Recent advances in dietary supplementation, in treating non-alcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is currently known as the most common liver problem, characterized by excessive lipid accumulation in hepatocytes, which may progress to other liver diseases such as nonalcoholic steatohepatitis, hepatic tissue fibrosis, liver cirrhosis, and failure or hepatocellular carcinoma. Since NAFLD is positively associated with the development of obesity, insulin resistance, and ultimately type 2 diabetes mellitus, it is often regarded as the hepatic manifestation of the metabolic syndrome. No pharmacologic treatment has yet been proven for this disease. For most patients with presumed or confirmed NAFLD, the only proven strategy is to offer lifestyle advice that can lead to sustained weight loss. Since insulin resistance, oxidative stress, inflammation, and necro-apoptosis are involved in NAFLD pathogenesis, it seems that every potential therapeutic agent should target one or some of these pathologic events. There are many well known anti-oxidants, anti-inflammatory, and insulin sensitizer dietary supplements which have shown beneficial effects on NAFLD improvement in animal and human studies. The purpose of this review is to explore the existing evidences on dietary supplements considered to have hepatoprotective properties, and to present some proposed mechanisms by which they may protect against NAFLD.


The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function.
Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet α cell development and function has important implications for the discovery of new therapies for diabetes. In this study, comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors, including the Pax6-associated lncRNA Paupar. We demonstrate that Paupar is enriched in glucagon-producing α cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential α cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 α cell target genes and corresponding α cell dysfunction, including blunted glucagon secretion. These findings illustrate a distinct mechanism by which a pancreatic lncRNA can coordinate glucose homeostasis by cell-specific regulation of a broadly expressed transcription factor.


The 27th Montreux Symposium on LC-MS.
The recent Montreux Symposium on LC-MS held in 2010 provided an insight into the key areas of present achievements and future developments in LC-MS. This domain is rapidly changing from a technology- to an application-driven enterprise. New demands for advanced options are coming from (medical) biology, biotechnology, pharmaceutical and nutrition research. In particular, new diagnostic options based on -omics technologies, miniaturization and advanced data handling are rapidly being developed in relation to questions coming from personalized medicine, claim support in nutritional research, biotechnology production support and the human microbiome.


Lipid profiles and obesity as potential risk factors of sudden sensorineural hearing loss.
The objective of our study was to establish whether increased lipid profiles and obesity affect the prevalence and prognosis of sudden sensorineural hearing loss (SSNHL). This was a case-controlled study with a longitudinal design. According to our criteria, 324 patients with SSNHL were included in this study. To manage potential covariates, 972 subjects with normal hearing from the Korean National Health and Nutrition Examination Survey were matched as control group according to their propensity scores. Age, level of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and body mass index (BMI) were obtained from the clinical data. Multivariate logistic regression analysis was used to investigate the association between SSNHL and lipid profiles or obesity in the 1296 subjects. Multivariate Cox regression analysis was used to determine whether lipid profiles and obesity are prognostic factors in patients with SSNHL. Mean body weight, BMI, TC, and TG were significantly higher in patients with SSNHL compared with control subjects (p<0.05). However, LDL-C values did not differ significantly between the two groups. Subjects with elevated TC and TG levels had a 2.20- (95% CI 1.50-3.24) and 1.50-fold (95% CI 1.08-2.08) increased odds, respectively, of SSNHL compared with subjects with normal TC and TG levels. Subjects with grade III BMI had a 1.59-fold (95% CI 1.17-2.16) increased odds of SSNHL. Multivariate Cox regression analyses revealed that BMI was an independent risk factor of treatment outcome, as patients with BMI ≥27.5 were less likely to achieve complete recovery than those with BMI <27.5 (p<0.05). The results of this study revealed that elevated TC and TG levels and increased BMI are significantly associated with the prevalence of SSNHL and its prognosis, indicating that vascular compromise may play an important role in the pathogenesis of SSNHL.


Quantitative Histopathology of Stained Tissues using Color Spatial Light Interference Microscopy (cSLIM).
Tissue biopsy evaluation in the clinic is in need of quantitative disease markers for diagnosis and, most importantly, prognosis. Among the new technologies, quantitative phase imaging (QPI) has demonstrated promise for histopathology because it reveals intrinsic tissue nanoarchitecture through the refractive index. However, a vast majority of past QPI investigations have relied on imaging unstained tissues, which disrupts the established specimen processing. Here we present color spatial light interference microscopy (cSLIM) as a new whole-slide imaging modality that performs interferometric imaging on stained tissue, with a color detector array. As a result, cSLIM yields in a single scan both the intrinsic tissue phase map and the standard color bright-field image, familiar to the pathologist. Our results on 196 breast cancer patients indicate that cSLIM can provide stain-independent prognostic information from the alignment of collagen fibers in the tumor microenvironment. The effects of staining on the tissue phase maps were corrected by a mathematical normalization. These characteristics are likely to reduce barriers to clinical translation for the new cSLIM technology.


Tubular lysosome morphology and distribution within macrophages depend on the integrity of cytoplasmic microtubules.
Pinocytosis of the fluorescent dye lucifer yellow labels elongated, membrane-bound tubular organelles in several cell types, including cultured human monocytes, thioglycolate-elicited mouse peritoneal macrophages, and the macrophage-like cell line J774.2. These tubular structures can be identified as lysosomes by acid phosphatase histochemistry and immunofluorescence localization of cathepsin L. The abundance of tubular lysosomes is markedly increased by treatment with phorbol 12-myristate 13-acetate (10 ng/ml). When labeled by pinocytosis of microperoxidase and examined by electron microscopic histochemistry, the tubular lysosomes have an outside diameter of approximately 75 nm and a length of several micrometers; they radiate from the cell's centrosphere in alignment with cytoplasmic microtubules and intermediate filaments. Incubation of phorbol myristate acetate-treated macrophages at 4 degrees C or in medium containing 5 microM colchicine or nocodazole at 37 degrees C leads to disassembly of microtubules and fragmentation of the tubular lysosomes. Return of the cultures to 37 degrees C or removal of nocodazole from the medium leads to reassembly of microtubules and the reappearance of tubular lysosomes within 10-20 min. We conclude that microtubules are essential for the maintenance of tubular lysosome morphology and that, in macrophages, a significant proportion of the lysosomal compartment is contained within these tubular structures.


How do similarities in spatial distributions and interspecific associations affect the coexistence of Quercus species in the Baotianman National Nature Reserve, Henan, China.
Congeneric species often have similar ecological characteristics and use similar resources. These similarities may make it easier for them to co-occur in a similar habitat but may also lead to strong competitions that limit their coexistence. Hence, how do similarities in congeneric species affect their coexistence exactly? This study mainly used spatial point pattern analysis in two 1 hm2 plots in the Baotianman National Nature Reserve, Henan, China, to compare the similarities in spatial distributions and interspecific associations of Quercus species. Results revealed that Quercus species were all aggregated under the complete spatial randomness null model, and aggregations were weaker under the heterogeneous Poisson process null model in each plot. The interspecific associations of Quercus species to non-Quercus species were very similar in Plot 1. However, they can be either positive or negative in different plots between the co-occurring Quercus species. The spatial distributions of congeneric species, interspecific associations with non-Quercus species, neighborhood richness around species, and species diversity were all different between the two plots. We found that congeneric species did have some similarities, and the closely related congeneric species can positive or negative associate with each other in different plots. The co-occurring congeneric species may have different survival strategies in different habitats. On the one hand, competition among congenerics may lead to differentiation in resource utilization. On the other hand, their similar interspecific associations can strengthen their competitive ability and promote local exclusion to noncongeneric species to obtain more living space. Our results provide new knowledge for us to better understand the coexistence mechanisms of species.


Polo kinase interacts with RacGAP50C and is required to localize the cytokinesis initiation complex.
The assembly and constriction of an actomyosin contractile ring in cytokinesis is dependent on the activation of Rho at the equatorial cortex by a complex, here termed the cytokinesis initiation complex, between a microtubule-associated kinesin-like protein (KLP), a member of the RacGAP family, and the RhoGEF Pebble. Recently, the activity of the mammalian Polo kinase ortholog Plk1 has been implicated in the formation of this complex. We show here that Polo kinase interacts directly with the cytokinesis initiation complex by binding RacGAP50C. We find that a new domain of Polo kinase, termed the intermediate domain, interacts directly with RacGAP50C and that Polo kinase is essential for localization of the KLP-RacGAP centralspindlin complex to the cell equator and spindle midzone. In the absence of Polo kinase, RacGAP50C and Pav-KLP fail to localize normally, instead decorating microtubules along their length. Our results indicate that Polo kinase directly binds the conserved cytokinesis initiation complex and is required to trigger centralspindlin localization as a first step in cytokinesis.


Effects of intra-amniotic lipopolysaccharide exposure on the fetal lamb lung as gestation advances.
Intra-amniotic lipopolysaccharide (LPS) exposure may affect neonatal outcome by altering fetal lung and immune system development. We hypothesized that intra-amniotic LPS exposure would cause persistent fetal pulmonary responses as the lungs develop in utero. Fetal lambs were exposed to intra-amniotic LPS at 118 or at 118 and 123 d of gestational age (GA) with delivery at 125, 133, or 140 d (term = 147 d). Immune responses, PU.1 expression, Toll-like receptor (TLR)-1,2,4,6 mRNA levels, mast cell levels, and pulmonary elastin deposition were evaluated. After a single dose of LPS, pulmonary inflammatory responses were observed with increases of (i) PU.1 and TLR1 at 125 d GA and (ii) monocytes, lymphocytes, TLR2, and TLR6 at 133 d GA. Repetitive LPS exposure resulted in (i) increases of neutrophils, monocytes, PU.1, and TLR1 at 125 d GA; (ii) increases of neutrophils, PU.1, and TLR2 at 133 d GA; and (iii) decreases of mast cells, elastin foci, TLR4, and TLR6 at early gestation. At 140 d GA, only PU.1 was increased after repetitive LPS exposure. The preterm fetal lung can respond to a single exposure or repeated exposures from intra-amniotic LPS in multiple ways, but the absence of inflammatory and structural changes in LPS-exposed fetuses delivered near term suggest that the fetus can resolve an inflammatory stimulus in utero with time.


