Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease.
Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (β, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.


The significance of Candida-specific serum IgE in recurrent vaginal candidiasis.
Total and Candida-specific serum concentrations of IgE were studied in 21 patients who fulfilled the criteria for recurrent vaginal candidiasis, and 45 controls. The candida specific IgE levels were significantly higher in patients with recurrent vaginal candidiasis than the controls. There was no significant difference in the total IgE levels between the patients and the controls. IgE is postulated to inhibit the cellular immune response to Candida and thereby prevent the eradication of the organism. There may be a genetic basis for the increased serum IgE levels. Hyposensitisation may be an effective mode of therapy.


Effect of Vocal Fry on Voice and on Velopharyngeal Sphincter.
Introduction It is known that the basal sound promotes shortening and adduction of the vocal folds and leaves the mucosa looser. However there are few studies that address the supralaryngeal physiological findings obtained using the technique. Objective To check the effectiveness of using vocal fry on the voice and velopharingeal port closure of five adult subjects, whose cleft palate has been corrected with surgery. Methods Case study with five subjects who underwent otolaryngology examination by means of nasopharyngoscopy for imaging and measurement of the region of velopharyngeal port closure before and after using the vocal fry technique for three minutes. During the exam, the subjects sustained the isolated vowel /a:/ in their usual pitch and loudness. The emission of the vowel /a:/ was also used for perceptual analysis and spectrographic evaluation of their voices. Results Four subjects had an improvement in the region of velopharyngeal port closure; the results of the spectrographic evaluation were indicative of decreased hypernasality, and the results of the auditory-perceptual analysis suggested improved overall vocal quality, adequacy of loudness, decreased hypernasality, improvement of type of voice and decreased hoarseness. Conclusion This study showed a positive effect of vocal fry on voice and greater velopharyngeal port closure.


Barriers to Medication Adherence among Hypertensive Patients in Deprived Rural Areas.
Poor adherence to medication regimen leads to poor health outcomes, increased medical costs and increased death rate due to hypertension. The aim of this study was to evaluate baseline barriers to medication adherence among hypertensive patients in deprived rural areas. A cross-sectional study was conducted on 238 hypertensive patients living in deprived rural areas of Iran. Data were collected using a questionnaire consisting of demographic information, Morisky medication adherence scale and the barriers to medication adherence that were reliable and valid. The results of the study showed that medication adherence was significantly decreased and had a significant positive correlation with gender and economic status, while it had a negative correlation with age. Medication Adherence had a positive correlation with the duration of hypertension, while it had a negative correlation with the number of medications used and concurrently with other diseases. Based on the present study it can be concluded that enhanced knowledge about illness and treatment in rural communities is improves the medical adherence. Financial supports along with the reduced number of prescribed drugs are also found to be the determining factors in the medical adherence.


Physical fitness of rural children compared with urban children in North Cyprus: a normative study.
The aim of this study was to investigate the effects of environmental factors on physical fitness of rural and urban children. To reveal the differences between physical fitness of children living in urban and rural districts of the Turkish Cypriot population, 3939 nine- to eleven-year-old male primary school children from 90 schools of North Cyprus were tested. Testing procedures were similar to the Eurofit tests. The results showed that body mass index and skinfold thicknesses were higher in the urban children (P<.05). Differences in cardiopulmonary and motor fitness were also found between groups. In addition, flexibility and muscle endurance were significantly higher in the rural children. The significantly lower flexibility, muscle endurance, and strength of urban children might indicate a lower habitual physical activity level.


