary to test these preliminary impressions and to compare their effectiveness with the results obtained with open approaches.


The relaxation exercise and social support trial-resst: study protocol for a randomized community based trial.
Studies suggests a possible link between vaginal discharge and common mental distress, as well as highlight the implications of the subjective burden of disease and its link with mental health. This is a community-based intervention trial that aims to evaluate the impact of a psycho-social intervention on medically unexplained vaginal discharge (MUVD) in a group of married, low-income Lebanese women, aged 18-49, and suffering from low to moderate levels of anxiety and/or depression. The intervention consisted of 12 sessions of structured social support, problem solving techniques, group discussions and trainer-supervised relaxation exercises (twice per week over six weeks). Women were recruited from Hey el Selloum, a southern disadvantaged suburb of Beirut, Lebanon, during an open recruitment campaign. The primary outcome was self-reported MUVD, upon ruling out reproductive tract infections (RTIs), through lab analysis. Anxiety and/or depression symptoms were the secondary outcomes for this trial. These were assessed using an Arabic validated version of the Hopkins Symptoms Checklist-25 (HSCL-25). Assessments were done at baseline and six months using face-to face interviews, pelvic examinations and laboratory tests. Women were randomized into either intervention or control group. Intent to treat analysis will be used. The results will indicate whether the proposed psychosocial intervention was effective in reducing MUVD (possibly mediated by common mental distress). The trial is registered at the Wellcome Trust Registry, ISRCTN assigned: ISRCTN: ISRCTN98441241.


Comparison of non-radiographic axial spondyloarthritis and ankylosing spondylitis patients--baseline characteristics, treatment adherence, and development of clinical variables during three years of anti-TNF therapy in clinical practice.
The relationship between non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) is currently debated. Using observational data from the South Swedish Arthritis Treatment Group register, we thus aimed to compare clinical development and treatment adherence between nr-axSpA and AS patients during three years of anti-TNF (tumor necrosis factor) therapy in clinical practice, and to explore the impact of inflammatory activity measured by CRP (C-reactive protein) at treatment initiation. Nr-axSpA and AS patients (n = 86/238) in southern Sweden, commencing anti-TNF therapy 1999-2011, were followed during three years. Anti-TNF cessation was defined as stopping therapy, without restarting another anti-TNF agent within three months. Differences in the three year developments of patient's visual analogue scale (VAS) scores for global health and pain, EuroQol 5-Dimensions utility, evaluator's global disease activity assessment, CRP, and ESR (erythrocyte sedimentation rate) were assessed by repeated ANOVA. Anti-TNF adherence was compared by Log rank test and Cox regression. In a subanalysis, the same outcomes were studied after splitting both groups into patients with/without baseline CRP elevation. Nr-axSpA patients were more often female and had lower acute phase reactants at baseline. Apart from CRP, which remained lower in the nr-axSpA group throughout follow-up (p = 0.004), no between-group differences were detected regarding clinical developments (p >0.1 for all comparisons) or anti-TNF adherence (hazard ratio: 1.1 (95% CI 0.7 to 1.8) for the nr-axSpA vs. AS group) during three years. Elevated baseline CRP was similarly associated with superior clinical outcomes and treatment adherence in both groups. With the exception of constantly lower CRP levels in the nr-axSpA group, three years anti-TNF therapy resulted in similar clinical outcomes and treatment adherence in nr-axSpA and AS patients, thus strengthening the hypothesis that these diagnoses represent different aspects/phases of the same disease.


Genomic evolution of vesicular stomatitis virus strains with differences in adaptability.
Virus strains with a history of repeated genetic bottlenecks frequently show a diminished ability to adapt compared to strains that do not have such a history. These differences in adaptability suggest differences in either the rate at which beneficial mutations are produced, the effects of beneficial mutations, or both. We tested these possibilities by subjecting four populations (two controls and two mutants with lower adaptabilities) to multiple replicas of a regimen of positive selection and then determining the fitnesses of the progeny through time and the changes in the consensus, full-length sequences of 56 genomes. We observed that at a given number of passages, the overall fitness gains observed for control populations were larger than fitness gains in mutant populations. However, these changes did not correlate with differences in the numbers of mutations accumulated in the two types of genomes. This result is consistent with beneficial mutations having a lower beneficial effect on mutant strains. Despite the overall fitness differences, some replicas of one mutant strain at passage 50 showed fitness increases similar to those observed for the wild type. We hypothesized that these evolved, high-fitness mutants may have a lower robustness than evolved, high-fitness controls. Robustness is the ability of a virus to avoid phenotypic changes in the face of mutation. We confirmed our hypothesis in mutation-accumulation experiments that showed a normalized fitness loss that was significantly larger in mutant bottlenecked populations than in control populations.


cometrics: A New Software Tool for Behavior-analytic Clinicians and Machine Learning Researchers.
Cometrics is a Microsoft Windows compatible clinical tool for the collection and recording of frequency- and duration-based target behaviors, physiological signals, and video data. This software package is designed to record in-vivo observational and physiological data. In addition, we have included features that allow observers to capture video from real-time camera feeds and import saved video for retroactive data collection. By using Microsoft Excel-based spreadsheets, also called keystroke files, assessment and treatment sessions are exported into a single document using the click of a button. Integrated interobserver agreement metrics allow comparisons across primary and reliability observers, with the output exported into a spreadsheet for easy reference. All file system interactions are handled by the user interface, so files and folders are created and managed without manual intervention. This software is available free-of-charge through the Microsoft Store for Windows 10 and 11 and the source code is publicly available on GitHub. The online version contains supplementary material available at 10.1007/s40617-023-00817-w.


miR-212/132 attenuates OVA-induced airway inflammation by inhibiting mast cells activation through MRGPRX2 and ASAP1.
Allergic asthma is a chronic inflammatory disease of airways involving complex mechanisms, including MAS-related GPR family member X2 (MRGPRX2) and its orthologue MRGPRB2 on mast cells (MCs). Although miRNAs have been previously shown to related to allergic asthma, the role of miR-212/132 in this process has not been studied. In this study, the predicted pairing of miRNAs and MRGPRX2 (MRGPRB2) mRNAs was carried out by online databases and the function was verify using in vivo and in vitro experiments. Database prediction showed that miR-212/132 interact with MRGPRX2 and MRGPRB2. miR-212/132 mimics alleviated MRGPRB2 mRNA expression as well as pathology changes in lungs and AHR of mice with airway inflammation in vivo. The expression level of MRGPRB2 in the mice lungs after inhaled OVA was also decreased by miR-212/132 mimics. Meanwhile, miR-212/132 inhibited MCs degranulation and cytokines release triggered by C48/80 in vitro. Further, ASAP1 (ARF GTPase-Activating Protein 1) was selected from the junction related pathways using RNAseq and KEGG enrichment. ASAP1 mRNA level was upregulated in airway inflammation and MCs activation and decreased by miR-212/132 mimics. miR-212/132 attenuated OVA-induced airway inflammation by inhibiting MCs activation through MRGPRX2 and ASAP1.