Diffusion kurtosis imaging study of prostate cancer: preliminary findings.
To evaluate the differences in parameters of diffusion kurtosis imaging (DKI) between prostate cancer, benign prostatic hyperplasia (BPH), and benign peripheral zone (PZ). Twenty-four foci of prostate cancer, 41 BPH nodules (14 stromal and 27 nonstromal hyperplasia), and 20 benign PZ from 20 patients who underwent radical prostatectomy were investigated. Diffusion-weighted imaging (DWI) was performed using 11 b-values (0-1500 s/mm(2) ). DKI model relates DWI signal decay to parameters that reflect non-Gaussian diffusion coefficient (D) and deviations from normal distribution (K). A mixed model analysis of variance and receiver operating characteristic (ROC) analyses were performed to assess the statistical significance of the metrics of DKI and apparent diffusion coefficient (ADC). K was significantly higher in prostate cancer and stromal BPH than in benign PZ (1.19 ± 0.24 and 0.99 ± 0.28 versus 0.63 ± 0.23, P < 0.001 and P < 0.001, respectively). K showed a trend toward higher levels in prostate cancer than in stromal BPH (1.19 ± 0.24 versus 0.99 ± 0.28, P = 0.051). On the ROC analyses, a significant difference in area under the curve was not observed between K and ADC, however, K showed the highest sensitivity among three parameters. DKI may contribute to the imaging diagnosis of prostate cancer, especially in the differential diagnosis of prostate cancer and BPH.


Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma.
Folic acid may affect the development of human cancers. However, few studies have evaluated the consumption of diet folate in the prognosis of patients with esophageal squamous cell carcinoma (ESCC). One hundred and twenty five ESCC patients underwent esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed up. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms on the prognosis of ESCC were evaluated by using Cox proportional hazard regression models. Our analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 3.06 years for low or moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval) [HRs (95% CI)] were 0.72 (0.36-1.46) for moderate and 0.39 (0.20-0.78) for high folate intake, respectively (P for trend = 0.007). This preventive effect was more evident in patients carrying MTHFR 677CC genotype. No significant relation was observed between aberrant DNA methylation of P16, MGMT and hMLH1 gene, as well as MTHFR C677T genetic polymorphisms and the prognosis of ESCC. Our research indicated that diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. From a practical viewpoint, the findings of our study help to establish practical intervention and surveillance strategies for managements of ESCC patients and can finally decrease the disease burden.


[Effects of lactulose treatment on the course of subclinical hepatic encephalopathy].
To observe the natural history of subclinical hepatic encephalopathy (SHE) and to compare the efficacy of long-term and short-term treatment of lactulose. Sixty SHE patients with abnormal psychometric tests performance and/or evoked potentials were randomly divided into 3 groups of 20 cases: control group (given vitamin B complex only for 24 weeks), short-term lactulose group (administered orally with lactulose 15 - 90 ml/d for 8 weeks in addition to vitamin B complex as described above), and long-term lactulose group (administered orally with lactulose 15 - 90 ml/d for 24 weeks in addition to vitamin B complex as described above). Blood ammonia, liver function, number connection test (NCT), digital symbol test (DST), quality of life, and somatosensory evoked potential (SEP) were investigated 0, 8, 16, and 24 weeks after the onset of experiment. The incidence of HE was recorded. No statistically significant difference was found in terms of liver function score of ENVER, and SEP any time after the onset of the experiment (all P > 0.05). Eight weeks after the onset of experiment the performance of NCT and DST was significantly improved in the 2 lactulose groups than in the control group (both P < 0.05), without significant difference between the two treatment groups (P > 0.05). However, significant difference failed to appear in blood ammonia 8 weeks after, and began to be found since the 16th week between the control group and long-term lactulose group (P < 0.05). Since the 16th week the condition of the long-term lactulose group was much better than those of the other 2 groups in terms of blood ammonia, NCT performance, scores of PHYS, PSYCH, and SCOIL (all P < 0.05), and not in DST performance (P > 0.05). 24 weeks after, the condition of the long-term lactulose group was still better than those of the other 2 groups (all P < 0.05), however, no significant difference was found in terms of the above-mentioned indicators between the control and short-term lactulose groups (all P > 0.05). The HE prevalence of the control, short-term lactulose, and long-term lactulose groups were 40%, 30%, and 5% respectively 24 weeks after, with a significant difference between the long-term lactulose group and between any of the other groups (both P < 0.05) and without a statistically significant difference between the control and short-term lactulose groups (P > 0.05). Long-term lactulose treatment lowers blood ammonia and improves the psychometric performance and quality of life, thus lowering the prevalence of clinical HE. However, short-term lactulose treatment fails to improve of the natural course of HE.


Hybrid fold recognition: combining sequence derived properties with evolutionary information.
Recent assessments of structure prediction have demonstrated that (i) although fold recognition methods can often identify remote similarities when standard sequence search methods fail, the score of the top-ranking fold is not always significant enough to allow a confident prediction; (ii) the use of structural information such as secondary structure increases recognition accuracy; (iii) modern sequence-based methods incorporating evolutionary information from neighboring sequences can often identify very remote similarities; (iv) there is no one single method that is superior to other methods when evaluated over a wide range of targets, and (v) extensive human-expert intervention is usually required for the most difficult prediction targets. Here, I describe a new, hybrid fold recognition method that incorporates structural and evolutionary information into a single fully automated method. This work is a first attempt towards the automation of some of the processes that are often applied by human predictors. The method is tested with two cases that are often applied by human predictors. The method is tested with two fold-recognition benchmarks demonstrating a superior performance. The higher sensitivity and selectivity enable the applicability of this method at genomic scales.


Subclinical trace element deficiency in children with undue susceptibility to infections.
Serum concentrations of iron, copper, zinc and magnesium and also serum transferrin and ceruloplasmin were investigated in 28 children aged 10 months to 10 years with undue susceptibility to infections. None of the children had any classical immune defect. Seven of them had had frequent upper respiratory tract infections, 16 had suffered from frequent infections of the middle ear and five from mainly lower respiratory tract infections. Thirteen healthy children aged 9 to 18 years residing in the same area served as controls. The children with undue susceptibility to infections had significantly lower mean serum iron (p less than 0.05) and zinc (p less than 0.001) levels than the healthy controls. The mean serum concentrations of copper and magnesium and of transferrin and ceruloplasmin did not differ between the patients and controls. Children with frequent middle ear infections seemed to account for most of the differences in the serum levels of iron and zinc. An inverse correlation was observed between duration of breast feeding and serum concentration of zinc, and between weight as well as height and serum magnesium. The reasons for these changes and the possible role of trace element deficiency as a factor predisposing to or perpetuating undue susceptibility to infections in children are discussed.


Establishing community advisory boards for clinical trial research in Malawi: engendering ethical conduct in research.
In this article I deal with extending the ethical principles of research to include communities through the establishment of Community Advisory Boards (CABs). The aim of the project on which this article is based demonstrates the need for protecting communities that participate in research in order to stimulate ethical conduct in research in Malawi. In the article, I provide an overview on the role and functions of CABs. I discuss the establishment of CABs in Malawi and present descriptions of the processes and challenges involved. I conclude by sharing experiences of some of the key lessons learnt from the establishment of CABs.


Shutoff of HeLa cell protein synthesis by encephalomyocarditis virus and poliovirus: a comparative study.
Previous experimental results have suggested that poliovirus and encephalomyocarditis (EMC) virus employ very different mechanisms for shutting off host protein synthesis. However, this conclusion is suspect, inasmuch as different cell types were used for the two viruses; hence the apparent mechanistic differences might be specific for cell type and not virus type. To test this possibility we compared shutoff mechanisms in poliovirus- and EMC virus-infected HeLa cells. Striking differences were seen: poliovirus-induced shutoff was much more rapid and extensive than that induced by EMC virus; relative translation rates of certain host proteins were inhibited to different extents by the two viruses; initiation factors prepared from poliovirus-infected cells were specifically defective for translation of capped mRNA's in vitro, whereas those from EMC virus-infected cells were not. These results indicate that EMC virus and poliovirus employ different mechanisms for the shutoff of HeLa cell protein synthesis. This conclusion is consistent with much earlier work and indicates that many differences previously reported are specific to virus type.


Brachial plexus catheter reservoir for the treatment of upper-extremity cancer pain: technical case report.
Infiltration of the brachial plexus with anesthetics can provide relief of upper-extremity pain from invasive cancer. Because the analgesia is short-lived, however, repeated invasive treatments are necessary. We describe the implantation of a catheter reservoir system, in which anesthetic injections through a subcutaneous port resulted in anesthetic infiltration of the brachial plexus. A 47-year-old Hispanic man with squamous cell carcinoma of the larynx had undergone surgical resection, radiation treatment, and chemotherapy. Two years later, he had locally recurrent disease involving the brachial plexus, neck, and chest wall. The patient's pain was minimally responsive to narcotics, which also caused severe nausea and anorexia. The brachial plexus was localized percutaneously with a needle electrode stimulator. Contrast injection under fluoroscopy confirmed entry into the plexus sheath. With use of the Seldinger technique, two Silastic catheters were placed within the brachial plexus and attached with a "Y" connector to a reservoir. The patient experienced complete relief of upper-extremity pain after a test injection with xylocaine. Thereafter, serial injections of bupivacaine with triamcinolone at 1-week intervals provided complete pain relief. After the treatments were initiated, the patient reported improved sleep and an improvement in his quality of life. A catheter reservoir system for brachial plexus analgesia can provide safe and effective analgesia for upper-extremity pain. This technique negates the need for repeated invasive procedures and avoids the complications of neurolysis.


