Magnetospirillum bellicus sp. nov., a novel dissimilatory perchlorate-reducing alphaproteobacterium isolated from a bioelectrical reactor.
Previously isolated dissimilatory perchlorate-reducing bacteria (DPRB) have been primarily affiliated with the Betaproteobacteria. Enrichments from the cathodic chamber of a bioelectrical reactor (BER) inoculated from creek water in Berkeley, CA, yielded a novel organism most closely related to a previously described strain, WD (99% 16S rRNA gene identity). Strain VDY(T) has 96% 16S rRNA gene identity to both Magnetospirillum gryphiswaldense and Magnetospirillum magnetotacticum, and along with strain WD, distinguishes a clade of perchlorate-reducing Magnetospirillum species in the Alphaproteobacteria. In spite of the phylogenetic location of VDY(T), attempted PCR for the key magnetosome formation genes mamI and mamL was negative. Strain VDY(T) was motile, non-spore forming, and, in addition to perchlorate, could use oxygen, chlorate, nitrate, nitrite, and nitrous oxide as alternative electron acceptors with acetate as the electron donor. Transient chlorate accumulation occurred during respiration of perchlorate. The organism made use of fermentation end products, such as acetate and ethanol, as carbon sources and electron donors for heterotrophic growth, and in addition, strain VDY(T) could grow chemolithotrophically with hydrogen serving as the electron donor. VDY(T) contains a copy of the RuBisCo cbbM gene, which was expressed under autotrophic but not heterotrophic conditions. DNA-DNA hybridization with strain WD confirmed VDY(T) as a separate species (46.2% identity), and the name Magnetospirillum bellicus sp. nov. (DSM 21662, ATCC BAA-1730) is proposed.


Aceriphyllic acid A, A new ACAT inhibitory triterpenoid, from Aceriphyllum rossii.
Two new triterpenoids along with three known ones, 3-oxoolean-12-en-27-oic acid (1), 3alpha-hydroxyolean-12-en-27-oic acid (2) and 3beta-hydroxyolean-12-en-27-oic acid (3), were isolated from Aceriphyllum rossii. The structures of the new compounds were determined to be a 3alpha,23-dihydroxyolean-12-en-27-oic acid (4) and a 3alpha,23-dihydroxyolean-12-en-29-oic acid (5) by spectroscopic and chemical methods; they were designated aceriphyllic acids A and B, respectively. Compounds 2, 3 and 4 remarkably inhibited the activity of ACAT.


Patent review: therapeutic applications for antisense oligonucleotides 1999-2000.
Over 200 patents disclosing antisense sequences have been published in the last year. 30 Of these, in which a therapeutic application is claimed, have been reviewed in this article. We have classified these under the headings of antibacterial, antiviral, inflammation, cardiovascular, apoptosis and anticancer. Although not exhaustive or covering all diseases, major areas of antisense research have been addressed.


American Cocker Spaniel chronic hepatitis in Japan.
American Cocker Spaniels are predisposed to chronic hepatitis. To describe the clinical and histological features of chronic hepatitis in Japanese American Cocker Spaniels. Thirteen cases examined from 2003 to 2009. Retrospective study. Medical records were searched for American Cocker Spaniels with chronic liver diseases. History, physical examination, clinicopathologic features, hepatic ultrasonographic findings, hepatic histopathology, and immunohistochemistry were evaluated. The median age was 4.6 (1.9-10.7) years. Clinical signs included inappetence (11/13), ascites (11/13), lethargy (9/13), diarrhea (7/13), and melena (2/13). Only 1/13 dogs was jaundiced. Clinicopathological abnormalities were increased liver enzymes (gamma-glutamyl transpeptidase: 9/12, aspartate aminotransferase: 7/10, alanine aminotransferase: 6/13, alkaline phosphatase: 6/13), increased total serum bile acid concentrations (10/12), and hypoalbuminemia (10/13). The liver had an irregular surface in all dogs and acquired portosystemic collaterals were verified in 11/13 dogs by abdominal ultrasound (2), laparoscopy (4), or both (5). Liver histology revealed severe fibrosis and cirrhosis in all cases, subdivided in lobular dissecting hepatitis (7), periportal fibrosis (1), micronodular cirrhosis (3), and macronocular cirrhosis (2). Inflammatory activity was low to mild. Immunohistochemical stains showed ductular proliferation. The median survival time was 913 (range: 63-1981) days. Hepatitis in Japanese American Cocker Spaniels is clinically silent until an advanced stage and is associated with severe hepatic fibrosis leading to cirrhosis, extensive ductular/putative hepatic progenitor cell proliferation, portal hypertension, and acquired portosystemic collateral shunting, but relatively long survival times. Lobular dissecting hepatitis seems more prevalent than in previously reported cases from other countries.


Investigation of the 1758G>C and 2880A>G variants within the NCOA3 gene in a breast cancer affected Australian population.
NCOA3 is a known low to moderate-risk breast cancer susceptibility gene, amplified in 5-10% and over expressed in about 60% of breast tumours. Additionally, this over expression is associated with Tamoxifen resistance and poor prognosis. Previously, two variants of NCOA3, 1758G>C and 2880A>G have been associated with breast cancer in two independent populations. Here we assessed the influence of the two NCOA3 variants on breast cancer risk by genotyping an Australian case-control study population. 172 cases and 178 controls were successfully genotyped for the 1758G>C variant and 186 cases and 182 controls were successfully genotyped for the 2880A>G variant using high-resolution melt analysis (HRM). The genotypes of the 1758G>C variant were validated by sequencing. χ(2) tests were performed to determine if significant differences exist in the genotype and allele frequencies between the cases and controls. χ(2) analysis returned no statistically significant difference (p>0.05) for genotype frequencies between cases and controls for 1758G>C (χ(2)=0.97, p=0.6158) or 2880A>G (χ(2)=2.09, p=0.3516). Similarly, no statistical difference was observed for allele frequencies for 1758G>C (χ(2)=0.07, p=0.7867) or 2880A>G (χ(2)=0.04, p=0.8365). Haplotype analysis of the two SNPs also showed no difference between the cases and the controls (p=0.9585). Our findings in an Australian Caucasian population composed of breast cancer sufferers and an age matched control population did not support the findings of previous studies demonstrating that these markers play a significant role in breast cancer susceptibility. Here, no significant difference was detected between breast cancer patients and healthy matched controls by either the genotype or allele frequencies for the investigated variants (all p ≥ 0.05). While an association of the two variants and breast cancer was not detected in our case-control study population, exploring these variants in a larger population of the same kind may obtain results in concordance with previous studies. Given the importance of NCOA3 and its involvement in biological processes involved in breast cancer and the possible implications variants of the gene could have on the response to Tamoxifen therapy, NCOA3 remains a candidate for further investigations.


Albuminuria and the renin-angiotensin system gene polymorphisms in type-2-diabetic and in normoglycemic hypertensive Chinese.
Albuminuria predicts nephropathy-related mortality in Caucasian and Chinese populations. The involvement of renin-angiotensin system (RAS) gene polymorphisms in the pathogenesis of nephropathy has been described predominantly in Caucasian populations. We have previously suggested that the angiotensinogen 235T variant may be associated with nephropathy in diabetic Chinese. To validate these findings and extend them to include non-diabetic nephropathy, we examined the association of albuminuria and gene polymorphisms of the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type I receptor A1166C polymorphisms in 614 Chinese subjects (66% type 2 diabetic, 16% normoglycemic hypertensives and 18% controls). Obesity and higher blood pressure were associated with albuminuria in both diabetes and normoglycemic hypertension. In the diabetic group, albuminuria was also associated with increased insulin resistance and glycemic indices, duration of diabetes and adverse lipid profiles. Only the ACE gene polymorphism showed evidence of association with albuminuria, with the D allele being less frequent in the normoglycemic hypertensive patients with albuminuria (25.0%) than the controls (41.4%) or normoalbuminuric group (39.6%) and in those hypertensives at increased risk (albumin-to-creatinine ratio > 5.6 mg/mmol) of end-stage renal disease than those at lower risk (all p < 0.05), but not in the diabetic group. The D allele was also less prevalent in the total (31.9%) and normoalbuminuric (32.2%) diabetic groups than in the controls (p < 0.05). In this cohort of Chinese subjects, the ACE gene polymorphism D allele was less frequent in normoglycemic hypertensive patients with albuminuria and in type 2 diabetes.


Short term effect of feedback on fitness and health measurements on self reported appraisal of the stage of change.
An individual's current status of physical activity and nutrition and readiness to change can be determined using PACE assessment forms. Practitioners have suggested that feedback on the fitness and health components can produce a change in a subject's awareness of their behaviour and thereby lead to a beneficial change in stage of behaviour change. To evaluate the short term effect of personalised feedback on fitness and health status on self reported appraisal of the stage of change. A total of 299 civil servants were randomised to an intervention or a reference group. After having been tested for fitness and health, the intervention group received immediate feedback on their test results, whereas the reference group did not. PACE assessment forms were completed twice: before testing and after testing (reference group), or after testing and feedback (intervention group). The time interval between was one hour. The influence of feedback was determined using a x(2) test and analysis of variance. On the basis of the x(2) test, no significant effect of feedback was found on the stage of change of physical activity, nor on the stage of change with regard to nutrition. Analysis of variance results showed no significant effect on the raw PACE score as to physical activity, intake of fruit and vegetables and dietary fat. However, a significant effect was observed on the PACE score of "calorie intake and weight management". Subjects in the intervention group significantly more often regressed on their PACE score on this topic than the reference subjects. Feedback at baseline on measurements of an intervention study can influence PACE scores and can be considered as a small but relevant start of the intervention itself.