Advantages of exercise in rehabilitation, treatment and prevention of altered morphological features in knee osteoarthritis. A narrative review.
Knee osteoarthritis (OA) represents one of the most common causes of disability in the world. It leads to social, psychological and economic costs with financial consequences, also because a further increase is expected. Different knee OA treatments are usually considered in relation to the stage of the disease, such as surgical management and pharmacologic and non-pharmacologic treatments. Treatment should begin with the safest and least invasive one, before proceeding to more invasive, expensive ones. Non-pharmacologic, behavioral treatments of knee OA are recommended not only in rehabilitation but also in prevention because many risk factors, such as excess weight, obesity and joint tissue inflammation, can be monitored and thus prevented. In the present review, we analyze data from the most recent literature in relation to the effects of physical exercise on prevention, therapy and rehabilitation in knee OA. All data suggest that physical exercise is an effective, economical and accessible tool to everyone, in the treatment and prevention of knee OA. The literature search was conducted on PubMed, Scopus and Google Scholar using appropriate keywords in relation to knee osteoarthritis.


Stability and change in temperament during adolescence.
This study assessed genetic and environmental contributions to temperament during adolescence within the Nonshared Environment and Adolescent Development project (NEAD; D. Reiss, J. M. Neiderhiser, E. M. Hetherington, & R. Plomin, 2000). NEAD is a national study that includes twins and other sibling types who vary in regard to genetic relatedness. Seven hundred twenty sibling pairs (aged 12.1-13.5 years) participated at Time 1, and 395 sibling pairs (aged 14.7-16.2 years) participated again at Time 2. At both Times, mothers and fathers rated their children's temperament (emotionality, activity, sociability, and shyness). At Times 1 and 2, genetic and nonshared environmental factors accounted for variance in temperament, whereas shared environmental contributions were negligible. However, at Time 1, genetic contributions were inflated, and shared environmental contributions were masked if sibling contrast effects were not taken into account. At Time 2, sibling interaction effects had little impact on estimates of genetic and environmental contributions to temperament. Last, temperament stability was primarily explained by genetic factors, whereas both genetic and nonshared environmental factors accounted for change.


Site-specific gene insertion mediated by a Cre-loxP-carrying lentiviral vector.
Retroviral vectors have been used to treat patients with the X-linked severe combined immunodeficiency disease and chronic granulomatous disease. In both cases, success has been undermined by clonal expansion of transduced cells in some patients due to insertional mutagenesis induced by random vector integration. This outcome underscores the importance of designing vectors for site-specific gene insertion to avoid unanticipated gene disruption or gene activation. In the present study, we incorporated the sequence-specific Cre protein into lentiviral virions. We demonstrated that the virion-associated Cre protein remained enzymatically active and was capable of directing site-specific insertion of a gene in the vector into a defined loxP site in the host genome. As there are loxP-like sequences throughout human genome that can be recognized by either wild-type Cre or Cre variants, our study demonstrates a new strategy of designing lentiviral-based vector for gene targeting.


Parvalbumin and GABA in the developing somatosensory thalamus of the rat: an immunocytochemical ultrastructural correlation.
The calcium binding protein parvalbumin (PV) is widely distributed in the mammalian nervous system and its relationship with GABAergic neurons differs within thalamic nuclei and animal species. In the rat somatosensory thalamus PV immunoreactive (ir) neurons were found only in the GABAergic reticular thalamic nucleus (RT), while a dense PVir neuropil is present in the ventrobasal complex (VB). In this study the distribution and relationship of PV and GABA were investigated in RT and VB during postnatal development at electron microscopic level. The pre-embedding immunoperoxidase detection of PV was combined with the post-embedding immunogold localization of GABA. In RT, at all developmental ages, neuronal cell bodies, dendrites and rare axonal terminals were both PVir and GABAir. In VB during the first postnatal week several small vesicle-containing profiles were double-labelled and some of them were identifiable as synaptic terminals. From postnatal day 7 (P7) to P9 the medial part of VB was more intensely PVir than the lateral one and some differences in the sequence of maturation of PVir terminals were noted between these two VB subdivisions. Single-labelled PVir profiles were first observed at P8, whereas single-labelled PVir terminals appeared at P12 and at P15 they became more frequent and larger, showing the typical morphology of ascending afferents described in adult VB. These results demonstrate the late expression of PV and acquisition of adult morphology in ascending terminals of rat VB during postnatal development in comparison with the innervation arising from the GABAergic RT.


Effects of microbial iron reduction and oxidation on the immobilization and mobilization of copper in synthesized Fe(III) minerals and Fe-rich soils.
The effects of microbial iron reduction and oxidation on the immobilization and mobilization of copper were investigated in a high concentration of sulfate with synthesized Fe(III) minerals and red earth soils rich in amorphous Fe (hydr)oxides. Batch microcosm experiments showed that red earth soil inoculated with subsurface sediments had a faster Fe(III) bioreduction rate than pure amorphous Fe(III) minerals and resulted in quicker immobilization of Cu in the aqueous fraction. Coinciding with the decrease of aqueous Cu, SO4(2-) in the inoculated red earth soil decreased acutely after incubation. The shift in the microbial community composite in the inoculated soil was analyzed through denaturing gradient gel electrophoresis. Results revealed the potential cooperative effect of microbial Fe(III) reduction and sulfate reduction on copper immobilization. After exposure to air for 144 h, more than 50% of the immobilized Cu was remobilized from the anaerobic matrices; aqueous sulfate increased significantly. Sequential extraction analysis demonstrated that the organic matter/sulfide-bound Cu increased by 52% after anaerobic incubation relative to the abiotic treatment but decreased by 32% after oxidation, indicating the generation and oxidation of Cu-sulfide coprecipitates in the inoculated red earth soil. These findings suggest that the immobilization of copper could be enhanced by mediating microbial Fe(III) reduction with sulfate reduction under anaerobic conditions. The findings have an important implication for bioremediation in Cucontaminated and Fe-rich soils, especially in acid-mine-drainage-affected sites.