Hemorrhage from the cosmetic otoplasty of Doberman Pinschers with von Willebrand's disease.
The hemorrhagic tendencies of 23 Doberman Pinscher pups were observed during cosmetic otoplasty and were ranked by a +1 to +4 grading system (+1 = least hemorrhage, and +4 = most hemorrhage). A second estimate of the hemostatic competencies of these dogs was made by counting the gauze sponges used in the otoplasties. Factor VIII-related antigen concentrations and coagglutinin cofactor concentrations were measured in plasma samples from blood drawn not more than 30 hours before the surgical procedures were done. The factor VIII-related antigen concentrations were between 9% and 147% of the concentration in a normal plasma pool, and the coagglutinin cofactor concentrations were between 1% and 165%, indicating that some of these dogs had von Willebrand's disease. The hemorrhagic tendencies of 12 pups were graded +1. This group had a mean antigen concentration of 75% (min-max, 38% to 147%) and a mean coagglutinin cofactor concentration of 89% (min-max, 42% to 165%). These were significantly greater than the antigen and cofactor concentrations of the grades +2 (n = 5), +3 (n = 3), or +4 (n = 3) dogs. Significant differences were not found when antigen concentrations of the grade +2 dogs (mean, 16%; min-max, 11% to 22%), grade +3 dogs (mean, 13%; 12% to 16%), and grade +4 dogs (mean, 11%; 9% to 12%) were compared with each other, nor were significant differences seen among the coagglutinin cofactor concentrations of the grade +2 dogs (mean, 7%; min-max, 1% to 11%), grade +3 dogs (mean, 6%, 4% to 8%), and grade +4 dogs (mean, 5%; 2% to 9%).(ABSTRACT TRUNCATED AT 250 WORDS)


Correlation between blood lead concentration and iron deficiency in Iranian children.
Iron deficiency anaemia is the most common nutritional anaemia among children. Lead toxicity is a serious health threat, especially in developing countries due to environmental pollution. It was thus aimed to investigate correlation between blood lead concentration and iron deficiency in children of Mashhad, Iran. This cross sectional study was performed on children between 1 year and 10 years, in Imam Reza teaching hospital of Mashhad, Iran, in 2010. Indeed during complete blood count (CBC), we measured iron and total iron binding capacity (TIBC) by colorimetric methods, ferritin by radioimmune assay and blood lead concentration by atomic absorption method. Results were analysed by Statistical Package for Social Sciences (SPSS) (version 11.5), using statistical tests including independent sample t-test, Mann-Whitney U test, Spearman's test and analysis of variance (ANOVA) and Pearson's or Spearman's correlation coefficient. P value ≤ 0.05 was considered as a significant level. We studied 223 cases including 98 control children and 125 patients. All children had lead intoxication. Mean (±SD) blood lead concentration in the control group was 57.1 ± 25.3 (ranged 20-212) μg/dl and in the patient group was 57 ± 20.4 (ranged 10.9-159) μg/dl with no significant difference (P value = 0.713). We also did not find any correlation between blood lead concentration and haemoglobin, ferritin, iron, TIBC, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), white blood cells (WBC) and platelets. Based on these results, no correlation was found between blood lead concentration and iron deficiency in the children. Because all children had lead intoxication, further studies in highly polluted and a comparison with a low polluted area are necessary to make a general conclusion.


Identity and phylogenetic placement of Spirogyra species (Zygnematophyceae, Charophyta) from California streams and elsewhere(1).
Diversity of the filamentous green algae in the genus Spirogyra (Zygnematophyceae) was investigated from more than 1,200 stream samples from California. We identified 12 species of Spirogyra not previously known for California (CA), including two species new to science, Spirogyra californica sp. nov. and Spirogyra juliana sp. nov. Environmental preferences of the Californian species are discussed in the light of their restricted distribution to stream habitats with contrasting nutrient levels. We also investigated the systematic relationships of Spirogyra species from several continents using the chloroplast-encoded genes ribulose-1,5-bisphosphate carboxylase/hydrogenase large subunit (rbcL) and the beta subunit of the ATP synthase (atpB). Californian species were positioned in most major clades of Spirogyra. The phylogeny of Spirogyra and its taxonomic implications are discussed, such as the benefits of combining structural and molecular data for more accurate and consistent species identification. Considerable infraspecific genetic variation of globally distributed Spirogyra species was observed across continental scales. This finding suggests that structurally similar species from distant regions may be genetically dissimilar and that Spirogyra may contain a large number of cryptic species. Correlating the morphological and genetic variation within the genus will be a major challenge for future researchers.


Tenacibaculum aestuariivivum sp. nov., isolated from a tidal flat.
A Gram-stain-negative, aerobic, non-motile, non-spore-forming bacterial strain, designated JDTF-79T, was isolated from a tidal flat in Jindo, an island of South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain JDTF-79T grew optimally at 25 °C and in the presence of 2.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain JDTF-79T fell within the clade comprising the type strains of species of the genus Tenacibaculum, clustering with the type strains of Tenacibaculum dicentrarchi, Tenacibaculum ovolyticum, 'Tenacibaculum haliotis' and Tenacibaculum soleae. The novel strain exhibited highest 16S rRNA gene sequence similarity (98.3 %) to the type strain of T. dicentrarchi and sequence similarities of 93.5-96.9 % to the type strains of the other species of the genus Tenacibaculum. Strain JDTF-79T contained MK-6 as the predominant menaquinone and anteiso-C15 : 0, iso-C15 : 0 3-OH and iso-C15 : 0 as the major fatty acids. The major polar lipids of strain JDTF-79T were phosphatidylethanolamine, one unidentified lipid and one unidentified aminophospholipid. The DNA G+C content of strain JDTF-79T was 30.3 mol%. Strain JDTF-79T had a mean DNA-DNA relatedness value of 19 % with the type strain of T. dicentrarchi. The differential phenotypic properties, together with the phylogenetic and genetic data, revealed that strain JDTF-79T is separated from other recognized species of the genus Tenacibaculum. On the basis of the data presented, strain JDTF-79T is considered to represent a novel species of the genus Tenacibaculum, for which the name Tenacibaculum aestuariivivum sp. nov. is proposed. The type strain is JDTF-79T (=KCTC 52980T=NBRC 112903T).


The time to offer treatments for COVID-19.
Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.


Epigenetic biomarkers in the diagnosis of ovarian cancer.
Current diagnostic methods for ovarian cancer have limited performance. Recent advances within the field of epigenetics have shifted the clinical implementation of epigenetic biomarkers as a diagnostic approach from a dream for the future to a present-day consideration. Patients could potentially benefit greatly from this novel diagnostic approach. Epigenetic mechanisms in cancer are discussed, with a focus on potential diagnostic epigenetic biomarkers in ovarian cancer in tissue and body fluids. A literature search was undertaken (on 22-09-2011) for these subjects using the search syntax ((((((((((((((("ovarian") OR "ovary") OR "ovarian cancer") OR "ovarian cancers") OR "cancer of the ovary") OR "tumour of the ovary") OR "ovarian tumor") OR "ovarian tumors") OR "ovarian tumour") OR "ovarian tumours") OR "ovarian neoplasm") OR "ovarian neoplasms" OR "ovarian carcinoma") OR "ovarian carcinomas") OR "carcinoma of the ovary")) AND ((((((((("epigenetics") OR "epigenetic") OR "epigenome") OR "methylation") OR "hypermethylation") OR "chromatin modification") OR "histone") OR "histones") OR "acetylation") To date no single epigenetic biomarker is able to accurately detect early ovarian cancer in either tissue or body fluids. A panel of epigenetic biomarkers based on aberrant DNA methylation in body fluids, especially blood, has the best chance of being implemented in clinical practice, as it is semi-invasive. However, progression toward clinical use is hampered by the lack of detection techniques combining high throughput and accuracy with low cost, by difficulties in establishing reliable reference values and by the heterogeneous nature of ovarian cancer. Until addressed, implementation as a diagnostic measure complimenting current techniques in select cases seems a far way to go, and implementation as a primary screening tool is yet even farther away.


Specificity of leaf mitochondrial and chloroplast processing systems for nuclear-encoded precursor proteins.
The specificity of the mitochondrial and chloroplast processing enzymes for the nuclear-encoded precursor proteins was investigated. Mitochondrial precursor proteins of the Nicotiana plumbaginifolia and the Neurospora crassa beta subunits of F1-ATPase and the Neurospora Rieske FeS precursor protein were processed to the correct mature size by matrix extracts isolated from spinach leaves, yeast, rat liver and beef heart. The mitochondrial extracts failed to process chloroplast precursor proteins of the stromal small subunit of ribulose 1,5-bisphosphate carboxylase and the thylakoid 33 kDa protein of the oxygen-evolving complex. Both mitochondrial F1 beta precursors were specifically processed by a soluble stromal extract from chloroplasts. However, no processing of the Rieske FeS precursor protein was observed under the same conditions with the chloroplast extract. The cleavage of the mitochondrial F1 beta precursors by the chloroplast extract was shown to be sensitive to the metal chelators EDTA and ortho-phenanthroline. The cleavage site of the mitochondrial F1 beta precursor by the chloroplast soluble extract appears to be located at the N-terminus.


Understanding anthelmintic resistance in livestock using "omics" approaches.
Widespread and improper use of various anthelmintics, genetic, and epidemiological factors has resulted in anthelmintic-resistant (AR) helminth populations in livestock. This is currently quite common globally in different livestock animals including sheep, goats, and cattle to gastrointestinal nematode (GIN) infections. Therefore, the mechanisms underlying AR in parasitic worm species have been the subject of ample research to tackle this challenge. Current and emerging technologies in the disciplines of genomics, transcriptomics, metabolomics, and proteomics in livestock species have advanced the understanding of the intricate molecular AR mechanisms in many major parasites. The technologies have improved the identification of possible biomarkers of resistant parasites, the ability to find actual causative genes, regulatory networks, and pathways of parasites governing the AR development including the dynamics of helminth infection and host-parasite infections. In this review, various "omics"-driven technologies including genome scan, candidate gene, quantitative trait loci, transcriptomic, proteomic, and metabolomic approaches have been described to understand AR of parasites of veterinary importance. Also, challenges and future prospects of these "omics" approaches are also discussed.