Mitochondrial pAL2-1 plasmid homologs are senescence factors in Podospora anserina independent of intrinsic senescence.
Since the first description of a linear mitochondrial plasmid in Podospora anserina, pAL2-1, and homologous plasmids have gone from being considered beneficial longevity plasmids, via neutral genetic elements, toward mutator plasmids causing senescence. The plasmid has an invertron structure, with terminal inverted repeats and encodes a DNA and a RNA polymerase. Here we test whether pAL2-1 homologs cause rapid aging independent of intrinsic and external conditions. We first analyzed a natural population of P. anserina and in 40% of the 112 isolates we detected pAL2-1 homologous plasmids. Though the lifespan varied considerably among the strains, plasmid-infected wild-type strains are on average shorter lived than plasmid-free strains and typically show a reduced lifespan extending effect of calorie restriction (CR). However, interesting exceptions were found, inviting further study. To further investigate the effect of pAL2-1 homologs under various conditions, we constructed and analyzed isogenic lines with and without the plasmid. We found that the presence of pAL2-1 homologs did not significantly affect growth rate as suggested by the population analysis, but reduced lifespan under all conditions. This effect was particularly clear for the lifespan extending conditions tested (CR, low temperature, antibiotics) supporting the idea that pAL2-1 homologs are additional senescence factors independent of the intrinsic senescence determinants.


Hydroxyapatite fractionation procedures in the study of the mammalian genome.
Three methods of fractionating DNA are described, in which DNA fragments are separated on the basis (1) of their base composition, (2) of the ability of denatured DNA to renature after incubation, and (3) of the presence of intrastrand secondary structure in denatured DNA. The ability of some of these fractions to form specific duplexes with whole denatured DNA isolated from the same and from a different mammal has been investigated. The results are presented to demonstrate how the fractionation procedures described may provide new information about the organization of the mammalian genome.


[Misuse of trihexyphenidyl (Artane, Parkinane): recent trends].
Recent observations suggest the existence of trihexyphenidyl abuse linked to its hallucinogenic and euphoric effects. In order to determine the importance of this practice and the characteristics of those involved, a study based on data from the Provence-Alpes-Côte-d'Azur and the Corsica health reimbursement system was carried out. Individuals from these regions affiliated to the French health reimbursement system who had a prescription for trihexyphenidyl (Artane, Parkinane) reimbursed between January 1, 2001, and February 15, 2001, were selected. The delivery of prescriptions was monitored over a 9-month period. In total, 3028 subjects were selected. A subgroup comprising 2.1% of subjects with deviant behaviour was identified by factorial analysis and compared with the subgroup without deviant behaviour. The subjects with deviant behaviour were young and mostly male. The dosage of trihexyphenidyl was higher in these subjects (28 mg/day versus 7 mg/day) and a greater proportion used benzodiazepine and high-dose buprenorphine compared with those without deviant behaviour. The number of prescriptions delivered was higher (23.0 versus 7.7) as well the number of different physicians (4.9 versus 1.5) and pharmacies (5.0 versus 1.3) for those subjects with deviant behaviour. This study confirms the abuse and dependence potential associated with trihexyphenidyl use and the need to increase the supervision of this drug.


The prognostic role of inflammatory markers in patients with metastatic colorectal cancer treated with bevacizumab: A translational study [ASCENT].
In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed. An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS. Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group. Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR. ClinicalTrials.gov: NCT01588990; posted May 1, 2012.


Power generation using adjustable Nafion/PTFE mixed binders in air-cathode microbial fuel cells.
Nafion, poly(tetrafluoroethylene) (PTFE) and polymers made of Nafion-PTFE mixture (Nafion and PTFE ratios of 1:2 and 2:1) were examined as catalyst binders in air-cathode microbial fuel cells (MFCs). MFC tests showed that the maximum power density (from 549 to 1060 mW/m2) increased with the increase of Nafion percentage in binders (from 0% to 100%). Multi-cycle tests (25 cycles) showed that the maximum voltages decreased by 4-6% with simultaneous increase in Coulombic efficiency in all MFCs using various binders (from 20% to 29% with Nafion binder; from 17% to 26% with other binders), indicating that adjustable Nafion/PTFE mixed polymers were applicable in MFCs as catalyst binders when considering both cost and performance of cathodes.


Avian influenza H5N1 virus infections in vaccinated commercial and backyard poultry in Egypt.
In this paper, we describe results from a high-pathogenic H5N1 avian influenza virus (AIV) surveillance program in previously H5-vaccinated commercial and family-backyard poultry flocks that was conducted from 2007 to 2008 by the Egyptian National Laboratory for Veterinary Quality Control on Poultry Production. The real-time reverse transcription PCR assay was used to detect the influenza A virus matrix gene and detection of the H5 and N1 subtypes was accomplished using a commercially available kit real-time reverse transcription PCR assay. The virus was detected in 35/3,610 (0.97%) and 27/8,682 (0.31%) of examined commercial poultry farms and 246/816 (30%) and 89/1,723 (5.2%) of backyard flocks in 2007 and 2008, respectively. Positive flocks were identified throughout the year, with the highest frequencies occurring during the winter months. Anti-H5 serum antibody titers in selected commercial poultry ranged from <2 (negative) to 9.6 log(2) when determined in the hemagglutination inhibition test using a H5 AIV antigen. In conclusion, despite the nationwide vaccination strategy of poultry in Egypt to combat H5N1 AIV, continuous circulation of the virus in vaccinated commercial and backyard poultry was reported and the efficacy of the vaccination using a challenge model with the current circulating field virus should be revised.


Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression.
Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostimulatory effectiveness of interleukin 1alpha (IL-1alpha) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunotherapeutic effects of short-term expression of IL-1alpha by malignant T lymphoma cells. Activation in culture of T lymphoma cells with lipopolysaccharide-stimulated macrophages induces the expression of IL-1alpha. The short-term expression of IL-1alpha persists in the malignant T cells for a few days (approximately 3-6 days) after termination of the in vitro activation procedure and, thus, has the potential to stimulate antitumor immune responses in vivo. As an experimental tumor model, we used the RO1 invasive T lymphoma cell line. Upon i.v. inoculation, these cells invade the vertebral column and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1alpha in a short-term manner, manifested reduced tumorigenicity: approximately 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because injection of activated RO1 cells together with IL-1-specific inhibitors, i.e., the IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tumorigenicity patterns and led to progressive tumor growth and death of the mice. Furthermore, activated RO1 cells could serve as a treatment by intervening in the growth of violent RO1 cells after tumor take. Thus, when activated RO1 cells were injected 6 or 9 days after the inoculation of violent cells, mortality was significantly reduced. IL-1alpha, in its unique membrane-associated form, in addition to its cytosolic and secreted forms, may represent a focused adjuvant for potentiating antitumor immune responses at low levels of expression, below those that are toxic to the host. Further assessment of the immunotherapeutic potential of short-term expression of IL-1alpha in activated tumor cells may allow its improved application in the treatment of malignancies.


Early pediatric formulation development with new chemical entities: Opportunities of e-tongue besides human taste assessment.
The palatability of a pediatric drug formulation is one of the key prerequisites for therapeutic success. Liquid formulations are often chosen for pediatric drug products, and they require special attention regarding their taste, as they have direct contact to the taste buds and a relatively long residence time in the oral cavity. For ethical reasons, the role of electronic tongues in the development of oral drug formulations with new chemical entities (NCEs) for pediatric use is growing, however, little is known about the strategies how this instrumental taste assessment can be performed. The present study illustrates two possibilities to combine in-vitro and in-vivo data for the characterization of the palatability of the new drug candidates CSE3104 and CSE3165. As a first step, the implementation and suitability of electronic tongue measurements has been demonstrated by comparison of in-vivo and in-vitro data. In alignment with the taste assessment results during a single-center, double-blinded, randomized, placebo-controlled, single ascending dose (SAD) study in healthy subjects, the bitter taste perception of CSE3104 was assessed with e-tongue measurements. Moreover, the sensor response pattern showed comparable results of the e-tongue measurements to the human taste study of CSE3165: With increasing concentration, the bitterness values were increased. In addition, the human taste pattern showed increasing values for sourness due to higher volumes of the citric acid buffer. Results of the hedonic descriptor "unpleasant" within the human taste assessments could be related to bitterness in the instrumental taste assessment. For the second step in electronic tongue guided formulation development two possibilities are depicted in the article focusing on the effect of different excipients on the formulation on the one hand and on the assessment and comparison of two drug formulations on the other hand. Based on these results, the low number of healthy volunteers for the taste assessment in a Phase 1 study led to a meaningful interpretation, by applying in addition the electronic tongue. Using this instrumental approach led to reproducible data versus the human taste assessment, without ethical concerns, and with a reduction in time and costs.


Molecular Cytogenetic Analysis of the European Hake Merluccius merluccius (Merlucciidae, Gadiformes): U1 and U2 snRNA Gene Clusters Map to the Same Location.
The European hake (Merluccius merluccius) is a highly valuable and intensely fished species in which a long-term alive stock has been established in captivity for aquaculture purposes. Due to their huge economic importance, genetic studies on hakes were mostly focused on phylogenetic and phylogeographic aspects; however chromosome numbers are still not described for any of the fifteen species in the genus Merluccius. In this work we report a chromosome number of 2n = 42 and a karyotype composed of three meta/submetacentric and 18 subtelo/telocentric chromosome pairs. Telomeric sequences appear exclusively at both ends of every single chromosome. Concerning rRNA genes, this species show a single 45S rDNA cluster at an intercalary location on the long arm of subtelocentric chromosome pair 12; the single 5S rDNA cluster is also intercalary to the long arm of chromosome pair 4. While U2 snRNA gene clusters map to a single subcentromeric position on chromosome pair 13, U1 snRNA gene clusters seem to appear on almost all chromosome pairs, but showing bigger clusters on pairs 5, 13, 16, 17 and 19. The brightest signals on pair 13 are coincident with the single U2 snRNA gene cluster signals. Therefore, the use of these probes allows the unequivocal identification of at least 7 of the chromosome pairs that compose the karyotype of Merluccius merluccius thus opening the way to integrate molecular genetics and cytological data on the study of the genome of this important species.