Primary and delayed closure after open irrigation and debridement of septic arthritis in children.
Seventy-one patients with 83 septic joints due to idiopathic septic arthritis were investigated retrospectively. Forty-three joints were closed primarily while 40 underwent delayed primary closure. Two joints in each group failed treatment and had to be reopened after definitive closure. Joints in patients 7 years of age or older had a substantially higher failure rate (12%), with either primary or delayed closure, than joints in patients younger than 7 years (1.7%). Two of 13 patients with a polymorphonuclear leukocyte count in the synovial fluid greater than 100,000 required repeat debridement after final closure. Three of the four patients who required repeat debridement showed evidence of osteomyelitis. The average length of stay was longer in the delayed primary closure group (7.0 days) than in the primary closure group (5.6 days). This study suggests that primary closure is a viable alternative to delayed primary closure with shorter hospital stays and similar outcomes in children with idiopathic septic arthritis. Care should be taken in children aged 7 and older or when concurrent osteomyelitis exists.


Predictors of somatic symptoms in depressive disorder.
We explored the relative contribution of potential psychological predictors of somatic symptoms in outpatients with major depressive disorder, including; 1) severity of depression; 2) general anxiety; 3) hypochondriacal worry; 4) somatosensory amplification; and, 5) alexithymia by sampling 100 consecutive outpatients with DSM-IV diagnoses of major depressive disorder attending the psychiatry clinics of general hospitals in Turkey. The subjects were rated by clinicians on depressive symptomatology (Hamilton Depression Rating Scale), and anxiety (Hamilton Anxiety Scale), and completed self-report measures of Hypochondriacal worry (7-item version of the Whiteley Index), the Somatosensory Amplification Scale, and the Toronto Alexithymia Scale. Multivariate models tested the independent contribution of each of the scales to the level of somatic symptoms as measured by a modified version of the SCL-90 somatization scale. At the bivariate level, somatic symptoms were associated with female gender and lower educational level, as well as the Hamilton Depression and Anxiety scales, the Whitely Index, and the Somatosensory Amplification and Alexithymia scales. In multiple regression models incorporating all variables, female gender and higher scores on the anxiety, somatosensory amplification and alexithymia scales all made independent contributions to the level of somatic symptoms and accounted for 54% of the variance. Therefore, somatic symptoms in depression are related to concomitant anxiety, tendency to amplify somatic distress, and difficulty identifying and communicating emotional distress. However, these factors do not account for the tendency for women to report more somatic symptoms.


Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2).
Hepatitis C virus (HCV)-infected patients with cirrhosis are historically a difficult-to-treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1-infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open-label, single-arm study (OPTIMIST-2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1-infected treatment-naive or treatment-experienced patients with cirrhosis. Patients (aged 18-70 years) with chronic HCV GT1 infection and documented presence of cirrhosis received oral simeprevir 150 mg once daily + sofosbuvir 400 mg once daily for 12 weeks. The primary efficacy endpoint of the study was the proportion of patients achieving SVR12 versus a composite historical control (SVR12 rate of 70%). Safety and patient-reported outcomes were assessed. Overall, 103 patients received treatment. SVR12 with simeprevir + sofosbuvir (83%, 95% confidence interval 76%-91%) met the primary objective of superiority versus the historical control (70%). SVR12 rates for treatment-naive and treatment-experienced patients were 88% (44/50) and 79% (42/53), respectively. Adverse events occurred in 72 (70%) patients, with most (64%) being grade 1 or 2. Serious adverse events (none considered related to study treatment) occurred in five (5%) patients, and three (3%) patients discontinued all study treatment due to adverse events. Patient-reported outcomes improved from baseline to follow-up week 12. Simeprevir + sofosbuvir for 12 weeks achieved superiority in SVR12 rates versus the historical control in treatment-naive and treatment-experienced HCV GT1-infected patients with cirrhosis and was generally safe and well tolerated. (Hepatology 2016;64:360-369).


Morphologic and histochemical analysis of the newt (Notophthalmus viridescens) liver.
Architectural arrangement, ultrastructure, and selected histochemical properties of the newt (Notophthalmus viridescens) liver were examined. Although hematopoietic tissue (1-4 cells thick) invested the liver, direct vascular communication between this tissue and hepatic parenchyma was not observed. The liver was intensely positive when stained with Oil-red-O and periodic acid-Schiff reagent and connective tissue was limited to large vascular channels and the capsule. A distinctive polarity was observed in the hepatic vascular system when lobes were viewed in cross section. Dorsally, portal venules accompanied arterioles and branches of the biliary system, while tributaries of hepatic veins were observed ventrally. Following perfusion fixation, hepatocytes appeared as sheets of cells 1-5 cells thick; however, lobules as defined in adult mammalian liver were absent. Hepatocytes contained abundant smooth endoplasmic reticulum, mitochondria, electron-dense lysosomes, patches of granular endoplasmic reticulum, and lipid droplets. Continuous endothelial cells lined sinusoids and exhibited fenestrae organized into structures similar to sieve plates observed in mammalian liver. Variable numbers of melanin-containing macrophages and subendothelial macrophages were observed; however, Kupffer cells and lipid containing perisinusoidal fat-storing cells were not seen. Patterns of reaction product for glucose-6-phosphatase (G-6-Pase), glucose-6-phosphate dehydrogenase (G-6-PDH), and succinic dehydrogenase (SDH) were localized in the newt liver. All enzymes exhibited a uniform distribution pattern; however, small punctate regions of intensely positive G-6-PDH cells were noted within hepatic parenchyma. Cells comprising the hematopoietic tissue were intensely positive for G-6-Pase, G-6-PHD, and negative for SDH.


Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions.
RNA localization is important for the establishment and maintenance of polarity in multiple cell types. Localized RNAs are usually transported along microtubules or actin filaments and become anchored at their destination to some underlying subcellular structure. Retention commonly involves actin or actin-associated proteins, although cytokeratin filaments and dynein anchor certain RNAs. RNA localization is important for diverse processes ranging from cell fate determination to synaptic plasticity; however, so far there have been few comprehensive studies of localized RNAs in mammalian cells. Here we have addressed this issue, focusing on migrating fibroblasts that polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. We used a fractionation scheme combined with microarrays to identify, on a genome-wide scale, RNAs that localize in protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. We find that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3' untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the adenomatous polyposis coli (APC) tumour suppressor and the fragile X mental retardation protein (FMRP). APC is required for the accumulation of transcripts in protrusions. Our results suggest a new type of RNA anchoring mechanism as well as a new, unanticipated function for APC in localizing RNAs.