Cerebrovascular reactivity is associated with maximal aerobic capacity in healthy older adults.
Recently, several high-impact reviews suggest that regular aerobic exercise is beneficial for maintaining cognitive function in aging adults. Higher cerebral blood flow and/or cerebrovascular reactivity may explain the favorable effect of exercise on cognition. In addition, prostaglandin-mediated vasodilator responses may be influenced by regular exercise. Therefore, our purpose was to evaluate middle cerebral artery (MCA) vasodilator responses in healthy adults before and after cyclooxygenase inhibition. A total of 16 young (26 ± 6 yr; 8 males, 8 females) and 13 older (64 ± 6 yr; 7 males, 6 females) healthy adults participated in the study. Aerobic fitness was determined by maximal aerobic capacity (Vo2max) on a cycle ergometer. MCA velocity (MCAv) was measured at baseline and during stepped hypercapnia (2%, 4%, and 6% FiCO2) before and after cyclooxygenase inhibition using indomethacin. To account for differences in blood pressure, cerebrovascular conductance index (CVCi) was calculated as MCAv/mean arterial pressure. Cerebrovascular reactivity slopes were calculated from the correlation between either MCAv or CVCi and end-tidal CO2. Young adults demonstrated greater MCAv reactivity (1.61 ± 0.17 vs. 1.06 ± 0.15 cm·s(-1)·mmHg(-1); P < 0.05) and CVCi reactivity (0.015 ± 0.002 vs. 0.007 ± 0.002 cm·s(-1)·mmHg(-1); P < 0.05) compared with the older adults. There was no association between cerebrovascular reactivity and Vo2max in the combined group of subjects; however, in older adults MCAv reactivity was correlated with maximal aerobic fitness (r = 0.64; P < 0.05). Furthermore, the change in MCAv reactivity (between baseline and indomethacin trials) was also associated with Vo2max (r = 0.59; P < 0.05) in older adults. Cerebral vasodilator responses to hypercapnia were associated with maximal aerobic capacity in healthy older adults. These results may explain the physiological link between regular aerobic exercise and improved cognitive function in aging adults.


Depot risperidone-induced adverse metabolic alterations in female rats.
Atypical antipsychotics are associated with adverse metabolic effects including weight gain, increased adiposity, dyslipidaemia, alterations in glucose metabolism and insulin resistance. Increasing evidence suggests that metabolic dysregulation precedes weight gain development. The aim of this study was to evaluate alterations in adipokines, hormones and basic serum biochemical parameters induced by chronic treatment with depot risperidone at two doses (20 and 40 mg/kg) in female Sprague-Dawley rats. Dose-dependent metabolic alterations induced by risperidone after 6 weeks of treatment were revealed. Concomitant to weight gain and increased liver weight, an adverse lipid profile with an elevated triglyceride level was observed in the high exposure group, administered a 40 mg/kg dose repeatedly, while the low dose exposure group, administered a 20 mg/kg dose, developed weight gain without alterations in the lipid profile and adipokine levels. An initial peak in leptin serum level after the higher dose was observed in the absence of weight gain. This finding may indicate that the metabolic alterations observed in this study are not consequent to body weight gain. Taken together, these data may support the primary effects of atypical antipsychotics on peripheral tissues.


Cerebral vascular responses to tolazoline infusions in the piglet.
Ventilated piglets were studied to determine the effects of intravenous tolazoline infusions during hypoxia on the cerebral circulation and to assess whether cerebral responses reflect tolazoline-induced alterations in the systemic vasculature. We measured cerebral blood flow (CBF), cardiac output (CO), mean arterial pressure (MAP) and cerebral arteriovenous differences of O2 content during normoxia, isocapnic hypoxia (FiO2 14%), and hypoxia (FiO2 14%) with infusions of either saline (n = 7) or tolazoline (n = 10). Hypoxia alone resulted in comparable cardiovascular alterations in both groups. During hypoxia + saline MAP remained stable, but decreased during hypoxia + tolazoline, reflecting reductions in systemic vascular resistance (SVR) and variable changes in CO (reductions in 4 piglets, increases in 6). In both groups CBF rose during hypoxia alone and remained elevated during hypoxia with saline or tolazoline. Cerebral O2 delivery, extraction and uptake were unchanged in both groups. Although mean CBF was similar during hypoxia with saline or tolazoline, CBF was variable during tolazoline, decreasing in 4 of 10 piglets; CBF never fell with saline. Tolazoline-induced changes in MAP correlated with CBF (r = 0.90, P less than 0.001) emphasizing the importance of MAP in maintaining CBF during hypoxia. Importantly, decreases in CBF also paralleled falls in CO. In the presence of a pressure-passive cerebral vasculature, the adequacy of increases in CO to offset tolazoline-induced reductions in SVR determines MAP and ultimately CBF. Thus, cerebral vascular responses to tolazoline infusions during hypoxia reflect tolazoline-induced systemic circulatory derangements.


A runs-test algorithm: contingent reinforcement and response run structures.
Four rats' choices between two levers were differentially reinforced using a runs-test algorithm. On each trial, a runs-test score was calculated based on the last 20 choices. In Experiment 1, the onset of stimulus lights cued when the runs score was smaller than criterion. Following cuing, the correct choice was occasionally reinforced with food, and the incorrect choice resulted in a blackout. Results indicated that this contingency reduced sequential dependencies among successive choice responses. With one exception, subjects' choice rule was well described as biased coin flipping. In Experiment 2, cuing was removed and the reinforcement criterion was changed to a percentile score based on the last 20 reinforced responses. The results replicated those of Experiment 1 in successfully eliminating first-order dependencies in all subjects. For 2 subjects, choice allocation was approximately consistent with nonbiased coin flipping. These results suggest that sequential dependencies may be a function of reinforcement contingency.


[Regulatory molecular mechanisms of the neurochemical processes. History and the present time].
Multiple neurochemical mechanisms (neurotransmitters, regulatory peptides, neurotrophic growth factors, and proteins of the signaling transducer systems) maintain the integrity of nerve cell circuits, facilitate the responses to environmental demands and promote the recovery of a function after injury. The recent application of modern approaches of molecular and cellular biology to the problem of "diseased (bad) brain" reveals a remarkable capacity within brain cells for adaptation to aging and resistance to a disease. The death of neurons in different neurological disorders involves apoptotic biochemical cascades leading to mitochondrial alterations, upstream pro-apoptotic effectors, and caspases activation. At the cellular level, neuronal apoptosis in ischemic and neurodegenerative disorders may be triggered by oxidative stress, mitochondrial compromise and disruption of calcium homeostasis. Both genetic and environmental factors, and the aging process itself, contribute to initiation of such neuronal apoptosis. Neuroprotective (antiapoptotic) signal pathways involving neurotrophic factors, neuropeptides, and mediators able to counteract with effects of aging and genetic predisposition in experimental models and clinical events of neuro-destructive disorders.


[História, Ciências, Saúde--Manguinhos: examining 12 years of regular circulation].
The article analyzes the trajectory of História, Ciências, Saúde--Manguinhos since it was first released in 1994. This multidisciplinary journal opens its pages to unpublished, peer-reviewed articles, images, documents, interviews, and other material that address issues and important figures in the history of medicine, public health, and the life sciences. Approaching from the perspectives of health and of historiography, the article explores the context in which the journal was born and discusses the daily workings of a scientific editorial office. Tables and graphs illustrate variations in the topics submitted for publication, acceptance and rejection rates for articles, the geographical origin of authors, and how the profiles of contributors and readers of the print and online versions differ in terms of their areas of interest.


The KH-type splicing regulatory protein (KSRP) regulates type III interferon expression post-transcriptionally.
Type III interferons (IFNs) are the latest members of the IFN family. They play an important role in immune defense mechanisms, especially in antiviral responses at mucosal sites. Moreover, they control inflammatory reactions by modulating neutrophil and dendritic cell functions. Therefore, it is important to identify cellular mechanisms involved in the control of type III IFN expression. All IFN family members contain AU-rich elements (AREs) in the 3'-untranslated regions (3'-UTR) of their mRNAs that determine mRNA half-life and consequently the expressional level of these cytokines. mRNA stability is controlled by different proteins binding to these AREs leading to either stabilization or destabilization of the respective target mRNA. The KH-type splicing regulatory protein KSRP (also named KHSRP) is an important negative regulator of ARE-containing mRNAs. Here, we identify the interferon lambda 3 (IFNL3) mRNA as a new KSRP target by pull-down and immunoprecipitation experiments, as well as luciferase reporter gene assays. We characterize the KSRP-binding site in the IFNL3 3'-UTR and demonstrate that KSRP regulates the mRNA half-life of the IFNL3 transcript. In addition, we detect enhanced expression of IFNL3 mRNA in KSRP-/- mice, establishing a negative regulatory function of KSRP in type III IFN expression also in vivo Besides KSRP the RNA-binding protein AUF1 (AU-rich element RNA-binding protein 1) also seems to be involved in the regulation of type III IFN mRNA expression.


Role of endothelin in mediating postmenopausal hypertension in a rat model.
Cardiovascular disease is the leading cause of death in women after menopause. Hypertension, a major cardiovascular risk factor, becomes more prevalent after menopause. The mechanisms responsible for the increase in blood pressure (BP) in postmenopausal women are unknown. We have recently characterized the aged, postestrous-cycling (PMR) spontaneously hypertensive rats (SHR) as a model of postmenopausal hypertension. The purpose of the present study was to determine whether endothelin plays a role in the increased BP in PMR. Premenopausal female SHR, aged 4-5 mo (YF), and PMR, aged 16 mo, were studied. Expression of preproendothelin-1 mRNA was not different in either renal cortex or medulla between PMR and YF (n = 7-8/group). In contrast, ET-1 peptide expression was significantly higher in renal cortex of PMR than in renal cortex of YF, but there was no difference in medullary ET-1. Expression of endothelin ET(A) receptor (ET(A)R) mRNA was lower in renal cortex and medulla of PMR than of YF. Additional groups of rats (n = 6-7/group) were treated for 3 wk with the ET(A)R antagonist ABT-627 (5 mg.kg(-1).day(-1)). BP was significantly higher in PMR than in YF. ET(A)R antagonist reduced BP in PMR by 20% to the level found in control YF. ET(A)R antagonist had no effect on BP in YF. These data support the hypothesis that the increase in BP in PMR is mediated in part by endothelin and the ET(A)R.