Adrenal control of erectile function and nitric oxide synthase in the rat penis.
Penile erection is a nitric oxide (NO)-mediated process that has been shown to be androgen dependent in rats. Castration reduces the activity of the penile enzyme involved in NO synthesis, nitric oxide synthase (NOS). To determine whether adrenal androgens and/or corticosteroids contribute to this control, the following groups of Fischer 344 adult male rats (n = 5-7) were studied: 1) intact, 2) castrated, 3) adrenalectomized alone, 4) castrated/adrenalectomized, 5) castrated/adrenalectomized with aldosterone (1.25 mg/kg, s.c.) and hydrocortisone (12 mg/kg, s.c.), 6) castrated/adrenalectomized with dihydrotestosterone (1.2-cm SILASTIC-brand tubing pellet; Dow Corning, Midland, MI), 7) castrated/adrenalectomized with dehydroepiandrosterone (2-cm tubing), 8) castrated/adrenalectomized with aldosterone (1.25 mg/kg, s.c.), and 9) castrated/adrenalectomized with hydrocortisone (12 mg/kg, s.c.). After 1 week, EFS was applied, and the maximal intracavernosal pressure (MIP) and mean arterial pressure (MAP) were recorded. The MIP/MAP ratio in the adrenalectomized group (0.37) was reduced to values found in the castrated group (0.40). The values in both groups were significantly less than those in intact controls (0.75). The most significant reduction in MIP/MAP was seen in the adrenalectomized/castrated group (0.16). Erectile response in animals submitted to adrenalectomy and castration was restored close to intact values with the administration of hydrocortisone and aldosterone (0.63). Similar results were obtained by the administration of either of the substances alone (0.56 and 0.67, respectively). Penile NOS activity assayed by the L-arginine/citrulline conversion was decreased by 55% in the castrated group compared with that in the intact group, but was not further reduced in the adrenalectomized/castrated or adrenalectomized groups. Penile neuronal NOS protein content, estimated by Western blot, was decreased only in the adrenalectomized/castrated animals (35%), and endothelial NOS content was not affected. These data suggest that the rat adrenal gland contributes to the maintenance of the erectile mechanism and may affect neuronal NOS content in the penis in the rat model. The possibility that hypotension may play a role in the erectile dysfunction observed in adrenalectomized rats cannot be discarded.


Molecular dynamics simulation of RAC1 protein and its de novo variants related to developmental disorders.
Neurodevelopmental disorders (NDDs) are conceptualized as childhood disability, but it has increasingly been recognized as lifelong neurological conditions that could notably impact adult functioning and quality of life. About 1%-3% of the general population suffers from NDDs including ADHD, ASD, IDD, communication disorders, motor disorders, etc. Studies suggest that Rho GTPases are key in neuronal development, highlighting the importance of altered GTPase signaling in NDDs. RAC1, a member of the Rho GTPase family, plays a critical role in neurogenesis, migration, synapse formation, axon growth, and regulation of actin cytoskeleton dynamics. We performed 6µs all-atom molecular dynamics simulation of native RAC1 (PDB: 3TH5) and three-point mutations (C18Y, N39S, and Y64D) related to developmental disorders to understand the impact of mutations on protein stability and functional dynamics. Our analysis, which included root mean square deviation (RMSD), root mean square fluctuation (RMSF), solvent accessible surface area (SASA), radius of gyration (Rg), free energy landscape (FEL), and principal component analysis (PCA), revealed that the N39S and Y64D mutations induced significant structural changes in RAC1. These alterations primarily occurred in the functional region adjacent to switch II, a region crucial for complex conformational rearrangements during the GDP and GTP exchange cycle.Communicated by Ramaswamy H. Sarma.


Advances in management of high-risk gestational trophoblastic tumors.
Multimodality therapy with combination chemotherapy employing etoposide, high-dose methotrexate, actinomycin D, cyclophosphamide and vincristine and adjuvant radiotherapy and surgery, when indicated, has resulted in cure rates of 80-90% in patients with high-risk metastatic gestational trophoblastic tumors. However, 25-30% of high-risk patients will have an incomplete response to first-line chemotherapy or will relapse from remission. Most of these patients will have a clinicopathologic diagnosis of choriocarcinoma, multiple metastases to sites other than the lung and vagina, and failed or inappropriate previous chemotherapy, resulting in very high World Health Organization scores. Salvage chemotherapy with cisplatin/etoposide, usually in conjunction with bleomycin or ifosfamide, as well as surgical resection of sites of resistant disease in selected patients, will result in a cure for most patients. Colony-stimulating factors should be used to prevent treatment delays and dose reductions. Newer anticancer agents, such as paclitaxel and gemcitibine, and high-dose chemotherapy with or without autologous bone marrow transplantation or peripheral blood stem cell support may play a role in the future management of selected patients.