Effects of increasing doses of UV-B radiation on photosynthesis and motility in Chlamydomonas reinhardtii.
Effects of increasing doses of UV-B radiation on photosynthetic efficiency (PE) and motility in Chlamydomonas reinhardtii were investigated. The exposure time ranged from 10 to 120 min at 0.73 W/m2 UV-B radiation. A decrease in compensation points (CP) was followed by an increase in PE on extending the UV-B treatment up to 60 min. The subsequent increase in PE was accompanied by increasing CPs. Enhanced doses of UV-B radiation thus have a stimulatory effect on the PE in C. reinhardtii. No inhibitory effects could be detected. No statistically significant differences in motility could be observed due to an extremely high variation of values.


Enhanced sensitivity of colon tumour cells to natural killer cell cytotoxicity after mild thermal stress is regulated through HSF1-mediated expression of MICA.
Previously we showed that mild thermal stress increased natural killer (NK) cell-mediated tumour cytotoxicity and that this could be blocked by anti-NKG2D or anti-MICA (major histolocompatability complex (MHC) class I related chain A) antibodies. Here, we investigated the role of the transcription factor heat shock factor 1 (HSF1) in thermal regulation of MICA expression in tumour cells in vitro and in vivo. Hyperthermia experiments were conducted in vitro and in mice using a target temperature of 39.5 °C. Apoptotic cells and NK cells in situ were visualised by use of the TUNEL assay or expression of NKp46 respectively. Using Colo205 cells, HSF1 message was blocked utilising siRNA while luciferase reporter assays were used to measure the activity of the MICA promoter in vitro. Cell surface MICA was measured by flow cytometry. Following whole body hyperthermia (WBH), tumour tissues showed an increase in NK cells and apoptosis. Mild thermal stress resulted in a transient increase in surface MICA and enhanced NK cytotoxicity of the Colo205 colon cancer cell line. Silencing (mRNA) HSF1 expression in Colo205 cells prevented the thermal enhancement of MICA message and surface protein levels, with partial loss of thermally enhanced NK cytotoxicity. Mutations of the HSF1 binding site on the MICA promoter implicated HSF1 in the thermal enhancement of MICA. Some, but not all, patient-derived colon tumour derived xenografts also exhibited an enhanced MICA message expression after WBH. Up-regulation of MICA expression in Colo205 cells and enhanced sensitivity to NK cell killing following mild thermal stress is dependent upon HSF1.


Eating patterns and nutrient intake for older people: analysis with different methodological approaches.
This study aims to analyse the eating patterns and nutrient intake in different eating patterns of elderly persons. This is a cross-sectional study with elderly people from Botucatu, São Paulo state, Brazil. The mean daily nutrient intake of individuals with high adherence to the eating patterns identified by factor analysis was analysed, comparing the intake by analysis of variance. Individuals with high adherence to the Healthy eating pattern had the highest mean intake of retinol, vitamin A and vitamin E. Individuals with high adherence to the eating pattern Snacks and weekend meal presented lower means of vitamin B12, vitamin C, phosphorus, and retinol intake and the highest means of iron, manganese and magnesium intake. Individuals with high adherence to Fruits had the lowest mean fibre intake. Individuals with high adherence to Light and whole foods had the highest means of vitamin C intake. Individuals with high adherence to Soft diet showed lower protein intake and increased added sugar intake. Individuals with high adherence to the Traditional eating pattern presented high means of nutrient intake. In general, a better characterization of the eating behaviour of elderly people who adhere to each of these eating patterns was possible.


Unsupervised Detection and Correction of Model Calibration Shift at Test-Time.
The wide adoption of predictive models into clinical practice require generalizability across hospitals and maintenance of consistent performance across time. Model calibration shift, caused by factors such as changes in prevalence rates or data distribution shift, can affect the generalizability of such models. In this work, we propose a model calibration detection and correction (CaDC) method, specifically designed to utilize only unlabeled data at a target hospital. The proposed method is very flexible and can be used alongside any deep learning-based clinical predictive model. As a case study, we focus on the problem of detecting and correcting model calibration shift in the context of early prediction of sepsis. Three patient cohorts consisting of 545,089 adult patients admitted to the emergency departments at three geographically diverse healthcare systems in the United States were used to train and externally validate the proposed method. We successfully show that utilizing the CaDC model can help assist the sepsis prediction model in achieving a predefined positive predictive value (PPV). For instance, when trained to achieve a PPV of 20%, the performance of the sepsis prediction model with and without the calibration shift estimation model was 18.0% vs 12.9% and 23.1% vs 13.4% at the two external validation cohorts, respectively. As such, the proposed CaDC method has potential applications in maintaining performance claims of predictive models deployed across hospital systems.Clinical relevance- Model generalizability is a requirement of wider adoption of clinical predictive models.


Phylogenetic relationships among the Nymphalidae (Lepidoptera) inferred from partial sequences of the wingless gene.
A cladistic analysis was performed on a 378 bp region of the wingless gene from 103 nymphalid species and three pierid outgroups in order to infer higher level patterns of relationship among nymphalid subfamilies and tribes. Although the data are highly homoplastic, in many instances the most parsimonious cladograms corroborate traditionally recognized groups. The results suggest that this short gene region provides a useful source of data for phylogenetic inference, provided that adequate effort is made to sample a diversity of taxa.


The combination of coagulation, acid cracking and Fenton-like processes for olive oil mill wastewater treatment: phytotoxicity reduction and biodegradability augmentation.
Olive oil mill wastewater (OOMW) is one of the most important industrial wastewaters in the world due to high organic load and phenolic compounds. In this study, an integration of three processes including coagulation, acid cracking and Fenton-like was evaluated to treat OOMW. The performance of alum, ferric chloride and polyaluminum chloride was studied as coagulants. Among coagulants, ferric chloride showed the best results in comparison with the others. Coagulation process with FeCl3 removed 91.2% chemical oxygen demand (COD), 91.3% phenol, 98.9% total suspended solids and 99.2% turbidity at condition of pH = 6 and 3,000 mg/L coagulant dosage. Acid cracking process following the coagulation process with ferric chloride could slightly degrade organic compounds and provided suitable condition for the next process. Fenton-like process with zero valent iron (ZVI) was applied after coagulation and acid cracking. The optimal removal efficiency was achieved by Fenton-like process which was accomplished in condition of 7 g/L ZVI, 1,000 mg/L H2O2 and 180 min reaction time. The biodegradability of final effluent of this integration was improved significantly and biochemical oxygen demand5/COD value increased from 0.14 to 0.83. The results of germination tests revealed that phytotoxicity of the final effluent decreased.


Pyelonephritis during pregnancy: a cause for an acquired deficiency of protein Z.
Pyelonephritis has a more severe course during pregnancy than in the non-pregnant state. This has been attributed to the increased susceptibility of pregnant women to microbial products. An acquired protein Z deficiency has been reported when there is excessive thrombin activity. The aim of this study was to determine whether pyelonephritis during pregnancy is associated with changes in maternal plasma protein Z concentrations. A cross-sectional study was conducted to compare plasma protein Z concentrations between normal pregnant women (N = 71) and pregnant women with pyelonephritis (N = 42). Protein Z concentrations were measured by enzyme-linked immunosorbent assay. Parametric and non-parametric statistics were used for analysis. Patients with pyelonephritis had a significantly lower median plasma concentration of protein Z than did patients with normal pregnancies (median 2.14 microg/mL (0.4-3.4) vs. median 2.36 microg/mL (1.09-3.36); p = 0.03). There was no difference in the median plasma concentration of anti-protein Z antibodies between patients with pyelonephritis and those with normal pregnancies. The median maternal plasma protein Z concentration was significantly lower in patients with pyelonephritis during pregnancy than in patients with normal pregnancies.


Thin Melanoma: A Generic Term Including Four Histological Subtypes of Cutaneous Melanoma.
Today, the scientific community is focusing on the prognostic significance of different histological subtypes of thin melanoma (1). The current staging system for melanoma of the American Joint Committee on Cancer (AJCC) uses Breslow thickness as the primary attribute: melanomas with up to 1 mm thickness is defined as thin, because they present a good prognosis after surgical excision, with a 10-year survival rate of 85-90% in case of a tumor-free margin ≥1 cm (2). There is a significant interaction between mitotic rate and Breslow depth, so the predictive value of the mitotic rate on sentinel lymph node (SLN) positivity can be dependent on Breslow thickness (3). Cutaneous melanoma generally evolves through three clearly discernible progression stages. At first, transformed melanocytes proliferate above the epidermal basement membrane (the in situ or epidermal radial growth phase); they then invade the papillary dermis (the micro-invasive radial growth phase); and subsequently acquire the capacity to grow as a well-known malignant tumor (the invasive vertical growth phase). More specifically, micro-invasive melanoma is a non-tumorigenic radial growth phase of cutaneous melanoma, which invades the superficial dermis without forming a tumor nodule or papule, in absence of regression (3). In contrast, the micro-invasive radial growth phase of cutaneous melanoma with regression will rarely metastasize and, for this reason, the lesion should be recognized and could also be categorized as a 'micro-invasive radial growth phase of uncertain tumorigenic potential' (4). The early vertical growth phase of tumorigenic melanoma is characterized by the presence of a cell cluster in the dermis that is larger than the largest cluster in the epidermis (5). This feature is typical of tumorigenicity, while the mitogenicity is documented by the observation of mitotic figures in dermal melanoma cells (5,6). The early vertical growth phase and the radial growth phase with regression have a statistical chance of distant metastases (7). Therefore, thin melanoma includes four main histological subtypes, which reflect a specific biological behavior: the in situ epidermal radial growth phase, the non-tumorigenic micro-invasive radial growth phase, the micro-invasive radial growth phase with regression of uncertain tumorigenic potential, and the tumorigenic early vertical growth phase. In conclusion, thin melanoma can be considered a generic term and its subtypes should be histologically distinguished beyond its site of origin (acral versus non-acral) because they have different prognostic relevance.