Relationship among alpha-synuclein accumulation, dopamine synthesis, and neurodegeneration in Parkinson disease substantia nigra.
The histologic hallmark of Parkinson disease (PD) is loss of pigmented neurons in the substantia nigra (SN) and locus ceruleus (LC) with accumulation of alpha-synuclein (alphaS). It has been reported that tyrosine hydroxylase (TH)-negative pigmented neurons are present in these nuclei of patients with PD. However, the relationship between TH immunoreactivity and alphaS accumulation remains uncertain. We immunohistochemically examined the SN and LC from patients with PD (n = 10) and control subjects (n = 7). A correlation study indicated a close relationship among decreased TH immunoreactivity, alphaS accumulation, and neuronal loss. In addition, 10% of pigmented neurons in the SN and 54.9% of those in the LC contained abnormal alphaS aggregates. Moreover, 82.3% of pigmented neurons bearing alphaS aggregates in the SN and 39.2% of those in the LC lacked TH immunoreactivity, suggesting that pigmented neurons in the SN have a greater tendency to lack TH activity than those in the LC. Recent studies have shown that this decrease of TH activity leads to a decrease of cytotoxic substances and that decreased dopamine synthesis leads to a reduction of cytotoxic alphaS oligomers. Therefore, the decrease of TH immunoreactivity in pigmented neurons demonstrated here can be considered to represent a cytoprotective mechanism in PD.


Seed-Mediated Synthesis of Metal-Organic Frameworks.
The synthesis of phase-pure metal-organic frameworks (MOFs) is of prime importance but remains a significant challenge because of the flexible and diversified coordination modes between metal ions and organic linkers. In this work, we report the synthesis of phase-pure MOFs via a facile seed-mediated approach. For several "accompanying" pairs of Zr-porphyrinic MOFs that are prone to yield mixtures, by fixing all reaction parameters except introducing seed crystals, MOFs in phase-pure forms have been obtained because the stage of MOF nucleation, which generates mixed nuclei, is bypassed. In addition, phase-pure MOF isomers with distinct pore structures have also been prepared through such an approach, revealing its versatility. To the best of our knowledge, this is an initial report on seed-assisted synthesis of phase-pure MOFs.


A case of bronchiolitis obliterans organising pneumonia associated with SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome.
A 57-year-old woman with SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome presented with recurrent episodes of pneumonia. She was treated with multiple courses of antibiotics with no success. The transbronchial biopsy undertaken via bronchoscopy revealed organising pneumonia (OP). She was treated with steroids and responded well with full clinical recovery and normalisation of her chest X-ray.To our knowledge, this is the first reported case of OP in association with SAPHO syndrome. This case report highlights the importance of considering OP in patients with SAPHO syndrome who present with chest infection.


Reversal of behavioural abnormalities by fetal allografts in a novel rat model of striatonigral degeneration.
We have developed a rodent model of striatonigral degeneration, one of the core pathologies underlying the disease multiple system atrophy (MSA). 6-Hydroxydopamine (6-OHDA) was administered into the left medial forebrain bundle of male Wistar rats, followed 3-4 weeks later by intrastriatal injection of quinolinic acid into the ipsilateral striatum. The 6-OHDA lesion resulted in ipsilateral rotation to (+)-amphetamine and contralateral rotation to apomorphine. Following the subsequent striatal lesion, amphetamine-induced ipsilateral rotation persisted, but apomorphine-induced contralateral rotation was reduced or abolished. Subsequently, the lesioned striatum was implanted with fetal CNS allografts consisting of cell suspensions derived from striatal primordium alone or combined with cografts of ventral mesencephalon. Cografted rats showed a reduction or reversal of amphetamine-induced rotation. This was not observed in animals receiving striatal grafts alone. Apomorphine-induced contralateral rotation was restored after striatal grafts alone, but only partially in animals receiving sham or cografts. Tyrosine hydroxylase (TH) and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP 32) immunocytochemistry showed mesencephalic and striatal graft survival in most animals. However, dopaminergic outgrowth was restricted to the graft deposit. The latter was surrounded by a markedly gliotic glial fibrillary acidic protein-positive capsule continuous with corpus callosum. Dopaminergic reinnervation of denervated and lesioned adult striatum itself was absent, suggesting that rotational recovery was due to diffuse dopamine release. The study shows that combined unilateral lesioning of rodent medial forebrain bundle and striatum results in a characteristic drug-induced rotational response that can be partly restored by mesencephalic/striatal cografts.


Plasma concentrations and dosing of 2 long-acting injectable formulations of aripiprazole.
Maintaining therapeutic plasma concentrations of an antipsychotic agent is essential in preventing relapse of symptoms in schizophrenia. Long-acting injectable (LAI) formulations provide extended exposure to antipsychotic therapy and have been useful in addressing treatment nonadherence. Aripiprazole is an atypical antipsychotic used in the treatment of schizophrenia and is available in 2 chemically different (aripiprazole monohydrate and aripiprazole lauroxil [AL]) and pharmaceutically different LAI formulations (aripiprazole once-monthly 400 mg [AOM 400] and AL). The pharmaceutical difference is that AL, unlike AOM 400, is a prodrug that requires additional metabolic steps to form the active drug aripiprazole. We present data demonstrating that aripiprazole plasma concentrations are similar for AOM 400 and the 882 mg dose of AL when administered once every 4 weeks and that both provide similar therapeutic plasma concentrations of aripiprazole when compared with therapeutic oral doses.


Cytotoxic xanthones from Garcinia pedunculata fruits.
Eight previously undescribed and seven known xanthones were isolated from the fruits of Garcinia pedunculata Roxb. The structures were identified by a variety of spectroscopic methods as well as by comparison with the literature. The isolates showed appreciable cytotoxicity against three human tumor cell lines (HepG2, A549, and MCF-7). Pedunculaxanthone G exhibited inhibitory activities with IC50 values of 12.41, 16.51, and 15.45 μM against the cancer cell lines and induced cell apoptosis in HepG2 cells.