Risk of Mortality Following Surgery in Patients With a Previous Cardiovascular Event.
There is a lack of consensus regarding the interval of time-dependent postoperative mortality risk following acute coronary syndrome or stroke. To determine the magnitude and duration of risk associated with the time interval between a preoperative cardiovascular event and 30-day postoperative mortality. This is a longitudinal retrospective population-based cohort study. This study linked data from the Hospital Episode Statistics for National Health Service England, Myocardial Ischaemia National Audit Project and the Office for National Statistics mortality registry. All adults undergoing a National Health Service-funded noncardiac, nonneurologic surgery in England between April 1, 2007, and March 31, 2018, registered in Hospital Episode Statistics Admitted Patient Care were included. Data were analyzed from July 2021 to July 2022. The time interval between a previous cardiovascular event (acute coronary syndrome or stroke) and surgery. The primary outcome was 30-day all-cause mortality. Secondary outcomes were postoperative mortality at 60, 90, and 365 days. Multivariable logistic regression models with restricted cubic splines were used to estimate adjusted odds ratios. There were 877 430 patients with and 20 582 717 without a prior cardiovascular event (overall mean [SD] age, 53.4 [19.4] years; 11 577 157 [54%] female). Among patients with a previous cardiovascular event, the time interval associated with increased risk of postoperative mortality was surgery within 11.3 months (95% CI, 10.8-11.7), with subgroup risks of 14.2 months before elective surgery (95% CI, 13.3-15.3) and 7.3 months for emergency surgery (95% CI, 6.8-7.8). Heterogeneity in these timings was noted across many surgical specialties. The time-dependent risk intervals following stroke and myocardial infarction were similar, but the absolute risk was greater following a stroke. Regarding surgical urgency, the risk of 30-day mortality was higher in those with a prior cardiovascular event for emergency surgery (adjusted hazard ratio, 1.35; 95% CI, 1.34-1.37) and an elective procedure (adjusted hazard ratio, 1.83; 95% CI, 1.78-1.89) than those without a prior cardiovascular event. In this study, surgery within 1 year of an acute coronary syndrome or stroke was associated with increased postoperative mortality before reaching a new baseline, particularly for elective surgery. This information may help clinicians and patients balance deferring the potential benefits of the surgery against the desire to avoid increased mortality from overly expeditious surgery after a recent cardiovascular event.


The French eHealth Acceptability Scale Using the Unified Theory of Acceptance and Use of Technology 2 Model: Instrument Validation Study.
Technology-based physical activity suggests new opportunities for public health initiatives. Yet only 45% of technology interventions are theoretically based, and the acceptability mechanisms have been insufficiently studied. Acceptability and acceptance theories have provided interesting insights, particularly the unified theory of acceptance and use of technology 2 (UTAUT2). In several studies, the psychometric qualities of acceptability scales have not been well demonstrated. The aim of this study was to adapt the UTAUT2 to the electronic health (eHealth) context and provide a preliminary validation of the eHealth acceptability scale in a French sample. In line with the reference validation methodologies, we carried out the following stages of validating the scale with a total of 576 volunteers: translation and adaptation, dimensionality tests, reliability tests, and construct validity tests. We used confirmatory factor analysis to validate a 22-item instrument with 7 subscales: Performance Expectancy, Effort Expectancy, Social Influence, Facilitating Conditions, Hedonic Motivation, Price Value, and Habit. The dimensionality tests showed that the bifactor confirmatory model presented the best fit indexes: χ2173=434.86 (P<.001), χ2/df=2.51, comparative fit index=.97, Tucker-Lewis index=.95, and root mean square error of approximation=.053 (90% CI .047-.059). The invariance tests of the eHealth acceptability factor structure by sex demonstrated no significant differences between models, except for the strict model. The partial strict model demonstrated no difference from the strong model. Cronbach alphas ranged from .77 to .95 for the 7 factors. We measured the internal reliability with a 4-week interval. The intraclass correlation coefficients for each subscale ranged from .62 to .88, and there were no significant differences in the t tests from time 1 to time 2. Assessments for convergent validity demonstrated that the eHealth acceptability constructs were significantly and positively related to behavioral intention, usage, and constructs from the technology acceptance model and the theory of planned behavior. The 22-item French-language eHealth acceptability scale, divided into 7 subscales, showed good psychometric qualities. This scale is thus a valid and reliable tool to assess the acceptability of eHealth technology in French-speaking samples and offers promising avenues in research, clinical practice, and marketing.


Preadmission Application of 2% Chlorhexidine Gluconate (CHG): Enhancing Patient Compliance While Maximizing Skin Surface Concentrations.
Surgical site infections (SSIs) are responsible for significant morbidity and mortality. Preadmission skin antisepsis, while controversial, has gained acceptance as a strategy for reducing the risk of SSI. In this study, we analyze the benefit of an electronic alert system for enhancing compliance to preadmission application of 2% chlorhexidine gluconate (CHG). Following informed consent, 100 healthy volunteers in an academic, tertiary care medical center were randomized to 5 chlorhexidine gluconate (CHG) skin application groups: 1, 2, 3, 4, or 5 consecutive applications. Participants were further randomized into 2 subgroups: with or without electronic alert. Skin surface concentrations of CHG (μg/mL) were analyzed using a colorimetric assay at 5 separate anatomic sites. Preadmission application of chlorhexidine gluconate, 2% Mean composite skin surface CHG concentrations in volunteer participants receiving EA following 1, 2, 3, 4, and 5 applications were 1,040.5, 1,334.4, 1,278.2, 1,643.9, and 1,803.1 µg/mL, respectively, while composite skin surface concentrations in the no-EA group were 913.8, 1,240.0, 1,249.8, 1,194.4, and 1,364.2 µg/mL, respectively (ANOVA, P<.001). Composite ratios (CHG concentration/minimum inhibitory concentration required to inhibit the growth of 90% of organisms [MIC90]) for 1, 2, 3, 4, or 5 applications using the 2% CHG cloth were 208.1, 266.8, 255.6, 328.8, and 360.6, respectively, representing CHG skin concentrations effective against staphylococcal surgical pathogens. The use of an electronic alert system resulted in significant increase in skin concentrations of CHG in the 4- and 5-application groups (P<.04 and P<.007, respectively). The findings of this study suggest an evidence-based standardized process that includes use of an Internet-based electronic alert system to improve patient compliance while maximizing skin surface concentrations effective against MRSA and other staphylococcal surgical pathogens.


Treatment of ruptured intracranial aneurysms: comparison of stenting and balloon remodeling.
Stent-assisted coiling (SAC) and balloon-assisted coiling (BAC) are 2 well-established techniques for the treatment of complex and wide-necked intracranial aneurysms. Most clinicians are reluctant to perform SAC in the setting of subarachnoid hemorrhage because of the need for dual antiplatelet therapy. To compare the safety and efficacy of SAC and BAC in acutely ruptured complex and wide-necked aneurysms. Forty-four patients underwent SAC and 40 underwent BAC. Patients treated with SAC received antiplatelet medications. Perioperative adverse events and outcomes at follow-up (mean, 7.4 months) were retrospectively studied. The 2 groups were statistically comparable with respect to all baseline characteristics except for older age in SAC patients (65.6 vs 56.5 years; P = .009). A higher proportion of SAC patients also had poor Hunt and Hess grades (III-V; 70.5% vs 55%; P = .l4). Hemorrhagic, thromboembolic, and overall procedural complications occurred in 6.8%, 11.4%, and 18.2% of the SAC group vs 2.5%, 7.5%, and 10% of the BAC group, respectively (P = .5, P = .6, P = .3, respectively). Favorable outcomes (modified Rankin Scale score 0-2) at follow-up were seen in 61.0% of the SAC group vs 77% of the BAC group (P = .1). In multivariable analysis, after controlling for differences in baseline characteristics, the type of treatment was not a predictor of procedural complications or clinical outcome. In this study, procedural complications and clinical outcomes did not differ significantly between SAC and BAC in patients with acutely ruptured aneurysms. SAC may be an acceptable alternative to BAC for complex aneurysms in the acute phase of subarachnoid hemorrhage.


Preconditioning the human heart.
The phenomenon of ischaemic preconditioning protects the myocardium by limiting infarct size in animal models of ischaemia and reperfusion. Ischaemic preconditioning may be induced by short periods of ischaemia and reperfusion. We investigated whether the human heart can be ischaemically preconditioned during coronary artery bypass grafting (CABG). Patients were enrolled into two separate studies. In the first study myocardial adenosine triphosphate (ATP) was used as the measured endpoint, assayed from myocardial biopsies taken at onset of cardiopulmonary bypass (CPB), at the end of the preconditioning stimulus, and at the end of a 10 min sustained ischaemic insult. In the second study the release of myocardial troponin T was used as the endpoint; taken at pre-CPB, and at 1, 6, 24, and 72 h after CPB. In both studies, patients were randomised into either the preconditioning group or the control group. Preconditioning was induced, after the onset of CPB, with two 3 min periods of crossclamping and an intervening 2 min of reperfusion, followed by 10 min sustained ischaemia. The control group only received 10 min of sustained ischaemia. Ischaemic preconditioning resulted in a slower rate of ATP (mumol/g dry weight) depletion in the preconditioned hearts at the end of the 10 min of sustained ischaemia (preconditioned: 11.5 +/- 0.8 vs control: 7.2 +/- 0.3; P < 0.005). Also, preconditioning resulted in a slower rate of troponin T release which was significantly different at 72 h after CPB in the preconditioned group (0.3 milligram) when compared with the control group (1.4 milligrams; P < 0.05). In addition, more patients in the preconditioned group had troponin T levels lower than 0.5 milligram at 72 h than in the control group (10 vs 3 patients). Both groups of patients received the same number of grafts, and underwent the same length of ischaemia during the procedure. We conclude that in patients undergoing CABG surgery, ischaemic preconditioning may reduce myocardial injury as shown by the favourable changes in myocardial ATP, and serum troponin T levels.