Crushing the curve, the role of national and international institutions and policy makers in COVID-19 pandemic
Nobody can be fully prepared to a pandemic. Of course there are signs of it, the scientists can predict, alarming speeches can be made. But there are always alarmist people around, maybe that is why sometimes even the most serious warnings may be not considered by the authorities on time. The first patients may be lost without a proper diagnosis. When everybody realizes that there may be a big problem in the horizon, sometimes it is too late. That is why it is very important to monitor contagious diseases and follow the warnings and releases of national and international disease control centers and other related organizations. China celebrated Lunar New Year with more than 40 thousand families on the 18 of January 2020. Nobody seem to be expecting this emerging new viral pneumonia outbreak appeared in Wuhan, in the last days of 2019, will break the chains and turn out to be a pandemic! But maybe this time it was not too late. There were four important pandemics within the last century: Spanish Flu, Hong Kong Flu, Asian Flu and Swine Flu. Each left different story behind. Millions of people had infected, hundreds, thousands of people died. This time, the Modern World had different tools to limit the SARS CoV2 outbreak. The national and international institutions of our globe were all communicating and taking precautions in a very fast manner than ever. However, this time, unexpectedly, the SARS-CoV-2 contagion was also faster. Besides the international organizations like WHO, UNESCO and UNICEF, the roles of local authorities, health ministries, disease control centers, health protection agencies, research centers and universities are all very important in different operational levels to control and survive from the pandemic. This paper will review the immediate response of different national and international institutions and authorities to COVID-19 pandemic.


Effect of Training School Teachers on Oral Hygiene Status of 8-10 Years Old Government School Children of Udaipur City, India.
Provision of oral health knowledge to the children by their teachers at the school level can prove to be more fruitful because it is the time period during which the children begin to learn the basic oral hygiene practices and are most prone to dental caries. This study was carried out to assess the effect of training school teachers on oral hygiene status of 8-10 years old government school children of Udaipur city, India. A total of nine school teachers and 279, 8-10 year old school children from two government schools were included in the study. The questionnaire on oral health knowledge and practice contained 17 questions to evaluate the knowledge and practice of children towards oral hygiene before and after the teachers training program. Baseline and six months post training data on oral health knowledge and practice was obtained by the questionnaire method. Baseline and six months post training data on oral hygiene status was obtained by OHI-S Index. Statistical analysis was done using software SPSS 22, the test used were McNemar's test, paired t-test. Pre and post training data were compared and it was found that there was a significant improvement in oral health knowledge and practices of school teachers and children. Also oral hygiene status of school children was significantly improved after the program. Results of the present study suggest that experiential learning is an effective school based oral health education method for improvement of oral hygiene in primary school children.


Mapping of the microvillar 110K-calmodulin complex: calmodulin-associated or -free fragments of the 110-kD polypeptide bind F-actin and retain ATPase activity.
The 110K-calmodulin complex isolated from intestinal microvilli is an ATPase consisting of one polypeptide chain of 110 kD in association with three to four calmodulin molecules. This complex is presumably the link between the actin filaments in the microvillar core and the surrounding cell membrane. To study its structural regions, we have partially cleaved the 110K-calmodulin complex with alpha-chymotrypsin; calmodulin remains essentially intact under the conditions used. As determined by 125I-calmodulin overlays, ion exchange chromatography, and actin-binding assays, a 90-kD digest fragment generated in EGTA remains associated with calmodulin. The 90K-calmodulin complex binds actin in an ATP-reversible manner and decorates actin filaments with an arrow-head appearance similar to that found after incubation of F-actin with the parent complex; binding occurs in either calcium- or EGTA-containing buffers. ATPase activity of the 90-kD digest closely resembles the parent complex. In calcium a digest mixture containing fragments of 78 kD, a group of three at approximately 40 kD, and a 32-kD fragment (78-kD digest mixture) is generated with alpha-chymotrypsin at a longer incubation time; no association of these fragments with calmodulin is observed. Time courses of digestions and cyanogen bromide cleavage indicate that the 78-kD fragment derives from the 90-kD peptide. The 78-kD mixture can also hydrolyze ATP. Furthermore, removal of the calmodulin by ion exchange chromatography from this 78-kD mixture had no effect on the ATPase activity of the digest, indicating that the ATPase activity resides on the 110-kD polypeptide. The 78 kD, two of the three fragments at approximately 40 kD, and the 32-kD fragments associate with F-actin in an ATP-reversible manner. Electron microscopy of actin filaments after incubation with the 78-kD digest mixture reveals coated filaments, although the prominent arrowhead appearance characteristic of the parent complex is not observed. These data indicate that calmodulin is not required either for the ATPase activity or the ATP-reversible binding of the 110K-calmodulin complex to F-actin. In addition, since all the fragments that bind F-actin do so in an ATP-reversible manner, the sites required for F-actin binding and ATP reversibility likely reside nearby.


Solventless supramolecular chemistry via vapor diffusion of volatile small molecules upon a new trinuclear silver(I)-nitrated pyrazolate macrometallocyclic solid: an experimental/theoretical investigation of the dipole/quadrupole chemisorption phenomena.
A comparative study on the tendency of a new trinuclear silver(I) pyrazolate, namely, [N,N-(3,5-dinitropyrazolate)Ag]3 (1), and a similar compound known previously, [N,N-[3,5-bis(trifluoromethyl)pyrazolate]Ag]3 (2), to adsorb small volatile molecules was performed. It was found that 1 has a remarkable tendency to form adducts, at room temperature and atmospheric pressure, with acetone, acetylacetone, ammonia, pyridine, acetonitrile, triethylamine, dimethyl sulfide, and tetrahydrothiophene, while carbon monoxide, tetrahydrofuran, alcohols, and diethyl ether were not adsorbed. On the contrary, 2 did not undergo adsorption of any of the aforementioned volatile molecules. Adducts of 1 were characterized by elemental analysis, IR, thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET) surface area, and diffusion NMR measurements. The crystal structures of 1·2CH3CN and compound 3, derived from an attempt to crystallize the adduct of 1 with ammonia, were determined by single-crystal X-ray diffractometric studies. The former shows a sandwich structure with a 1:2 stoichiometric [Ag3]/[CH3CN] ratio in which one acetonitrile molecule points above and the other below the centroid of the Ag3N6 metallocycle. Compound 3 formed via rearrangement of the ammonia adduct to yield an anionic trinuclear silver(I) derivative with an additional bridging 3,5-dinitropyrazolate and having [Ag(NH3)2](+) as the counterion, [Ag(NH3)2][N,N-(3,5-dinitropyrazolate)4Ag3]. Irreversible sorption and/or decomposition upon vapor exposure are desirable advantages toward toxic gas filtration applications, including ammonia inhalation. TGA confirms the analytical data for all of the samples, showing weight loss for each adsorbed molecule at temperatures significantly higher than the corresponding boiling temperature, which suggests a chemical-bonding nature for adsorption as opposed to physisorption. BET surface measurements of the "naked" compound 1 excluded physical adsorption in its porous cavities. Density functional theory simulation results are also consistent with the chemisorption model, explain the experimental adsorption selectivity for 1, and attribute the lack of similar adsorption by 2 to significantly less polarizable electrostatic potential and also to strong argentophilic bonding whose energy is even higher than the quadrupole-dipole adduct bond energy upon proper selection of the density functional.


The Impact of Limited Prosthetic Socket Documentation: A Researcher Perspective.
The majority of limb prostheses are socket mounted. For these devices, the socket is essential for adequate prosthetic suspension, comfort, and control. The socket is unique among prosthetic components as it is not usually mass-produced and must instead be custom-made for individual residual limbs by a prosthetist. The knowledge of what constitutes "good" socket fit is gained by expert prosthetists and technicians over years of experience, and rarely documented. The reliance on tacit knowledge makes it difficult to standardize the criteria for a well-fitting socket, leading to difficulties understanding the impact of socket fit. Despite its importance, the workflow for socket fitting is often overlooked in literature. Due to the customized nature of sockets, if information is provided in literature, generally only the type of socket and suspension mechanism is noted, with information regarding the fitting and manufacturing processes omitted. In this article, the concerns, issues and consequences arising from lack of upper and lower limb socket documentation are discussed from a researcher perspective, supported by healthcare professionals and socket fabrication specialists. Key changes are proposed to the way socket manufacturing and evaluation are documented to assist future research.


Astrophysical constraints on Planck scale dissipative phenomena.
The emergence of a classical spacetime from any quantum gravity model is still a subtle and only partially understood issue. If indeed spacetime is arising as some sort of large scale condensate of more fundamental objects, then it is natural to expect that matter, being a collective excitation of the spacetime constituents, will present modified kinematics at sufficiently high energies. We consider here the phenomenology of the dissipative effects necessarily arising in such a picture. Adopting dissipative hydrodynamics as a general framework for the description of the energy exchange between collective excitations and the spacetime fundamental degrees of freedom, we discuss how rates of energy loss for elementary particles can be derived from dispersion relations and used to provide strong constraints on the base of current astrophysical observations of high-energy particles.