An Accurate Estimate of the Amino Acid Content of Human Milk Collected from Chinese Women Adjusted for Differences in Amino Acid Digestibility.
The amino acid (AA) composition of human milk is used to define the AA requirements of the infant. Thus, it is important that estimates of composition be as complete and accurate as possible. When determining AA composition using standard hydrolysis methods, some AAs are progressively destroyed while others are incompletely released. For accuracy, AA composition needs to be determined using multiple hydrolysis times. The true ileal digestibility of AAs also needs to be taken into consideration. The objective was to bring together AA compositional (determined using multiple hydrolysis intervals) and digestibility data determined using the piglet to give an estimate of the absorbed AA profile of human milk with reference in particular to Asian females. Mature milk was collected from Chinese females. AA analysis using multiple hydrolysis intervals and a nonlinear regression model was used to accurately estimate AA composition. Human milk, as well as a protein-free diet, were fed to piglets (n = 6), and ileal digesta were collected (piglet age, 21 d) to determine the true ileal AA digestibility of AAs in human milk. True ileal AA digestibility coefficients ranged from (mean ± standard error of the mean) 0.61 ± 0.081 for tyrosine to 1.01 ± 0.030 for tryptophan, with a digestibility for total nitrogen of 0.90 ± 0.013. Convergence criteria were met for the modeling for each AA, and the model had a level of significance of P < 0.0001 for each AA. The amount of available AAs (total AA content as per the model prediction multiplied by the true ileal AA digestibility coefficient determined in the piglet) are reported. An estimate of the absorbed AA profile of mature milk collected from Chinese females is provided. For the first time, data is presented for cysteine.


Application of robotics in blood banking.
To demonstrate the feasibility of using robots in blood banking applications several prototype systems were developed. Activities associated with sample testing and component preparation were examined. In one project, a general-purpose laboratory robot (Zymate Laboratory Automation System, Zymark, Inc., Hopkinton, Mass.) was configured to prepare samples for microplate-based ABO/Rh testing. In a second project, this same robot was configured to carry out specific steps in evaluating bar-coded labels, as part of a quality control procedure. A fluid-handling robot (Sampler 505, Tecan AG, Hombrechtikon, Switzerland) was used to prepare the dilution of serum samples for the evaluation of an anti-HTLV-III test kit. It was then configured to aspirate, dilute and dispense samples for anti-HTLV-III and HBsAg testing. This robotic system is now in field trial. The use of large industrial robots for automating component production was also considered. The key element in this design was the development of a fixture that would hold the blood bag set during the balancing, centrifugation and expressing steps. However, a fixture which was capable of performing these operations and that was equivalent in size and adaptable to a standard centrifuge bucket could not be fabricated.


Gas-chromatographic determination of ethylene glycol in serum.
We describe a new gas-chromatographic procedure for ethylene glycol in serum, determined as the cyclic phenylboronate ester. The method is rapid, requires only 100 microL of serum, and either an OV-1 or an OV-17 column is used. The linear dynamic range extends to at least 5000 mg/L, with a lower limit of detection of 10 mg/L. Analytical recovery of ethylene glycol from serum averaged 97% (95-101%) over the concentration range of 250-5000 mg/L. The method demonstrates good precision, with CVs less than 2.5%, over the concentration range 500-2000 mg/L.


[Bilateral breast cancer after Hodgkin disease. Clinical and pathological characteristics and therapeutic possibilities: an analysis of 13 cases].
Though Hodgkin's disease (HD) is one of the malignancies in which considerable progress has been made, long-term side effects have been observed, second primary cancer being the most significant. Several recent reports have indicated an increased risk of breast cancer (BC) in girls and young women among HD patients. In a retrospective multicenter analysis, 63 women treated for HD subsequently developed BC. Results that were obtained in 13 women (21%) who developed either synchronous (five cases) or metachronous (eight cases) BC were analyzed. The median age at diagnosis of HD was 19 years. Seven patients underwent exclusive radiotherapy (RT) (including "mantle" supradiaphragmatic irradiation) and six received concomittant radiation therapy and chemotherapy. The first breast tumor occurred after a median delay of 16 years. According to the TNM classification, we showed nine stage T0 (non palpable lesions), four stage T1, five stage T2, one stage T3, two stage T4 and five stage Tx BC. Seventeen infiltrating carcinomas, two fibrosarcomas and seven ductal carcinomas in situ were observed. Among 15 axillary dissections performed for invasive carcinomas, histological involvement was found in 10 cases. Seventeen tumors were treated by mastectomy and nine patients underwent conservative surgical treatment. With a 70-month median follow-up (range: 15-125), three patients developed locoregional recurrence and four other metastases. At present, eight are alive with no evidence of disease and one died of intercurrent disease. According to previous works, BC represents 6.3 to 9% of all second cancers occurring after HD treatment. The risk is higher in young women treated before 20 years of age, especially before 15 years of age. Factors that favour the development of secondary BC are: supradiaphragmatic irradiation, very young age at treatment, chemotherapy with alkylating agents, and probably genetic factors. We conclude that young women and girls treated for HD should be carefully monitored at least 10 years after the end of the treatment for HD, using clinical examination, mammography and ultrasonography. The optimal rythm of this follow-up is not yet clearly defined. Moreover, after multidisciplinary concertation, we suggest that secondary BC be sometimes treated by conservative radiosurgical approach.


Conditional grandmother effects on age at marriage, age at first birth, and completed fertility of daughters and daughters-in-law in historical Krummhörn.
Based on historical data pertaining to the Krummhörn population (eighteenth and nineteenth centuries, Germany), we compared reproductive histories of mothers according to whether the maternal grandmother (MGM) or the paternal grandmother (PGM) or neither of them was resident in the parents' parish at the time of the mother's first birth. In contrast to effects of PGMs, we discovered conditional differences in the MGM's effects between landless people and wealthier, commercial farmers. Our data indicate that the presence of the MGM only lowers the woman's age at marriage (AAM) and her age at the birth of her first child (AFB) in the case of landless families. However, among commercial farmers, who can generally be characterized by a lower AAM and AFB, we found opposite tendencies for the MGM's effect leading to a relatively small delay in AAM and AFB. Moreover, we also analyzed differences in the completed fertility (i.e., children ever born: CEB). Results indicate that landless families in general do have fewer CEB compared with commercial farmers except for those families in which the MGM has been present. Emphasizing that the adaptiveness of investment decisions should depend on the interaction of genetic, lineage-specific (intrinsic) and ecologically imposed (extrinsic) constraints, we conclude that kin strategies consequently address different fitness components under different conditions.