MAGE-A1 interacts with adaptor SKIP and the deacetylase HDAC1 to repress transcription.
MAGE-A1 belongs to a family of 12 genes that are active in various types of tumors and silent in normal tissues except in male germ-line cells. The MAGE-encoded antigens recognized by T cells are highly tumor-specific targets for T cell-oriented cancer immunotherapy. The function of MAGE-A1 is currently unknown. To analyze it, we attempted to identify protein partners of MAGE-A1. Using yeast two-hybrid screening, we detected an interaction between MAGE-A1 and Ski Interacting Protein (SKIP). SKIP is a transcriptional regulator that connects DNA-binding proteins to proteins that either activate or repress transcription. We show that MAGE-A1 inhibits the activity of a SKIP-interacting transactivator, namely the intracellular part of Notch1. Deletion analysis indicated that this inhibition requires the binding of MAGE-A1 to SKIP. Moreover, MAGE-A1 was found to actively repress transcription by binding and recruiting histone deacetylase 1 (HDAC1). Our results indicate that by binding to SKIP and by recruiting HDACs, MAGE-A1 can act as a potent transcriptional repressor. MAGE-A1 could therefore participate in the setting of specific gene expression patterns for tumor cell growth or spermatogenesis.


A Macrophage Subversion Factor Is Shared by Intracellular and Extracellular Pathogens.
Pathogenic bacteria have developed strategies to adapt to host environment and resist host immune response. Several intracellular bacterial pathogens, including Salmonella enterica and Mycobacterium tuberculosis, share the horizontally-acquired MgtC virulence factor that is important for multiplication inside macrophages. MgtC is also found in pathogenic Pseudomonas species. Here we investigate for the first time the role of MgtC in the virulence of an extracellular pathogen, Pseudomonas aeruginosa. A P. aeruginosa mgtC mutant is attenuated in the systemic infection model of zebrafish embryos, and strikingly, the attenuated phenotype is dependent on the presence of macrophages. In ex vivo experiments, the P. aeruginosa mgtC mutant is more sensitive to macrophage killing than the wild-type strain. However, wild-type and mutant strains behave similarly toward macrophage killing when macrophages are treated with an inhibitor of the vacuolar proton ATPase. Importantly, P. aeruginosa mgtC gene expression is strongly induced within macrophages and phagosome acidification contributes to an optimal expression of the gene. Thus, our results support the implication of a macrophage intracellular stage during P. aeruginosa acute infection and suggest that Pseudomonas MgtC requires phagosome acidification to play its intracellular role. Moreover, we demonstrate that P. aeruginosa MgtC is required for optimal growth in Mg2+ deprived medium, a property shared by MgtC factors from intracellular pathogens and, under Mg2+ limitation, P. aeruginosa MgtC prevents biofilm formation. We propose that MgtC shares a similar function in intracellular and extracellular pathogens, which contributes to macrophage resistance and fine-tune adaptation to host immune response in relation to the different bacterial lifestyles. In addition, the phenotypes observed with the mgtC mutant in infection models can be mimicked in wild-type P. aeruginosa strain by producing a MgtC antagonistic peptide, thus highlighting MgtC as a promising new target for anti-virulence strategies.


Antibiotic-resistant invasive pediatric Streptococcus pneumoniae clones in Israel.
Antibiotic-resistant international clones of Streptococcus pneumoniae are increasingly reported in different parts of the world. We investigated the spread of these clones through an active surveillance performed at the Israeli Streptococcal National Center during 1998 and 1999. Isolates were tested for antibiotic susceptibility, serotyped, and genotyped by random amplified polymorphic DNA analysis and pulsed-field gel electrophoresis. Of 437 isolates, 276 (63.4%) were antibiotic resistant and 156 (35%) were penicillin nonsusceptible (PNS). The PNS isolates were less frequently encountered in southern Israel (27 of 136 [20%]) than in other regions (127 of 301 [42%]). Among 276 antibiotic-resistant isolates, 43 fingerprint patterns were observed. The most common clones were 9V/14-a (19.2%), 5-a (17.8%), and 1-a (10%). The 9V/14-a clone was less common, while the 1-a clone was more frequent in the south than in other regions. The 5-a clone was more common in Jerusalem than in other regions. Among the Jewish and Arab populations the most frequent clones were 9V/14-a (20%) and 1-a (25%), respectively. Three international clones, 9V/14-a-Spain(9V)-3, 6B-a-Spain(6B)-2, and 5-a-Colombia(5)-19, comprised 40% of all antibiotic-resistant isolates and 56% of all PNS isolates. The seven-valent conjugate vaccine covers 58% of the most common clones, all highly PNS clones, and 94% of the multidrug-resistant clones in Israel, while the nine-valent vaccine covers all of them. The most common antibiotic-resistant invasive pediatric S. pneumoniae clones-mainly the three international ones-contribute significantly to increases in antibiotic resistance. Their geographic distribution varies within the country and between the different populations.


Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms.
Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.


Detection of multiple stresses in Scots pine growing at post-mining sites using visible to near-infrared spectroscopy.
Heavy metal contamination, low pH and high substrate heterogeneity are multiple stress factors that often occur at the post-mining sites and make difficult the biological reclamation. Efficient tools for detection of the status of reclaimed vegetation at post-mining sites are needed. We tested the potential of visible to near-infrared (VNIR) spectroscopy to detect multiple stresses in Scots pine (Pinus sylvestris L.) at acidic substrates rich in As. The needle chemical traits (chlorophyll a + b - Cab; carotenoids - Car; Car/Cab; relative water content - RWC; soluble phenolics; lignin contents) were tested for sensitivity to different soil conditions of post-mining sites. For Scots pine growing on degraded substrates, at least three non-specific stress indicators (RWC, photosynthetic pigments and phenolics) are required to achieve good site separability corresponding to the stress load. We constructed and validated empirical models of selected needle chemical traits using VNIR spectroscopy: calibration of Cab (R(2) = 0.97, RMSE = 0.17 mg g(-1)), RWC (R(2) = 0.88, RMSE = 1.41 mg g(-1)), Car (R(2) = 0.66, RMSE = 0.08 mg g(-1)), phenolics (R(2) = 0.64, RMSE = 23.01 mg g(-1)) and lignin (R(2) = 0.45, RMSE = 3.32 mg g(-1)). The reflectance data yielded comparable site separability with the separability calculated from the laboratory data. The presented approach has potential for large-scale monitoring of Scots pine status, thus, assessment of reclamation quality in post-mining regions using air-born or satellite hyperspectral data.


Influence of Carboxylate Anions on Phase Behavior of Choline Ionic Liquid Mixtures.
Mixing ionic liquids is a suitable strategy to tailor properties, e.g., to reduce melting points. The present study aims to widen the application range of low-toxic choline-based ionic liquids by studying eight binary phase diagrams of six different choline carboxylates. Five of them show eutectic points with melting points dropping by 13 to 45 °C. The eutectic mixtures of choline acetate and choline 2-methylbutarate were found to melt at 45 °C, which represents a remarkable melting point depression compared to the pure compounds with melting points of 81 (choline acetate) and 90 °C (choline 2-methylbutarate), respectively. Besides melting points, the thermal stabilities of the choline salt mixtures were investigated to define the thermal operation range for potential practical applications of these mixtures. Typical decomposition temperatures were found between 165 and 207 °C, with choline lactate exhibiting the highest thermal stability.


Action in human blood of methoxylated flavones which confer disease resistance on both plants and animals: concept of a dietary conditioned mechanism of defense against disease-1,2.
The antiadhesive action of methoxylated flavones on cells in blood of hospitalized patients was significantly associated with calcium, probably at membrane interfaces. This action is consistent with the role of calcium in cell aggregation and disaggregation. These and other recent findings suggest the body has a capacity for an environmentally related dietary conditioned, resistance to disease. The concept is based on evidence that phenylbenzo-gamma-pyrone derivatives, methyoxylated flavonoids and related compounds, synthesized in plants with antiviral, antifungal and bacteriostatic action may be absorbed into the body and attach reversibly to blood cells. In the body, in addition to any potential action against pathogens, certain of these compounds potentiate enzymes which detoxify carcinogenic hydrocarbons, exhibit antiinflammatory activity, exert antiadhesive action on blood cells and show antithrombogenic activity. The evidence indicates that of this class of compounds, a few are broad spectrum in their action, while several others possess one or another of the above functions. Also, some compounds are active in practically all subjects while others are active only in some patients. Specificities appear to be involved in action of the compounds on both pathogens and body processes.


Antiviral drugs against severe acute respiratory syndrome coronavirus 2 infection triggering the coronavirus disease-19 pandemic.
So far, lots of analyses have been conducted to invent the appropriate therapeutic targets for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The category and the strategies for treating the virus are described in this review together with mentioning some specific drugs. Of them, saikosaponin possesses affinity of the drug toward nonstructural protein 15 and the spike glycoprotein of the SARS-CoV-2. The nucleotide inhibitors such as sofosbuvir, ribavirin, galidesivir, remdesivir, favipiravir, cefuroxime, tenofovir, and hydroxychloroquine (HCHL), setrobuvir, YAK, and IDX-184 were found to be effective in binding to SARS-CoV-2 RNA-dependent RNA polymerase. From the antimalarial and anti-inflammatory category, chloroquine and its derivative HCHL have already been approved by the U.S. Food and Drug Administration for emergency treatment of SARS-CoV-2 infection. The other drugs such as favipiravir and lopinavir/ritonavir under the antiviral category, the angiotensin-converting enzyme 2 (the renin-angiotensin system inhibitors), remdesivir (RNA polymerase inhibitor) from antiviral category, cepharanthine from anti-inflammatory category, etc., have been pointed based on the previous literature published. Besides, the assessment of the drug repositioning candidates with the related targets is also significant for the viral mitigation.