Aflibercept for Diabetic Macular Edema in Eyes Previously Treated With Ranibizumab and/or Bevacizumab May Further Improve Macular Thickness.
To evaluate the short-term anatomic and visual outcomes after aflibercept (Eylea; Regeneron, Tarrytown, NY) in eyes with diabetic macular edema (DME) previously treated with ranibizumab (Lucentis; Genentech, South San Francisco, CA) and/or bevacizumab (Avastin; Genentech, South San Francisco, CA). A single-center, retrospective, noncomparative study of 30 eyes in 23 patients with DME treated with prior ranibizumab and/or bevacizumab before switching to aflibercept. Eyes received an average of 16 prior injections (range: three injections to 31 injections; median: 17 injections). The mean central subfoveal thickness (CST) improved from 453 µm at the time of first anti-vascular endothelial growth factor (VEGF) injection (range: 304 µm to 686 µm; median: 429 µm), to 374 µm at the time of the switch to aflibercept (range: 267 µm to 547 µm; median: 361 µm; P = .02), to 332 µm after the first aflibercept injection (range: 242 µm to 545 µm; median: 318 µm; P < .001). Visual acuity improved after switching to aflibercept at the first follow-up visit (logMAR 0.40 [Snellen equivalent 20/50]) to logMAR 0.35 (Snellen equivalent 20/45) (P = .044). In eyes with persistent DME treated with ranibizumab and/or bevacizumab, switching to aflibercept may further improve macular thickness. Given the cost difference between the three drugs, a randomized trial evaluating a stepwise approach may be worthwhile. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:836-839.].


Does ultrasound measurement improve the accuracy of electronic brachytherapy in the treatment of superficial non-melanomatous skin cancer?
Electronic brachytherapy (eBT) is a form of contact radiation therapy used for thin superficial non-melanomatous skin cancers (NMSCs). An accurate measurement of diameter and depth is important for eBT treatment planning. Therefore, we compared clinical measurements by an experienced physician to measurements obtained using ultrasound (US), an objective imaging modality, in order to determine if clinical measurements were accurate enough for adequate NMSC treatment. Eighteen patients with 20 biopsy-proven NMSCs first had a clinical examination and then an US evaluation prior to starting eBT. One physician provided a clinical measurement for diameter and depth based on physical examination during radiation oncology consultation. The patients then had an US evaluation with a 14 or 18 MHz US unit, to determine both the diameter and depth measurements; eBT dose prescription was done using the US derived measurements. The clinical measurements and US measurements were compared using a t-test. Seventeen lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). The difference between the clinical and the US derived measurements for the second largest diameter was found to be statistically significant (p = 0.03), while the difference for the largest diameter of the lesions was not (p = 0.24). More importantly, the depth measurements obtained with US were also found to be significantly different from the clinical estimates (p = 0.02). All patients have had a complete response to therapy with a median follow-up of 24 months. Statistically different measurements were obtained in 2 of 3 parameters used in choosing applicator size and prescription depth using an US assessment. The data presented suggests that US is a more objective modality than clinical judgment for determining superficial NMSC diameter and prescription depth for personalized eBT planning.


Allosteric linkers in cAMP signalling.
Weak interactions mediated by dynamic linkers are key determinants of allosteric regulation in multidomain signalling proteins. However, the mechanisms of linker-dependent control have remained largely elusive. In the present article, we review an allosteric model introduced recently to explain how signalling proteins effectively sense and respond to weak interactions, such as those elicited by flexible linkers flanking globular domains. Central to this model is the idea that near degeneracy within the free energy landscape of conformational selection maximally amplifies the response to weak (~2RT), but conformation-selective interactions. The model was tested as proof of principle using the prototypical regulatory subunit (R) of protein kinase A and led to the unanticipated finding that dynamic linkers control kinase activation and inhibition by tuning the inhibitory pre-equilibrium of a minimally populated intermediate (apo R). A practical implication of the proposed model is a new strategy to design kinase inhibitors with enhanced potency through frustration-relieving mutations.


Partial Identification of the Average Treatment Effect Using Instrumental Variables: Review of Methods for Binary Instruments, Treatments, and Outcomes.
Several methods have been proposed for partially or point identifying the average treatment effect (ATE) using instrumental variable (IV) type assumptions. The descriptions of these methods are widespread across the statistical, economic, epidemiologic, and computer science literature, and the connections between the methods have not been readily apparent. In the setting of a binary instrument, treatment, and outcome, we review proposed methods for partial and point identification of the ATE under IV assumptions, express the identification results in a common notation and terminology, and propose a taxonomy that is based on sets of identifying assumptions. We further demonstrate and provide software for the application of these methods to estimate bounds. Supplementary materials for this article are available online.


[Standard conformations of a polypeptide chain in irregular protein regions].
A detailed stereochemical analysis of known protein structures has been made which shows that: (1) irregular regions of proteins consist of a limited number of standard structures formed by three, four of more residues; (2) an amino acid residue of a protein can adopt one of the six sterically allowed conformations designated here as alpha, alpha L, beta, gamma, delta, and epsilon. It is shown that there are two allowed conformations of a polypeptide chain at the N-end of an alpha-helix, beta alpha n- and beta gamma alpha n-conformations, where n is a number of residues in the alpha-helix. At the C-end of the alpha-helix there are two conformations as well, alpha n gamma beta- and alpha n gamma alpha L beta-ones. Two beta-strands in a beta-hairpin can be joined, for example, by standard structures with beta beta alpha L beta-, beta alpha gamma alpha L beta-, beta alpha alpha gamma alpha L beta-conformations which are referred to as turns. In the regions where a polypeptide chain passes from one layer to another there are standard structures with beta gamma beta-, beta alpha beta beta-, beta alpha gamma beta-conformations etc., referred to as cross-overs. A structure of any protein irregular region can be represented as a combination of these and other standard turns and cross-overs considered in the paper. The major part of the turns and cross-overs has residues in alpha L- or epsilon-conformations which must be glycine or other residues with small or flexible side chains. Massive hydrophobic residues must not occupy the first beta-positions of the most standard structures. The results obtained can be successfully applied for prediction of the location of the turns and cross-overs in proteins from their amino acid sequences and for interpretation of electron density maps.


Sex differences in fat distribution influence the association between BMI and arterial stiffness.
The increase in arterial stiffness in patients with the metabolic syndrome is strongly related to the amount of visceral adipose tissue. In clinical practice, anthropometric measurements such as BMI and waist circumference are commonly used to assess general and abdominal adiposity. Waist circumference is a composite measure of subcutaneous and visceral abdominal adipose tissue. As the distribution of intra-abdominal fat differs between men and women, we investigated the sex-specific associations between different anthropometric measures for general and abdominal obesity with arterial stiffness. A cross-sectional descriptive study was performed in 1517 participants of the Nijmegen Biomedical Study, aged 50-70 years. After measurement of height, waist circumference and hip circumference, the following indices were calculated: BMI, waist-hip ratio and waist-height ratio (WHtR). Arterial stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV). The association between the anthropometric indices and vascular stiffness was investigated by linear regression analysis adjusting for the traditional cardiovascular risk factors. BMI, waist circumference, waist-hip ratio and WHtR correlated positively with PWV in univariate analysis both in men and women (all P < 0.016). Hip circumference was only associated with PWV in women (P < 0.001). After adjustment for age and heart rate, waist circumference and WHtR (standardized beta of 0.142 and 0.141, respectively, both P < 0.001) showed the strongest associations with PWV in men, whereas in women only BMI was associated with PWV (standardized beta of 0.177, P < 0.001). In men, WHtR was independently related to increased arterial stiffness, after adjustment for BMI and traditional cardiovascular risk factors. In women, in multivariate analyses, BMI remained significantly positively associated with PWV, whereas WHtR became negatively associated with PWV. Sex-related differences in adipose tissue distribution influence the association between anthropometric measures of obesity and vascular stiffness as measured with by PWV. We found that in men, WHtR showed the strongest association with PWV, whereas in women BMI was best associated with a higher PWV.


Associations with anticoagulation: a cross-sectional registry-based analysis of stroke survivors with atrial fibrillation.
To describe vitamin K antagonist (VKA) anticoagulation prescribing patterns in stroke survivors with atrial fibrillation (AF), with particular emphasis on sociodemographic associations with VKA prescription. We conducted a cross-sectional analysis of city-wide Glasgow primary care data held as part of the Local Enhanced Services (LES) for the year 2010. We collated clinical and sociodemographic data of community-dwelling ischaemic stroke survivors with AF, including risk factors; comorbidity; socioeconomic status and prescribing. We described stroke risk and bleeding risk using recommended stratification tools (CHA2DS2-VASC and HAS-BLED). Univariate and multivariate associations with anticoagulant prescription were described by ORs and corresponding 95% CI. We identified 3429 community-dwelling, ischaemic stroke survivors with AF; median age 78 (IQR 72-84); 1699 (49%) male. Median CHA2DS2-VASC score was 5 (IQR 4-6). VKA was prescribed in 1165 (34%). On univariate analysis, higher CHA2DS2-VASC was associated with fewer VKA prescriptions (OR 0.90, 95% CI 0.45 to 0.95). On multivariate analysis, older age (OR 0.97, 95% CI 0.96 to 0.98) and higher deprivation scores (OR 0.59, 95% CI 0.57 to 0.76) were independently associated with non-prescription of VKA. Anticoagulation was underused in this high-risk population, and those at highest risk were less likely to be treated. Strategies need to be developed to improve prescription of anticoagulation treatment.