Which early 'red flag' symptoms identify children with meningococcal disease in primary care?
Symptoms are part of the initial evaluation of children with acute illness, and are often used to help identify those who may have serious infections. Meningococcal disease is a rapidly progressive infection that needs to be recognised early among children presenting to primary care. To determine the diagnostic value of presenting symptoms in primary care for meningococcal disease. Data on a series of presenting symptoms were collected using a parental symptoms checklist at point of care for children presenting to a GP with acute infection. Symptom frequencies were compared with existing data on the pre-hospital features of 345 children with meningococcal disease. UK primary care. The study recruited a total of 1212 children aged under 16 years presenting to their GP with an acute illness, of whom 924 had an acute self-limiting infection, including 407 who were reported by parents to be febrile. Symptom frequencies were compared with those reported by parents of 345 children with meningococcal disease. Main outcome measures were diagnostic characteristics of individual symptoms for meningococcal disease. Five symptoms have clinically useful positive likelihood ratios (LR+) for meningococcal disease: confusion (LR+ = 24.2, 95% confidence interval [CI] = 11.5 to 51.3), leg pain (LR+ = 7.6, 95% CI = 4.9 to 11.9), photophobia (LR+ = 6.5, 95% CI = 3.8 to 11.0), rash (LR+ = 5.5, 95% CI = 4.3 to 7.1), and neck pain/stiffness (LR+ = 5.3, 95% CI = 3.5 to 8.3). Cold hands and feet had limited diagnostic value (LR+ = 2.3, 95% CI = 1.9 to 3.0), while headache (LR+ = 1.0, 95% CI = 0.8 to 1.3), and pale colour (LR+ = 0.3, 95% CI = 0.2 to 0.5) did not discriminate meningococcal disease in children. This study confirms the diagnostic value of classic 'red flag' symptoms of neck stiffness, rash, and photophobia, but also suggests that the presence of confusion or leg pain in a child with an unexplained acute febrile illness should also usually prompt a face-to-face assessment to exclude meningococcal disease. Telephone triage systems and primary care clinicians should consider these as 'red flags' for serious infection.


Natural Variation in RNA m6A Methylation and Its Relationship with Translational Status.
N 6 -methyladenosine (m6A) is the most abundant modification of eukaryotic mRNA. Although m6A has been demonstrated to affect almost all aspects of RNA metabolism, its global contribution to the post-transcriptional balancing of translational efficiency remains elusive in plants. In this study, we performed a parallel analysis of the transcriptome-wide mRNA m6A distribution and polysome profiling in two maize (Zea mays) inbred lines to assess the global correlation of m6A modification with translational status. m6A sites are widely distributed in thousands of protein-coding genes, confined to a consensus motif and primarily enriched in the 3' untranslated regions, and highly coordinated with alternative polyadenylation usage, suggesting a role of m6A modification in regulating alternative polyadenylation site choice. More importantly, we identified that the m6A modification shows multifaceted correlations with the translational status depending on its strength and genic location. Moreover, we observed a substantial intraspecies variation in m6A modification, and this natural variation was shown to be partly driven by gene-specific expression and alternative splicing. Together, these findings provide an invaluable resource for ascertaining transcripts that are subject to m6A modification in maize and pave the way to a better understanding of natural m6A variation in mediating gene expression regulation.


Computational perspectives in the history of science: to the memory of Peter Damerow.
Computational methods and perspectives can transform the history of science by enabling the pursuit of novel types of questions, dramatically expanding the scale of analysis (geographically and temporally), and offering novel forms of publication that greatly enhance access and transparency. This essay presents a brief summary of a computational research system for the history of science, discussing its implications for research, education, and publication practices and its connections to the open-access movement and similar transformations in the natural and social sciences that emphasize big data. It also argues that computational approaches help to reconnect the history of science to individual scientific disciplines.


Effect of different prosthetic abutments on peri-implant soft tissue. A randomized controlled clinical trial.
This randomized clinical trial assessed the effect of three different prosthetic abutments (titanium, gold-hue titanium and zirconia) on peri-implant soft tissue 2 years after treatment in partially edentulous subjects. Baseline data concerning (1) thickness of the buccal peri-implant soft tissue, (2) soft tissue thickness above the bone crest, (3) depth/length of transmucosal pathway, and (4) periodontal biotype at adjacent teeth were collected. The final sample consisted of 47 subjects (21 males, 26 females) with a total of 97 implants. A two-level (patient, implant) statistical model was applied. At the 2-year clinical observation, recession of the gingival margin was observed only at 13% of implants irrespective of the type of abutment. No significant correlation between periodontal biotype at adjacent teeth and peri-implant biotype was observed. Furthermore, none of the investigated variables at patient level (age, gender, implant type, periodontal biotype) or at implant level (keratinized tissue thickness, probing depth, soft tissue thickness) was identified as a significant predictor of recession. In conclusion, this study pointed out that (1) abutment type was not able to influence peri-implant variables after 2 years, and (2) caution should be used in considering periodontal biotype at patient level as a possible indicator of the future peri-implant biotype.


Patterns of changes and diagnostic values of FEF50%, FEF25%-75% and FEF50%/FEF25%-75% ratio in patients with varying control of bronchial asthma.
The pattern of change in FEF50%, FEF25%-75% and FEF50%/FEF25%-75% ratio depends on mechanics of forceful expiration, provided that non-homogenous lung emptying is faithfully recorded in the expiratory flow-volume loops. To assess the potential clinical value of FEF50%, FEF25%-75% and FEF50%/FEF25%-75% ratio as an indicator of bronchial asthma (BA) control. The study involved 75 patients with BA matched for age and gender with 45 non-asthmatic subjects. Based on asthma control test (ACT) and spirometry, asthmatic patients were subdivided into controlled and poorly controlled/uncontrolled. The relationship between FEF50% and FEF25%-75% as well as FEF50%/FEF25%-75% ratio and ACT score were assessed using linear regression. ROC curves were used to assess reliability of FEF25%-75% and FEF50% to diagnose BA in patients with different degree of asthma control. FEF50% correlated strongly with FEF25%-75% (r = 0.989, P < 0.001) and the relationship between the two indices is governed by the formula FEF50% = 1.132* FEF25%-75% - 0.003. There was no significant correlation (r = - 0.159, P = 0.083) between FEF50%/FEF25-75% ratio and ACT score. The diagnostic capability of FEF25%-75% for spirometric diagnosis of BA is only marginally better compared to FEF50% (area under ROC curves were 0.88 and 0.89 respectively, P < 0.001); however, diagnostic power of both spirometric indices deceased with poor BA control. FEF50%/FEF25%-75% has no clinical value as an indicator for BA control. Role of FEF25%-75% in evaluation of BA is marginally better than FEF50%; however, efficiency of both indices declined substantially as BA control worsened.