Structure and activity of the acid-sensing ion channels.
The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of complex behaviors including fear, anxiety, pain, depression, learning, and memory. ASICs have also been implicated in neuronal degeneration accompanying ischemia and multiple sclerosis. As a whole, ASICs represent novel therapeutic targets for several clinically important disorders. An understanding of the correlation between ASIC structure and function will help to elucidate their mechanism of action and identify potential therapeutics that specifically target these ion channels. Despite the seemingly simple nature of proton binding, multiple studies have shown that proton-dependent gating of ASICs is quite complex, leading to activation and desensitization through distinct structural components. This review will focus on the structural aspects of ASIC gating in response to both protons and the newly discovered activators GMQ and MitTx. ASIC modulatory compounds and their action on proton-dependent gating will also be discussed. This review is dedicated to the memory of Dale Benos, who made a substantial contribution to our understanding of ASIC activity.


Lethal graft-vs-host disease across major histocompatibility barriers: requirement for leucyl-leucine methyl ester sensitive cytotoxic T cells.
L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) is selectively toxic for human natural killer (NK) cells and cytotoxic T lymphocytes (CTL) at both the precursor and effector stage of differentiation. The present studies explored the effects of Leu-Leu-OMe on murine spleen cell function. Leu-Leu-OMe exposure removed NK function from murine spleen cells but spared their capacity to proliferate in response to lipopolysaccharide and Con A. The capacity to generate CTL from both L3T4 (+) and Lyt-2 (+) precursors was lost after Leu-Leu-OMe treatment, whereas alloantigen-induced proliferation and interleukin 2 (IL 2) production by L3T4 (+) T helper cells remained intact. Lethal graft vs host disease (GVHD), which developed in irradiated (C57BL/6 X DBA/2)F1 recipients of C57BL/6 bone marrow and spleen cells was completely prevented by Leu-Leu-OMe treatment of donor cells. In contrast depletion of Lyt-2 positive cells from the donor inoculum did not prevent acute GVHD in this fully major histo-compatibility complex (MHC) incompatible strain combination. However, Leu-Leu-OMe treatment of the Lyt-2 depleted inoculum completely prevented lethal GVHD, although the treated cells retained the capacity to proliferate and secrete IL 2 normally after in vitro stimulation with (C57BL/6 X DFA/2)F1 spleen cells. These findings indicate that L3T4 (+) T helper cells alone are unable to initiate lethal GVHD in this H-2 incompatible strain combination. Rather, lethal GVHD requires the transfer of a Leu-Leu-OMe sensitive T cell subset, likely to be thymus educated pre-CTL. Leu-Leu-OMe treatment should provide a useful way to delineate subpopulations of cells involved in the production of lethal GVHD and an approach to preventing this complication of bone marrow transplantation.


The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a spectrum of disorders characterized by abdominal discomfort and pain, associated with altered bowel habits. Though gut motility, secretion and sensation may be altered in patients with IBS, the pathophysiology of this condition remains to be fully understood. The endocannabinoid system is involved in the regulation of numerous gastrointestinal functions including motility, sensation and secretion under both physiological and pathophysiological conditions. Activation of cannabinoid (CB)(1) and CB(2) receptors under various circumstances reduces motility, limits secretion and decreases hypersensitivity in the gut. Drugs that alter the levels of endocannabinoids in the gut also reduce motility and attenuate inflammation. In this review, we discuss the role of the endocannabinoid system in gastrointestinal physiology. We go on to consider the involvement of the endocannabinoid system in the context of symptoms associated with IBS and a possible role of this system in the pathophysiology and treatment of IBS.


Prevalence of Feline Immunodeficiency Virus and Toxoplasma gondii in Feral Cats on St. Kitts, West Indies.
Toxoplasma gondii (T. gondii) is a cosmopolitan protozoan parasite that infects all warm-blooded species including humans. The definitive hosts of T. gondii are felid vertebrates including the domestic cat. Domestic cats shed oocysts for approximately two weeks in their feces after the primary infection. It has been shown that feline immunodeficiency virus (FIV) positive cats have a higher prevalence of and a higher titer of antibodies to T. gondii than those of FIV-negative cats. The main purposes of this study were to determine FIV prevalence and to investigate the oocysts shedding in FIV-positive and FIV-negative feral cats on St. Kitts. Fecal samples were collected from feral cats while their FIV statues were determined using a commercial SNAP kit. Total fecal DNA of each cat was tested for the presence of T. gondii DNA using a polymerase chain reaction (PCR) consistently detecting one genome equivalent. A FIV-positive status was detected in 18 of 105 (17.1%, 95% confidence interval (CI): 9.9%-24.3%) feral cats sampled. Furthermore, males were three times more likely to be FIV positive than females (p = 0.017) with an odds ratio of 3.93 (95% CI: 1.20-12.89). Adults were found to have at least twice the prevalence of FIV compared to cats younger than one year of age (p = 0.056) with an odds ratio of 3.07 (95% CI: 0.94-10.00). Toxoplasma gondii DNA was not detected in the feces of any of the 18 FIV-positive (95% CI: 0%-0.18%) and 87 FIV-negative cats (95% CI: 0%-0.04%). A follow-up study with a much bigger sample size is needed to prove or disprove the hypothesis that FIV-positive cats have a higher prevalence of shedding T. gondii oocysts than FIV-negative cats.


[Bioinformatic analysis of nucleotide sequences records retrieved from GenBank].
Methods and macros used for processing of samples of NP bacteria retrieved from GenBank are described. The goal of the processing is to transform lists of NP bacteria retrieved from GenBank into Excel table with classification of data concerning bacterial genes, species, and genomes of bacteria, as well as accompanying information about NP bacteria. The list is processed using several macros and the result of processing is stored in table. Each line of the table contains information about one record of initial list of NP bacteria. Information about genes, species, and genomes of NP bacteria is contained in columns of table. The capacity of the macros is demonstrated using the list of NP bacteria of the genus Ureaplasma. The developed macros can be applied to lists of NP bacteria and viruses available from GenBank. This information can be used in studies of interspecies and intraspecies genetic polymorphism and genetic targets for various problems of molecular biology (genotyping of viruses and bacteria).


The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D.
Sodium taurocholate co-transporting polypeptide (NTCP) is the receptor for the hepatitis B virus (HBV) and hepatitis D virus (HDV) entry into hepatocytes. Ezetimibe is a cholesterol-lowering drug that possesses the pharmacophore features to inhibit NTCP. This study evaluates the efficacy of ezetimibe in patients with chronic HDV infection in a nonrandomized trial. This proof of concept phase 2 trial evaluated the efficacy and safety of ezetimibe 10 mg daily in (interferon treatment-experienced or interferon ineligible) patients with chronic hepatitis D (CHD). Forty-four patients with CHD were recruited, 38 male and 6 female patients, mean age 35.2±8.7 (range 19-64). Fifteen (34%) patients were on concomitant nucleoside therapy, and cirrhosis was present in 14 subjects. The primary therapeutic endpoint was a decline in HDV RNA at one log or more from the baseline at week 12. The mean HDV RNA level was 5.4±1.3 log10 IU/mL. HBeAg was non-reactive in 43 (98%). HBV DNA was undetectable in 28 (64%). One patient stopped treatment at week 4, and one patient did not follow-up. One log or more reduction in the HDV RNA levels was observed in 18/44 (41%) patients. No log reduction occurred in 16 patients, and 8 experienced a log increase. No adverse effects from the concomitant nucleoside analogue use or clinical cirrhosis were observed. The drug exhibited a positive safety profile. Treatment of CHD patients with ezetimibe resulted in a one log reduction of viral load in 43% (18/42) of the patients who completed the 12 weeks of therapy.


Prediction of mechanical properties of multilayer gradient hydroxyapatite reinforced poly(vinyl alcohol) gel biomaterial.
Functional graded materials provided us one new concept for artificial articular cartilage design with graded component and graded structure. In this article, a novel functional material design was proposed by functionalizing hydroxyapatite (HA) particles in poly(vinyl alcohol) (PVA) hydrogel. The goal of the present study was to fabricate a multilayer gradient HA/PVA gel biocomposites through layer-by-layer casting method combining with freeze/thaw cycle technology and establish a mechanical model to predict the compressive mechanical properties of multilayer gradient gel biocomposites. The results showed that the compressive strength of the multilayer gradient gel biocomposites increased with the rise of HA content, but it presented decreasing trend with the rise of interlayer gradient concentration of HA particles. Furthermore, the compressive strength of multilayer gradient biocomposites would be approximately predicted by the established mechanical model. The maximum error between theoretical compressive strength predicted by the model and the experimental strength is less than 7%. On the other hand, the compressive mechanical properties of multilayer gradient composites could be designed and controlled by the mechanical model as established in this study.


Chest pain and reappearance of esophageal peristalsis in treated achalasia.
We wanted to evaluate the clinical significance of the esophageal peristalsis that appears in some achalasia patients after treatment. We prospectively investigated the reappearance of esophageal peristalsis in 106 achalasic patients treated with forceful dilatation under endoscopic control (86 metallic dilatations and 20 pneumatic dilatations) and followed up clinically and manometrically for 1 year. Patients were divided in two groups in accordance with the presence (n = 26) or persistent absence (n = 80) of postdilatation esophageal peristalsis. Before treatment, clinical data and manometric findings were comparable in both groups except for esophageal wave amplitude, which was higher in patients with postdilatation peristalsis (36 +/- 5 mmHg versus 24 +/- 2 mmHg, P < 0.05). One year after dilatation manometric findings were similar in the two groups, but esophageal wave amplitude remained higher in the group with postdilatation peristalsis (46 +/- 4 mmHg versus 21 +/- 2 mmHg, P < 0.05). The proportion of patients with persistent dysphagia was similar in the two groups (15% versus 12.5%). However, 10 patients with postdilatation peristalsis (38%) complained of chest pain as opposed to only 5 patients (6%) in the group with aperistalsis (P < 0.01). The appearance of esophageal peristalsis after forceful dilatation in achalasic patients is frequently associated with persistent or new chest pain.