[Endoscopic hemostasis in pulmonary hemorrhage].
As the result of applying endoscopic occlusion of the bronchus in complex treatment of 95 patients with pulmonary, predominantly massive, hemorrhage recovery was achieved in 77.9% of cases. Twenty-one patients died. Hemorrhage was the direct cause of death of 5 patients, 16 patients died from advancement of the principal disease, background conditions, and complications of the postoperative period not associated with pulmonary bleeding.


Genomic approach to study floral development genes in Rosa sp.
Cultivated for centuries, the varieties of rose have been selected based on a number of flower traits. Understanding the genetic and molecular basis that contributes to these traits will impact on future improvements for this economically important ornamental plant. In this study, we used scanning electron microscopy and sections of meristems and flowers to establish a precise morphological calendar from early rose flower development stages to senescing flowers. Global gene expression was investigated from floral meristem initiation up to flower senescence in three rose genotypes exhibiting contrasted floral traits including continuous versus once flowering and simple versus double flower architecture, using a newly developed Affymetrix microarray (Rosa1_Affyarray) tool containing sequences representing 4765 unigenes expressed during flower development. Data analyses permitted the identification of genes associated with floral transition, floral organs initiation up to flower senescence. Quantitative real time PCR analyses validated the mRNA accumulation changes observed in microarray hybridizations for a selection of 24 genes expressed at either high or low levels. Our data describe the early flower development stages in Rosa sp, the production of a rose microarray and demonstrate its usefulness and reliability to study gene expression during extensive development phases, from the vegetative meristem to the senescent flower.


Subcellular Control over Focal Adhesion Anisotropy, Independent of Cell Morphology, Dictates Stem Cell Fate.
Although microscale patterning techniques have been used to control cell morphology and shape, they only provide indirect control over the formation of the subcellular cytoskeletal elements that determine contractility. This paper addresses the hypotheses that nanoscale anisotropic features of a patterned matrix can direct the alignment of internal cytoskeletal actin fibers within a confined shape with an unbiased aspect ratio, and that this enhanced control over cytoskeletal architecture directs programmed cell behaviors. Here, large-area polymer pen lithography is used to pattern substrates with nanoscale extracellular matrix protein features and to identify cues that can be used to direct cytoskeletal organization in human mesenchymal stem cells. This nanopatterning approach is used to identify how anisotropic focal adhesions around the periphery of symmetric patterns yield an organized and contractile actin cytoskeleton. This work reports the important finding that anisotropic cues that increase cell contractility within a circular shape redirect cell differentiation from an adipogenic to an osteogenic fate. Together, these experiments introduce a programmable approach for using subcellular spatial cues to control cell behavior within defined geometries.


A shift from indoor residual spraying (IRS) with bendiocarb to long-lasting insecticidal (mosquito) nets (LLINs) associated with changes in malaria transmission indicators in pyrethroid resistance areas in Benin.
Indoor residual spraying (IRS) was implemented in the department of Ouémé-Plateau, southern Benin, in 2008 and withdrawn in 2011, when long lasting insecticidal nets (LLINs) were distributed to the communities that were previously targeted by IRS. Did the LLIN strategy provide a better level of protection against malaria transmission than IRS? Entomological surveillance was carried out to assess indicators of transmission risk during the last year of IRS and the first year after the LLIN intervention was put in place (2010-2011). Mosquito biting density was sampled by human landing collection (HLC). Females of Anopheles gambiae s.l. were dissected to estimate the parity rates and the blood meal index. A subsample of the An. gambiae s.l. collection was tested for presence of Plasmodium falciparum sporozoites. In addition, window exit traps and pyrethrum spray catches were performed to assess exophagic behavior of Anopheles vectors. There were significant increases in all the indicators following withdrawal of IRS. Vector biting density (p<0.001) and longevity (OR=3.81[3.01-4.82] 95% CI; p<0.001) of the An. gambiae s.l. increased significantly; so too did the blood meal index (OR=1.48 [1.1-1.99] 95% CI; p<0.001). Entomological inoculation rate, after IRS withdrawal at one surveillance site, Adjohoun, rose two fold (9.0 infected bites/person/9 months (Apr-Dec 2011) versus 3.66 infective bites/person during the 9 months preceding IRS (Apr-Dec 2010). A second site, Missérété, experienced a six-fold increase after IRS cessation (15.1 infective bites/person/9 months versus 2.41 during IRS). Exophily after IRS cessation decreased significantly in all areas (p<0.001) suggesting that mosquitoes were more likely to rest in houses with LLINs, than in houses subjected to IRS. LLINs did not impact on indicators of transmission to the same levels as did IRS after IRS withdrawal.


[Phone sessions in Covid-19 environment: The frame and his limits].
To deal with the Covid 19 pandemic, health protection measures require changes to our clinical practices. Faced up with the unprecedented nature of this situation, the liberal psychotherapist is led to rethink some aspects of the framework of his practice in order to preserve the thread of the transferential relationship. The authors develop a clinical reflection on the clinical setting in a pandemic period by exploring in particular the dynamics of telephone sessions. For telephone interviews, the question of the sound envelope is central, in particular regarding the psychic function of silence. We choose to illustrate our point with short vignettes than by relying on long-term clinical cases, more likely to represent the variety of new clinical situations encountered and the questions that accompany them. This article introduces his point by recounting the plague epidemic in ancient Greece to show the impact of the environment on humans and its collective fantasy implications. Being faced up with death, contamination, the invisible enemy brings out a palpable concern. It is indeed quite remarkable that these same reactions and concerns in front of death caused by the pandemic match whith what is related by Thucydides who survived the plague, which affected Athens during the Peloponnesian War. In another context, Winnicott highlights the place and importance of the therapeutic environment. It is both a question of adjusting the framework according to the context while maintaining certain intangible aspects representing the permanence of the link and its framework. A framework cannot exist without being kept, which is equivalent to thinking of the framework above all as an internal framework, questioning the clinician about what he values and what he makes sense in his practice. In the current context, these questions arise from the perspective of a certain flexibility, depending on the human context (child, adolescent, consultations, etc.) or external context (crisis linked to a virus, etc.) showing that it is more than never question of exercising on a case-by-case basis, taking into account changes in the environment. The initial observation during this period of confinement concerns the fact that some patients contact a therapist for the first time by telephone and wish to initiate psychotherapy (during this period) when they explain that such an initiative was not possible. despite the difficulties already encountered in the past. But there is also the opposite case: patients who have no intention of continuing the work already started during this time. Thus, faced up with the injunction of confinement, they show themselves in the psychic impossibility of following the treatment by other means such as, for example, telephone sessions. In this perspective, the silence on the phone takes on a different tone; silence reveals itself to be a source of greater anxiety than in presence: the presence of bodies, of its movements perceptible as imperceptible, of a gesture that carries or accompanies the senses, breathing, the visual context of the office and of its "decor", represent as many essential elements in the usual capacity of the frame; in the absence of these basic sensory elements, silence can be experienced as a void, or even a gap in the bond, opening Pandora's box of paranoid fantasies acting unconsciously. If silence is representative of the whole framework, it promotes in this context the partialization of the clinician's body reduced to one ear and not to a whole body. Here, it is the change of framework that mobilizes the difference, established by Mr. Klein, between the partial and total object; this circumstance neo-framework could therefore call for regressive movements, undoing the silence of its symbolic function when the bodies are present.


Zooplankton biogeographic boundaries in the California Current System as determined from metabarcoding.
Within the southern California Current ecosystem there are two well-documented breaks in marine community structure at Point Conception and Punta Eugenia. We explored the presence of similar breaks in a diverse zooplankton community through metabarcoding of mixed net tow tissue samples collected during an expedition from Monterey to Baja California in February of 2012. We recovered a high diversity of species as well as patterns of species presence that align with their previously documented ranges in this region. We found a clear break at Punta Eugenia in overall zooplankton community structure, while Point Conception was weakly linked to changes in community structure. We analyzed this dataset through two parallel bioinformatic pipelines to examine the robustness of these results. Our overall conclusions were consistent across both pipelines, however there were differences in species detection. This study illustrates the utility of metabarcoding analysis on mixed tissue samples for recovering known patterns of diversity, as well as allowing elucidation of broad patterns of community differentiation across many groups of organisms.


Efficiency over thoroughness in laboratory testing decision making in primary care: findings from a realist review.
Existing research demonstrates significant variation in test-ordering practice, and growth in the use of laboratory tests in primary care. Reviews of interventions designed to change test-ordering practice report heterogeneity in design and effectiveness. Improving understanding of clinicians' decision making in relation to laboratory testing is an important means of understanding practice patterns and developing theory-informed interventions. To develop explanations for the underlying causes of patterns of variation and increasing use of laboratory tests in primary care, and make recommendations for future research and intervention design. Realist review of secondary data from primary care. Diverse evidence, including data from qualitative and quantitative studies, was gathered via systematic and iterative searching processes. Data were synthesised according to realist principles to develop explanations accounting for clinicians' decision making in relation to laboratory tests. A total of 145 documents contributed data to the synthesis. Laboratory test ordering can fulfil many roles in primary care. Decisions about tests are incorporated into practice heuristics and tests are deployed as a tool to manage patient interactions. Ordering tests may be easier than not ordering tests in existing systems. Alongside high workloads and limited time to devote to decision making, there is a common perception that laboratory tests are relatively inconsequential interventions. Clinicians prioritise efficiency over thoroughness in decision making about laboratory tests. Interventions to change test-ordering practice can be understood as aiming to preserve efficiency or encourage thoroughness in decision making. Intervention designs and evaluations should consider how testing decisions are made in real-world clinical practice.