Health Status in the Islamic Republic of Iran, Middle East and North Africa Countries: Implications for Global Health.
The aim of this study was to evaluate the health status of the Iranians following the sustainable development goals' (SDGs) introduction and the recent health reform implementation in Iran and to compare with those of the Middle East and North Africa region (MENA) and global average. This comparative study used secondary data to investigate socio-demographic and health status indicators. The sources included census, population-based surveys and death registries. Global and regional health status indicators were obtained from international databases including WHO, the World Bank and the Institute for Health Metric and Evaluation (IHME). Life expectancy and human development index improved following the reform implementation. Among causes of death, 74.6% were attributed to non-communicable diseases (NCDs). There was an increasing trend in risk factors for NCDs in Iran, while at the same time neonatal, infant and under-5 mortality rates reduced. Compared to the MENA, Iran has a lower maternal mortality ratio, neonatal, infant, and under-5 mortality rates, and a higher life expectancy. NCDs and road traffic injuries accounted for a larger portion of disability-adjusted life years in Iran compared to the MENA and worldwide. Actions against communicable diseases and road traffic injuries are required together with continued efforts to address NCDs. Although based on the results, Iran has relatively high rankings, there is a need to develop a roadmap to accelerate achieving global health goals and SDGs targets.


Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour.
Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.


Identification of ovine adenovirus types five and six in an epizootic of respiratory tract disease in recently weaned lambs.
Eight hundred fourteen Polypay-cross lambs, 32 to 35 days old, were housed in an isolation barn under semiconfinement conditions. The lambs were observed twice daily for clinical signs of respiratory tract disease. During the 8-week observation period, an epizootic of respiratory tract disease developed, in which the combined morbidity and mortality was approximately 13%. The overall mortality was 4.1%, of which 57.6% was attributable to pneumonia. Pasteurella haemolytica was isolated from 11 (58%) of the 19 lung specimens obtained at necropsy. Serotyping revealed the presence of multiple serotypes: A1, A2, A5, A6, A9, and A12. Viruses with properties consistent with ovine adenovirus were isolated from 36% of the lung specimens. Five of the isolates were selected to determine their antigenic serotype. Results of virus neutralization testing indicated that in this group of lambs, there was concurrent infection with Mastadenovirus ovi type 5 and type 6.


Harris-Benedict Equation and Resting Energy Expenditure Estimates in Critically Ill Ventilator Patients.
In routine practice, assessment of the nutritional status of critically ill patients still relies on traditional methods such as anthropometric measurements, biochemical markers, and predictive equations. To compare resting energy expenditure measured by indirect calorimetry (REEIC) with REE calculated by using the Harris-Benedict equation with 3 different sources of body weight (from bed scale, REEHB1; ideal body weight, REEHB2; and predicted body weight, REEHB3). This study included 205 critically ill patients (115 men, 90 women) evaluated within the first 48 hours of admission and undergoing mechanical ventilation. REE was measured by indirect calorimetry for 30 minutes and calculated by using the Harris-Benedict equation with the 3 sources of body weight. Data were compared by the Bland-Altman method. The values based on ideal and predicted body weight (REEHB2 and REEHB3) did not agree with REEIC. Bland-Altman analysis showed that the limits of agreement varied from +796.1 kcal/d to -559.6 kcal/d for REEHB2 and from +809.2 kcal/d to -564.7 kcal/d for REEHB3. REEIC and REEHB1 (body weight determined by bed scale) agreed the best; the bias was -18.8 kcal/d. However, REEHB1 still overestimated REEIC by +555.3 kcal/d and underestimated it by -593.0 kcal/d. For measuring REE in critically ill patients undergoing mechanical ventilation, calculation via the Harris-Benedict equation, regardless of the source of body weight, cannot be substituted for indirect calorimetry.


Epidemiology of hospital-based emergency department visits due to sports injuries.
Sports-related injuries in adolescents incur a significant amount of hospital resources. Sports-related injuries are not an uncommon cause of ED visit; however, national estimates of such injuries in teenagers are unknown. The aim of this study was to identify and characterize emergency department (ED) visits that result from sports-related injuries among teenagers across the United States. This study describes the outcomes associated with sports-related injuries necessitating ED visits among teenagers at a national level. This is a descriptive epidemiology study. The 2008 Nationwide Emergency Department Sample data set, the largest all-payer health care database in the United States, was used to identify ED visits with external cause of injury related to sports occurring in patients aged 13 through 19 years. Outcomes examined included discharge status after the ED visit and presence of concomitant injuries. Descriptive statistics was used to summarize the estimates. Nationwide representative estimates were computed using the discharge weight variable. There were 432,609 ED visits by those between the ages of 13 and 19 years who experienced sports-related injuries, with total charges close to $447.4 million, with a mean total per-visit charge of $1205. The male patients accounted for 76.8% of the total ED visits. The most frequently occurring injuries were superficial injury or contusion (n = 118,250 ED visits); sprains and strains (n = 105,476); fracture of the upper limb (n = 63,151); open wounds of the head, the neck, and the trunk (n = 46,176); as well as intracranial injury (n = 30,726). Close to 29% of all ED visits occurred among those residing in geographical areas with median household income levels of greater than $64,000. After the ED visit, 1.6% were admitted to the same hospital, with a mean length of stay of 2.4 days and a mean hospital charge for ED visit and inpatient services of $22,703. The male patients composed 87.5% of the hospitalizations. The total of hospitalization charges across the entire United States was $154.8 million. Sports injuries account for a substantial number of 2008 teenage ED visits in the United States. Patient- and hospital-level characteristics were analyzed and highlighted.


The yin, the yang, and the angiopoietin-1.
Twenty years after the discovery of the vascular endothelial Tie receptor tyrosine kinases and 15 years after the discovery of the Tie2 ligand, angiopoietin-1 (Angpt1, also known as Ang1), a study published in the current issue of the JCI reveals an unexpected loss-of-function phenotype of mice conditionally deleted of the Angpt1 gene. The results suggest that Angpt1 is needed as a vascular stabilizing factor that organizes and limits the angiogenesis response and protects from pathological consequences, such as tissue fibrosis.