Examining concurrent validity between COMLEX-USA Level 2-Cognitive Evaluation and COMLEX-USA Level 2-Performance Evaluation.
The Comprehensive Osteopathic Medical Licensing Examination of the United States of America (COMLEX-USA) is a three level examination used as a pathway to licensure for students in osteopathic medical education programs. COMLEX-USA Level 2 includes a written assessment of Fundamental Clinical Sciences for Osteopathic Medical Practice (Level 2-Cognitive Evaluation [L2-CE]) delivered in a computer based format and separate performance evaluation (Level 2-Performance Evaluation [L2-PE]) administered through live encounters with standardized patients. L2-PE was designed to augment L2-CE. It is expected that the two examinations measure related yet distinct constructs. To explore the concurrent validity of L2-CE with L2-PE. First attempt test scores were obtained from the National Board of Osteopathic Medical Examiners database for 6,639 candidates who took L2-CE between June 2019 and May 2020 and matched to the students' L2-PE scores. The sample represented all colleges of osteopathic medicine and 97.5% of candidates who took L2-CE during the complete 2019-2020 test cycle. We calculated disattenuated correlations between the total score for L2-CE, the L2-CE scores for the seven competency domains (CD1 through CD7), and the L2-PE scores for the Humanistic Domain (HM) and Biomedical/Biomechanical Domain (BM). All scores were on continuous scales. Pearson correlations ranged from 0.10 to 0.88 and were all statically significant (p<0.01). L2-CE total score was most strongly correlated with CD2 (0.88) and CD3 (0.85). Pearson correlations between the L2-CE competency domain subscores ranged from 0.17 to 0.70, and correlations which included either HM or BM ranged from 0.10 to 0.34 with the strongest of those correlations being between BM and L2-CE total score (0.34) as well as between HM and BM (0.28).The largest increase between corresponding Pearson and disattenuated correlations was for pairs of scores with lower reliabilities such as CD5 and CD6, which had a Pearson correlation of 0.17 and a disattenuated correlation of 0.68. The smallest increase in correlations was observed in pairs of scores with larger reliabilities such as L2-CE total score and HM, which had a Pearson correlation of 0.23 and a disattenuated correlation of 0.28. The reliability of L2-CE was 0.87, 0.81 for HM, and 0.73 for BM. The reliabilities for the L2-CE competency domain scores ranged from 0.22 to 0.74. The small to moderate correlations between the L2-CE total score and the two L2-PE support the expectation that these examinations measure related but distinct constructs. The correlations between L2-PE and L2-CE competency domain subscores reflect the distribution of items defined by the L2-PE blueprint, providing evidence that the examinations are performing as designed. This study provides evidence supporting the validity of the blueprints for constructing COMLEX-USA Levels 2-CE and 2-PE examinations in concert with the purpose and nature of the examinations.


Thick meniscus field correctors.
Thick meniscus lenses with almost equal curvatures are routinely used for the correction of spherical aberration in optical systems. The use of such quasi-concentric menisci (QCM) for correction of field curvature and astigmatism is less well known. Three limiting forms of QCM can be identified, namely, equal curvatures, true concentric, and zero deviation, and each exhibits radically different field aberrations. A doublet lens has field curvature and astigmatism; the former can be removed by adding a strong negative lens at the image plane, but the latter is uncorrected. Use of a QCM, however, corrects both aberrations, moreover, without causing the chief rays to diverge as the conventional field flattener does. Indeed the chief rays may be made to converge so that the QCM can be used as a field-correcting field lens, and we illustrate its use in a periscopic vehicle sight comprising an objective lens, relay stage, and eyepiece. Even in cases in which a measure of field curvature and astigmatism correction is possible, for example, when a double Gauss-type relay lens is used, the QCM results in smaller high-order aberrations and lower ray heights through the system.


Persons Living With Primary Immunodeficiency Act as Citizen Scientists and Launch Prospective Cohort Body Temperature Study.
Although fever is considered a sign of infection, many individuals with primary immunodeficiency (PI) anecdotally report a lower-than-normal average body temperature on online forums sponsored by the Immune Deficiency Foundation (IDF). There is limited knowledge about the average body temperature and fever response in PI. This study aims to compare median body temperatures between adults with and without PI diagnoses living in the same household and to engage individuals living with PI throughout the research process. Patients with PI designed and launched a prospective cohort comparison study as citizen scientists. A multidisciplinary team designed and implemented a patient-informed study with continuous patient-driven input. Median body temperatures were compared between the 2 cohorts using the Mann-Whitney test with Bonferroni correction. The IDF conducted a post-study patient experience survey. Data from 254 households were analyzed (254/350, 72.6% participation rate). The PI population was predominantly female (218/254, 85.8%), White (248/254, 97.6%), and with a median age of 49 years. The non-PI population was largely male (170/254, 66.9%), White (236/254, 92.9%), and with a median age of 53 years. Common variable immunodeficiency was the most common PI diagnosis (190/254, 74.8%). Of the 254 individuals with PI, 123 (48.4%) reported a lower-than-normal nonsick body temperature, whereas 108 (42.5%) reported a normal (between 97°F and 99°F) nonsick body temperature. Among individuals with PI, when infected, 67.7% (172/254) reported the absence of fever, whereas 19.7% (50/254) reported a normal fever response. The recorded median body temperature was minimally but statistically significantly higher for patients with PI in the morning. Although 22.4% (57/254) of patients with PI self-reported illness, a fever of 100.4°F or higher was uncommon; 77.2% (196/254) had a normal temperature (between 97°F and 99°F), and 16.2% (41/254) had a lower-than-normal temperature (between 95.0°F and 96.9°F) when sick. For these sick patients with PI, the median body temperature was minimally but statistically significantly higher for patients in the morning and early evening. Overall, 90.9% (231/254) of participants would be very likely to participate in future IDF studies, although 94.1% (239/254) participants had never taken part in previous studies. To our knowledge, this is the first study to evaluate average body temperature in individuals with PI. Although there were small statistically significant differences in body temperatures between PI and non-PI subjects, the clinical significance is unclear and should be interpreted with caution, given the methodological issues associated with our small convenience sample and study design. As PIs are heterogeneous, more research is needed about how the fever response differs among diverse PIs compared with healthy controls. This study highlights that individuals with PI are knowledgeable about their health and can offer unique insights and direction to researchers and clinicians.


Health Hazards and Complications Associated with Electronic Cigarettes: A Review.
Electronic cigarettes (ECs) are devices that vaporize and release a sweetened liquid containing nicotine as a substitute for burning tobacco. EC manufacturers have suggested that "vaping" is a safer alternative to conventional smoking because of the potential reduction of exposure to toxic substances. In 2019, National Youth Tobacco Survey reported that 10.5% and 27.5% of middle and high school students used ECs in the previous 30 days (0.6% and 1.5% in 2011, 3.3% and 11.7% in 2017, and 4.9% and 20.8 in 2018), respectively. Increased EC use among younger individuals is mainly because of the widespread perception that ECs are relatively less harmful than conventional cigarettes as they do not involve smoking tobacco and contain little or no nicotine. This review suggests that ECs may not be completely harmless. There are increasing number of case reports on various complications arising from using ECs, which are especially popular among young individuals and could negatively affect their health. Reported complications include lipoid pneumonia, acute eosinophilic pneumonia, hypersensitivity pneumonia, organizing pneumonia, diffuse alveolar hemorrhage, multiple reactive pulmonary nodules, subacute bronchiolitis, mouth and tongue injuries, dental injuries, complex facial fractures, thermal injuries, nickel contact allergy, C1 and C2 fractures, and fatal intoxication after ingesting liquids. Complications that develop directly from the substances in the devices and those resulting from device explosion and burning are being reported with increasing frequency. There is an urgent need for legislation and restriction regarding the sale of these devices considering their increasing frequency of use by younger individuals.


Predictors of neonatal brachial plexus palsy subsequent to resolution of shoulder dystocia.
The objective was to ascertain factors among deliveries complicated by shoulder dystocia (SD) and neonatal brachial plexus palsy (NBPP). At 11 hospitals, deliveries complicated by SD were identified. The inclusion criteria were vaginal delivery of non-anomalous, singleton at 34-42 weeks. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated. Receiver operating characteristic (ROC) curves were created to evaluate the predictive value of the models for NBPP. Of the 62,939 individuals who delivered vaginally, 1,134 (1.8%) had SD and met other inclusion criteria. Among the analytic cohort, 74 (6.5%) had NBPP. The factor known before delivery which was associated with NBPP was diabetes (aOR = 3.87; 95% CI = 2.13-7.01). After delivery, the three factors associated with NBPP were: (1) birthweight of at least 4000 g (aOR = 1.83; 95% CI = 1.05-3.20); (2) calling for help during the SD (aOR = 4.09, 95% CI = 2.29-7.30), and (3) the duration of SD ≥120 sec (aOR = 2.47, 95% CI = 1.30-4.69). The AUC under the ROC curve for these independent factors was 0.79 (95% CI = 0.77 - 0.82). Few factors were identified that were associated with NBPP after SD, but they could not reliably predict which neonates will experience the complication.


Identification of the evolutionarily conserved nuclear envelope proteins Lem2 and MicLem2 in Tetrahymena thermophila.
Lem2 family proteins, i.e. the LAP2-Emerin-MAN1 (LEM) domain-containing nuclear envelope proteins, are well-conserved from yeasts to humans, both of which belong to the Opisthokonta supergroup. However, whether their homologs are present in other eukaryotic phylogenies remains unclear. In this study, we identified two Lem2 homolog proteins, which we named as Lem2 and MicLem2, in a ciliate Tetrahymena thermophila belonging to the SAR supergroup. Lem2 was localized to the nuclear envelope of the macronucleus (MAC) and micronucleus (MIC), while MicLem2 was exclusively localized to the nuclear envelope of the MIC. Immunoelectron microscopy revealed that Lem2 in T. thermophila was localized to both the inner and outer nuclear envelopes of the MAC and MIC, while MicLem2 was mostly localized to the nuclear pores of the MIC. Molecular domain analysis using GFP-fused protein showed that the N-terminal and luminal domains, including the transmembrane segments, are responsible for nuclear envelope localization. During sexual reproduction, enrichment of Lem2 occurred in the nuclear envelopes of the MAC and MIC to be degraded, while MicLem2 was enriched in the nuclear envelope of the MIC that escaped degradation. These findings suggest the unique characteristics of Tetrahymena Lem2 proteins. Our findings provide insight into the evolutionary divergence of nuclear envelope proteins.