Relationship between clinical and electrophysiological findings and indicators of heavy exposure to 2,3,7,8-tetrachlorodibenzo-dioxin.
In this study the prevalence rate of peripheral neuropathy in a population living in an area polluted with 2,3,7,8-tetrachlorodibenzo-dioxin (dioxin-TCDD) was determined. Of the 723 subjects invited to the first screening in 1977, 470 (65%) attended. At the second screening in 1978, of the 710 invited subjects, 319 (45%) attended. Prevalence rate ratios for peripheral neuropathy and the associated 95% confidence limits were calculated for subgroups determined by the presence of (i) predisposing factors to neuropathy (alcoholism, diabetes, occupational exposure to neurotoxic agents, etc) or (ii) conditions thought to result from exposure to dioxin-TCDD such as chloracne or abnormal serum hepatic enzyme levels. The prevalence rate of peripheral neuropathy among those subjects with predisposing factors and among those with chloracne or abnormal serum hepatic enzyme levels was nearly three times greater than among those without these manifestations. The results derived from this study may be useful qualitative pointers for identifying subjects at risk in the neurological follow-up.


Additive, antagonistic, and synergistic effects of procyanidins and polyunsaturated fatty acids over inflammation in RAW 264.7 macrophages activated by lipopolysaccharide.
Macrophages play an important role in immunogenic challenges and can aggravate and propagate local inflammation. Nuclear factor-kappa B (NF-κB) and activator protein 1 pathways can regulate these inflammatory processes by modulating expression of proinflammatory genes. Bioactive molecules present in food, such as procyanidins and polyunsaturated fatty acids, possess antiinflammatory effects in vivo and in vitro. Our aim was to assess whether they have synergistic antiinflammatory effects in murine macrophages. A nitric oxide production assay, a phosphoprotein assay, and a low-density array for 91-gene expression related to inflammation, oxidative stress, and metabolism were performed to assess the synergistic antiinflammatory effects of dimeric procyanidins (B1, B2, B3, B4) (5 μg/mL), and the polyunsaturated fatty acids, docosahexaenoic acid, and eicosapentaenoic acid (30 μM) coincubated with lipopolysaccharide for 19 h to mimic inflammation in RAW 264.7 macrophages (mouse leukaemic monocyte macrophage cell line). Adding eicosapentaenoic acid plus B3 had synergistic effects leading to decreased nitric oxide levels; the modulation of phosphoprotein levels, such as P-nuclear factor-[kappa] B p65 and P-stress-activated protein kinase/Jun-amino-terminal kinase; the down-regulation of proinflammatory genes, such as interleukins, chemokines, transcription factors; and up-regulation of antioxidant genes. This combination has a stronger antiinflammatory effect than either of these molecules separately in RAW macrophages. These results could lead to in vivo studies that may yield novel preventive or palliative nutritional treatments for obesity, atherosclerosis, and cardiovascular diseases.


Shaping the Future of Research: a perspective from junior scientists.
The landscape of scientific research and funding is in flux and affected by tight budgets, evolving models of both publishing and evaluation, and questions about training and workforce stability. As future leaders, junior scientists are uniquely poised to shape the culture and practice of science in response to these challenges. A group of postdocs in the Boston area who are invested in improving the scientific endeavor, planned a symposium held on October 2 (nd) and 3 (rd), 2014, as a way to join the discussion about the future of US biomedical research. Here we present a report of the proceedings of participant-driven workshops and the organizers' synthesis of the outcomes.


From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects.
Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.


Regulation of protein kinase inhibitor by follicle-stimulating hormone in Sertoli cells in vitro.
The heat-stable protein inhibitor of cAMP-dependent protein kinase is specifically regulated by hormones in cultures of rat Sertoli cells maintained under completely defined conditions. Hormones that are known to elevate Sertoli cell cAMP concentrations, namely FSH and isoproterenol, produce a 4- to 5-fold increase in the specific activity of protein kinase inhibitor, whereas testosterone and LH have no effect. The stimulatory effects of FSH or isoproterenol on protein kinase inhibitor are completely mimicked by dibutyryl cAMP. The ability of FSH to stimulate protein kinase inhibitor is dependent upon the age of the animals used as a source for the Sertoli cells. FSH stimulates protein kinase inhibitor activity in cells from 9- and 16-day-old animals, but not in cells from 32-day-old animals. On the other hand, isoproterenol or dibutyryl cAMP will stimulate protein kinase inhibitor in cells from both young and old animals. FSH can stimulate protein kinase inhibitor activity in older cells only in the added presence of the phosphodiesterase inhibitor, 1-methyl-3-isobutyl xanthine. Using specific antibodies to protein kinase inhibitor, we have shown that this protein is regulated by hormones via preferential stimulation of de novo synthesis of the inhibitor. (Endocrinology 108: 427, 1981)


The clinical significance of memory T cells and its subsets in gastric cancer.
Long life of memory T cell (Tm) determines its crucial role in the carcinogenesis and carcinogenic progression which usually take long time. The Tm compartment contains two populations, central memory T cells (Tcm) and effector memory T cells (Tem), based on their phenotypic markers, functional attributes, and migratory properties. We investigated the subsets of the Tm in peripheral blood and tumor microenvironments in patients with gastric cancer by flow cytometry, and aimed to explore the correlation between the Tm and clinicopathologic features of gastric cancer. The percentages of CD4(+)/CD8(+) Tm and CD4(+)/CD8(+) Tcm in peripheral blood from gastric cancer patients were statistically lower, whereas the percentages of CD4(+)/CD8(+) Tem were significantly higher than healthy controls. The proportion of CD4(+)/CD8(+) Tcm increased after tumor resection, while the percentage of the CD4(+)/CD8(+) Tem decreased significantly. Significant associations were detected between the peripheral CD4(+)/CD8(+) Tm and clinical stage, as well as the CD8(+) Tcm and clinical stage and nodal involvement. Tumor infiltrating CD8(+) Tm expressed both central and effector memory phenotypes, whereas CD4(+) Tm displayed predominantly an effector memory phenotype. Higher percentages of tumor infiltrating CD4(+)/CD8(+) Tm were significantly associated with the early disease stage. Tm and its subsets were good immune indicators for the disease stage of gastric cancer. The proportion of Tm subsets may reflect the immune suppressive and immune response to the tumor associated antigen.


Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells.
Glucagon-Like Peptide-1 (GLP-1) undergoes rapid inactivation by dipeptidyl peptidase-4 (DPP4) suggesting that target receptors may be activated by locally produced GLP-1. Here we describe GLP-1 positive cells in the rat and human stomach and found these cells co-expressing ghrelin or somatostatin and able to secrete active GLP-1 in the rats. In lean rats, a gastric load of glucose induces a rapid and parallel rise in GLP-1 levels in both the gastric and the portal veins. This rise in portal GLP-1 levels was abrogated in HFD obese rats but restored after vertical sleeve gastrectomy (VSG) surgery. Finally, obese rats and individuals operated on Roux-en-Y gastric bypass and SG display a new gastric mucosa phenotype with hyperplasia of the mucus neck cells concomitant with increased density of GLP-1 positive cells. This report brings to light the contribution of gastric GLP-1 expressing cells that undergo plasticity changes after bariatric surgeries, to circulating GLP-1 levels.


Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.
Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy.Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242-50. ©2017 AACR.


The effect of public policies on the demand for higher education.
A binomial logit model is fitted to the college attendance behavior of 27,046 male high-school juniors in 1960, divided into 20 subgroups defined by student ability and family income. Tuition, high admissions standards, travel costs, and room and board costs all have significant negative effects on attendance. The highest elasticities of demand are found to occur in the low-income strata and lower-middle ability quartile, suggesting that an efficient subsidy program should focus on these groups. Coefficients of forgone earnings and measures of the local payoff to college attendance are small but generally have the expected sign.


Aberration of lncRNA LINC00460 is a Promising Prognosis Factor and Associated with Progression of Clear Cell Renal Cell Carcinoma.
Long noncoding RNAs have been studied more and more as potential prognostic markers. However, the prognostic of LINC00460 in clear cell renal cell carcinoma (ccRCC) has not been explored. In this study, the potential role of LINC00460 was investigated in ccRCC. One hundred thirteen pairs of ccRCC tissues and para-normal tissues were collected. The expressions of LINC00460 in these tissues and ccRCC cells were evaluated via qRT-PCR. The prognostic value of LINC00460 was accessed with the use of Kaplan-Meier analysis and Cox proportional hazards model analysis. The influence of LINC00460 on ccRCC cell proliferation, migration, and invasion was determined via cell counting kit-8 (CCK-8) and Transwell assays. The results revealed that LINC00460 was significantly enhanced in ccRCC tissues, as well as in ccRCC cell lines. The overexpression of LINC00460 was significantly associated with lymph node metastasis and TNM stage, and lead to poor overall survival. Knockdown of LINC00460 reduces the cell ability of proliferation, migration, and invasion. LINC00460 could sponge to miR-149-5p. LINC00460 may be developed as a prognostic biomarker and molecular therapy target for ccRCC.


Maxillary and mandibular overlay removable partial dentures for the restoration of worn teeth.
This clinical report describes the fabrication of maxillary and mandibular cast overlay removable partial dentures for the restoration of severely worn teeth with accompanying loss of vertical dimension of occlusion. The frameworks supported porcelain veneers for esthetics and metal occlusal surfaces for strength and durability.