Computational and structural evidence for neurotransmitter-mediated modulation of the oligomeric states of human insulin in storage granules.
Human insulin is a pivotal protein hormone controlling metabolism, growth, and aging and whose malfunctioning underlies diabetes, some cancers, and neurodegeneration. Despite its central position in human physiology, the in vivo oligomeric state and conformation of insulin in its storage granules in the pancreas are not known. In contrast, many in vitro structures of hexamers of this hormone are available and fall into three conformational states: T6, T3Rf3, and R6 As there is strong evidence for accumulation of neurotransmitters, such as serotonin and dopamine, in insulin storage granules in pancreatic β-cells, we probed by molecular dynamics (MD) and protein crystallography (PC) if these endogenous ligands affect and stabilize insulin oligomers. Parallel studies independently converged on the observation that serotonin binds well within the insulin hexamer (site I), stabilizing it in the T3R3 conformation. Both methods indicated serotonin binding on the hexamer surface (site III) as well. MD, but not PC, indicated that dopamine was also a good site III ligand. Some of the PC studies also included arginine, which may be abundant in insulin granules upon processing of pro-insulin, and stable T3R3 hexamers loaded with both serotonin and arginine were obtained. The MD and PC results were supported further by in solution spectroscopic studies with R-state-specific chromophore. Our results indicate that the T3R3 oligomer is a plausible insulin pancreatic storage form, resulting from its complex interplay with neurotransmitters, and pro-insulin processing products. These findings may have implications for clinical insulin formulations.


SAFA: semi-automated footprinting analysis software for high-throughput quantification of nucleic acid footprinting experiments.
Footprinting is a powerful and widely used tool for characterizing the structure, thermodynamics, and kinetics of nucleic acid folding and ligand binding reactions. However, quantitative analysis of the gel images produced by footprinting experiments is tedious and time-consuming, due to the absence of informatics tools specifically designed for footprinting analysis. We have developed SAFA, a semi-automated footprinting analysis software package that achieves accurate gel quantification while reducing the time to analyze a gel from several hours to 15 min or less. The increase in analysis speed is achieved through a graphical user interface that implements a novel methodology for lane and band assignment, called "gel rectification," and an optimized band deconvolution algorithm. The SAFA software yields results that are consistent with published methodologies and reduces the investigator-dependent variability compared to less automated methods. These software developments simplify the analysis procedure for a footprinting gel and can therefore facilitate the use of quantitative footprinting techniques in nucleic acid laboratories that otherwise might not have considered their use. Further, the increased throughput provided by SAFA may allow a more comprehensive understanding of molecular interactions. The software and documentation are freely available for download at http://safa.stanford.edu.


Beneficial Effects of Adding Topical Atorvastatin 5% Cream to Topical Betamethasone 1% Ointment on Chronic Hand Eczema.
Hand eczema (HE) refers to a common inflammatory dermatological condition. Several studies have shown that statins may have anti-inflammatory effects. This study aimed at investigating the efficacy of adding topical atorvastatin to topical betamethasone in the treatment of chronic HE. This randomized, double-blind, placebo-controlled research was done between October 2017 and August 2018 in Hamadan, Iran. Of 130 cases treated for HE, 88 were randomly assigned to groups receiving either betamethasone 1% ointment plus atorvastatin 5% cream (n = 44) or betamethasone 1% ointment plus vehicle cream (n=44). Both groups applied their medications twice a day for 10 days. The primary outcome was changes in the severity of HE, assessed by hand eczema severity index (HECSI). The secondary outcomes were changes in itching evaluated via visual analogue scale (VAS) and quality of life examined through dermatology life quality index (DLQI). Seventy-two out of 88 eligible cases completed the study. The mean HECSI scores decreased in both groups after the intervention, although the change in HECSI was greater in the atorvastatin group (adjusted mean difference [AMD]: 5.756; 95% CI: 5.168 to 6.344, P<0.001). The mean VAS scores decreased in both groups after the intervention, although the change in VAS was greater in the atorvastatin group (AMD: 10.535; 95% CI: 7.005 to 14.064, P<0.001). Treatment with topical atorvastatin was more effective in improving DLQI (AMD: 1.990; 95% CI: 1.821 to 2.158, P<0.001). Addition of topical atorvastatin to topical betamethasone is beneficial in treatment of chronic HE. Identifier: IRCT2017070922965N10; https://www.irct.ir/.


Pathogenic mechanisms of human immunodeficiency virus (HIV)-associated pain.
Chronic pain is a prevalent neurological complication among individuals living with human immunodeficiency virus (PLHIV) in the post-combination antiretroviral therapy (cART) era. These individuals experience malfunction in various cellular and molecular pathways involved in pain transmission and modulation, including the neuropathology of the peripheral sensory neurons and neurodegeneration and neuroinflammation in the spinal dorsal horn. However, the underlying etiologies and mechanisms leading to pain pathogenesis are complex and not fully understood. In this review, we aim to summarize recent progress in this field. Specifically, we will begin by examining neuropathology in the pain pathways identified in PLHIV and discussing potential causes, including those directly related to HIV-1 infection and comorbidities, such as antiretroviral drug use. We will also explore findings from animal models that may provide insights into the molecular and cellular processes contributing to neuropathology and chronic pain associated with HIV infection. Emerging evidence suggests that viral proteins and/or antiretroviral drugs trigger a complex pathological cascade involving neurons, glia, and potentially non-neural cells, and that interactions between these cells play a critical role in the pathogenesis of HIV-associated pain.


Short-term complexity of cardiac autonomic control during sleep: REM as a potential risk factor for cardiovascular system in aging.
Sleep is a complex phenomenon characterized by important modifications throughout life and by changes of autonomic cardiovascular control. Aging is associated with a reduction of the overall heart rate variability (HRV) and a decrease of complexity of autonomic cardiac regulation. The aim of our study was to evaluate the HRV complexity using two entropy-derived measures, Shannon Entropy (SE) and Corrected Conditional Entropy (CCE), during sleep in young and older subjects. A polysomnographic study was performed in 12 healthy young (21.1±0.8 years) and 12 healthy older subjects (64.9±1.9 years). After the sleep scoring, heart period time series were divided into wake (W), Stage 1-2 (S1-2), Stage 3-4 (S3-4) and REM. Two complexity indexes were assessed: SE(3) measuring the complexity of a distribution of 3-beat patterns (SE(3) is higher when all the patterns are identically distributed and it is lower when some patterns are more likely) and CCE(min) measuring the minimum amount of information that cannot be derived from the knowledge of previous values. Across the different sleep stages, young subjects had similar RR interval, total variance, SE(3) and CCE(min). In the older group, SE(3) and CCE(min) were reduced during REM sleep compared to S1-2, S3-4 and W. Compared to young subjects, during W and sleep the older subjects showed a lower RR interval and reduced total variance as well as a significant reduction of SE(3) and CCE(min). This decrease of entropy measures was more evident during REM sleep. Our study indicates that aging is characterized by a reduction of entropy indices of cardiovascular variability during wake/sleep cycle, more evident during REM sleep. We conclude that during aging REM sleep is associated with a simplification of cardiac control mechanisms that could lead to an impaired ability of the cardiovascular system to react to cardiovascular adverse events.