Analgesic and antihyperalgesic effects of melatonin in a human inflammatory pain model: a randomized, double-blind, placebo-controlled, three-arm crossover study.
Antinociceptive effects of melatonin have been documented in a wide range of experimental animal models. The aim of this study was to investigate the analgesic, antihyperalgesic, and anti-inflammatory properties of melatonin using a validated burn injury (BI) model in healthy male volunteers. The design was a randomized, double-blind, placebo-controlled, three-arm crossover study. Each volunteer participated in 3 identical study sessions with intravenous administration of placebo, melatonin 10 mg, or melatonin 100 mg. Sixty minutes after bolus injection of study medication, a BI was induced by a computerized contact thermode (47.0°C, 420 seconds, 5.0 × 2.5 cm). Pain ratings during the BI and quantitative sensory testing at baseline and at 1, 2, 4, and 6 hours after the BI were performed. Quantitative sensory testing included assessments of secondary hyperalgesia areas, mechanical and thermal thresholds in the BI area, and pressure algometry. Furthermore, markers of inflammation, skin-reflectance spectrophotometry, and high-resolution ultrasonography were applied to measure skin erythema and dermal thickness in the BI area. Pain during the BI and secondary hyperalgesia areas were defined as primary outcomes. Twenty-nine volunteers were randomized and completed the study. While the BI induced large secondary hyperalgesia areas and significantly increased the markers of inflammation, no significant effects of melatonin were observed with respect to primary or secondary outcomes, compared with placebo. The administration of melatonin was not associated with any adverse effects. Melatonin did not demonstrate any analgesic, antihyperalgesic, or anti-inflammatory properties in the BI model.


Type I interferon and lupus.
Patients with lupus have signs of an ongoing production of type I interferons (IFNs) that are of importance both for the etiopathogenesis and the clinical manifestations. In this review, we summarize the latest information concerning the type I IFN system in lupus. Activated plasmacytoid dendritic cells are responsible for the IFNalpha production in lupus and can be found in target organs such as glomeruli. The plasmacytoid dendritic cells are triggered by interferogenic immune complexes, and produced IFNalpha activates the immune system and impairs T-regulatory cell function. Autoantibodies, which can form interferogenic immune complexes, are not only present in serum of lupus patients but also in the cerebrospinal fluid of patients with neuropsychiatric manifestations. There is a strong association between risk to develop lupus and gene variants connected to the production and effects of type I IFN. Risk variants can not only cause either increased serum IFNalpha activity or sensitivity but also a more severe disease phenotype. Administration of monoclonal anti-IFNalpha antibodies to lupus patients downregulates several proinflammatory pathways and reduces disease activity. Increasing evidence indicates that the activated type I IFN system in lupus is critical in the etiopathogenesis of the disease and is an important therapeutic target.


CD4+ T cells in the pathogenesis of murine ocular toxoplasmosis.
The role of CD4(+) T cells in the pathogenesis of ocular toxoplasmosis was investigated in murine models utilizing inbred C57BL/6 mice deficient either in CD4(+), CD8(+), or B cells (microMT). Severe necrosis and inflammation with replicating parasites were observed in the eyes of control mice after primary ocular infection, and near-normal histology with few tachyzoites was observed in the eyes of mice immunized intraperitoneally with the avirulent ts-4 strain followed by intraocular challenge with the RH strain of Toxoplasma gondii. In contrast, mild inflammation without evidence of necrosis associated with increased parasite burdens were observed in the eyes of CD4 knockout (KO) mice after both primary ocular infection and challenge with RH tachyzoites. CD8 KO mice, as well as microMT mice, demonstrated increased ocular necrosis in response to either primary ocular infection or challenge. The parasite burden was increased in the eyes of both CD8 KO and microMT mice in which the parasite load was even higher. As expected, there were no increases in the levels of immunoglobulin G in serum or aqueous humor in microMT mice, and there was no increase in the levels of gamma interferon and tumor necrosis factor alpha in the sera of CD4 KO mice after both infection and challenge. These results suggest that the ocular inflammatory response to the parasite is mediated primarily by the CD4(+)-T-cell response. CD8(+) T cells and B cells may play an important role in limiting tachyzoite proliferation in the eyes. Mice deficient in CD8(+) CD4(+) T cells or B cells exhibit diminished vaccine-induced resistance and increased ocular parasite burden after challenge.


Tele-Neuro-Ophthalmology Utilization, Availability, and Attitudes: Update 1 Year Into the COVID-19 Public Health Emergency.
Telehealth was rapidly adopted early in the COVID-19 pandemic as a way to provide medical care while reducing risk of SARS-CoV2 transmission. Since then, telehealth utilization has evolved differentially according to subspecialty. This study assessed changes in neuro-ophthalmology during the first year of the COVID-19 pandemic. Telehealth utilization and opinions pre-COVID-19, early pandemic (spring 2020), and 1 year later (spring 2021) were surveyed among practicing neuro-ophthalmologists in and outside the United States using an online platform. Demographics, self-reported utilization, perceived benefits, barriers, and examination suitability were collected over a 2-week period in May 2021. A total of 135 practicing neuro-ophthalmologists (81.5% United States, 47.4% females, median age 45-54 years) completed the survey. The proportion of participants using video visits remained elevated during COVID + 1 year (50.8%) compared with pre-COVID (6%, P < 0.0005, McNemar), although decreased compared with early COVID (67%, P < 0.0005). Video visits were the most commonly used methodology. The proportion of participants using remote testing (42.2% vs 46.2%), virtual second opinions (14.5% vs 11.9%, P = 0.45), and eConsults (13.5% vs 16.2%, P = 0.38) remained similar between early and COVID + 1 year ( P = 0.25). The majority selected increased access to care, better continuity of care, and enhanced patient appointment efficiency as benefits, whereas reimbursement, liability, disruption of in-person clinic flow, limitations of video examinations, and patient technology use were barriers. Many participants deemed many neuro-ophthalmic examination elements unsuitable when collected during a live video session, although participants believed some examination components could be evaluated adequately through a review of ancillary testing or outside records. One year into the COVID-19 pandemic, neuro-ophthalmologists maintained telemedicine utilization at rates higher than prepandemic levels. Tele-neuro-ophthalmology remains a valuable tool in augmenting patient care.


The onchocerciasis focus at Kinsuka/Kinshasa (Republic of Zaire) in 1985. II. Parasitological and clinical aspects.
Since the antivectorial control in 1948, the parasitological and clinical aspects of the onchocerciasis focus at Kinsuka/Kinshasa have not been studied further until now. The population examined was selected for its daily contact with the vector. It constituted 143 adults, including fishermen, stonebreakers and women cultivators, and 26 children aged from 10 to 16 years. People were subjected to an ophthalmological examination as well as to an investigation for Onchocerca volvulus microfilariae. Adults were examined for the presence of nodules as well as for dermal and lymphatic manifestations of onchocerciasis. The microfilaria carrier rate (MfCR) was 59.2%. The mean microfilaria density (MfD) was 9.7 mf mg-1. Only 20% of the adults presented with small onchocercal nodules. Cutaneous lesions were mild. Lymphatic complications such as adenolymphocele, hydrocele and elephantiasis of the lower limbs were observed in 18% of the adults. No one was blind from onchocerciasis, although nine patients of 60 years or over had lost the use of one eye. Punctate keratitis occurred commonly in young people. Ocular lesions, except for punctate keratitis, developed progressively after 55 years and they became worse with the degree of infection, age and length of stay. Hyperendemic and insufferable in 1940, onchocerciasis has become, in 1985, hypoendemic and no longer a public health problem. One could deduce that a situation similar to that in Kinsuka may occur within 30 years in other foci which are today hyperendemic and where prophylaxis has been started.


Use of healthcare resources, family function, and socioeconomic support during the first four years after preterm birth.
To assess the use of healthcare resources for preterm infants and to evaluate family function and socioeconomic support in a defined population from birth to 4 years of age. In a prospective case-control study, 39 singleton preterm infants without prenatal abnormalities born during an 18 month period were studied together with their families. The population consisted of 19 very preterm infants (less than 32 weeks) and 20 randomised moderate preterm infants (32-35 weeks), and the control group comprised 39 full term infants. Contacts with medical services, child health services, and the social welfare system were registered, and family function and life events were studied. The preterm children were more often readmitted to hospital (odds ratio (OR) 6.6, 95% confidence interval (CI) 2.0 to 22.1) and had more outpatient attendances (OR 5.6, 95% CI 2.1 to 15.0) during their first year of life. Mothers in the preterm group more often used temporary parental allowance than the control mothers (p < 0.001). The number of contacts with the child health services and the social welfare system did not differ significantly from the controls. Neither was there any significant difference with regard to family function or life events at 4 years of age. A large proportion of the premature children used specialist care during the first years of life. However, the families of the preterm infants were socially well adapted up to four years after birth compared with the control families.


Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation.
Multinucleated giant cells are formed by the fusion of macrophages and are a characteristic feature in numerous pathophysiological conditions including the foreign body response (FBR). Foreign body giant cells (FBGCs) are inflammatory and destructive multinucleated macrophages and may cause damage and/or rejection of implants. However, while these features of FBGCs are well established, the molecular mechanisms underlying their formation remain elusive. Improved understanding of the molecular mechanisms underlying the formation of FBGCs may permit the development of novel implants that eliminate or reduce the FBR. Our previous study showed that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel/receptor, is required for FBGC formation and FBR to biomaterials. Here, we have determined that (a) TRPV4 is directly involved in fusogenic cytokine (interleukin-4 plus granulocyte macrophage-colony stimulating factor)-induced activation of Rac1, in bone marrow-derived macrophages; (b) TRPV4 directly interacts with Rac1, and their interaction is further augmented in the presence of fusogenic cytokines; (c) TRPV4-dependent activation of Rac1 is essential for the augmentation of intracellular stiffness and regulation of cytoskeletal remodeling; and (d) TRPV4-Rac1 signaling axis is critical in fusogenic cytokine-induced FBGC formation. Together, these data suggest a novel mechanism whereby a functional interaction between TRPV4 and Rac1 leads to cytoskeletal remodeling and intracellular stiffness generation to modulate FBGC formation.