Small low-density lipoprotein cholesterol concentration is a determinant of endothelial dysfunction by peripheral artery tonometry in men.
Endothelial dysfunction is an initial step in the progression of atherosclerosis. Precise measurements of lipoprotein subclass distribution by high-performance liquid chromatography (HPLC) have been established. Here, we investigated the potential associations between lipoprotein subclass cholesterol concentrations and endothelial dysfunction evaluated by digital reactive hyperemia peripheral arterial tonometry (PAT). We recruited 120 apparently healthy Japanese men. Endothelial function was assessed by digital reactive hyperemia PAT, expressed as the logarithmic-scaled reactive hyperemia index (RHI). Plasma cholesterol concentrations in lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RHI was inversely correlated with age (r=-0.258, p=0.004), followed by LDL cholesterol (r=-0.236, p=0.010) and small LDL cholesterol (r=-0.223, p=0.014). In addition, RHI was significantly inversely associated with heart rate, hemoglobin A1c, total cholesterol, medium LDL cholesterol, apolipoprotein B100, and non-HDL cholesterol. In stepwise multiple regression analysis, age (β=-0.266, p=0.024), small LDL cholesterol (β=-0.213, p=0.015), and heart rate (β=-0.183, p=0.036) were found to be independent determinants of RHI (adjusted R(2) =0.132, p<0.001). Small LDL cholesterol concentration was an important, independent determinant of endothelial dysfunction in men.


From the mind to the brain: an unusual pathway.
One of the most unrecognized aspects of Golgi's life was his deep interest in neuropsychiatry. From 1865 to 1868 he attended the Clinica per le Malattie Nervose e Mentali in Pavia directed by Cesare Lombroso, the founder of modern criminology. Golgi was involved in research on the etiology of psychiatric ailments. During this short period of time he produced significant theoretic advances in clinical psychiatry. However, very soon he started to criticize the conceptual approach as well as the nosological system proposed by his academic mentor. In July 1868 he left Lombroso's school in search for a more rational method of studying brain functions and diseases. In spite of his anatomical approach to the central nervous system, he always maintained curiosity in the phenomenology of functional and organic mental disorders. This predisposition is witnessed by his capability to relate clinical observations to neuropathological findings.


Assessing the implications of positive genomic screening results.
Aim: Before population screening of 'healthy' individuals is widely adopted, it is important to consider the harms and benefits of receiving positive results and how harms and benefits may differ by age. Subjects & methods: Participants in a preventive genomic screening study were screened for 17 genes associated with 11 conditions. We interviewed 11 participants who received positive results. Results: Interviewees expressed little concern about their positive results in light of their older age, the risk condition for which they tested positive, or other pressing health concerns. Conclusion: Researchers and clinicians should recognize that returning positive results may not have the impact they presume given the diversity of the conditions screened and those who choose to undergo screening.


Starch Digestion-Related Amylase Genetic Variants, Diet, and Changes in Adiposity: Analyses in Prospective Cohort Studies and a Randomized Dietary Intervention.
Salivary amylase, encoded by the AMY1 gene, is responsible for the digestion of carbohydrates. We investigated associations of AMY1 genetic variations with general and central adiposity changes considering dietary carbohydrate intake among 32,054 adults from four prospective cohort studies. A genetic risk score (GRS) was calculated based on nine AMY1 single-nucleotide polymorphisms, with higher AMY1-GRS indicating higher activity of salivary amylase. We meta-analyzed interactions between AMY1-GRS and dietary intake for changes in general and central adiposity over 5.5-10 years. We found that carbohydrate food intake significantly altered associations of AMY1-GRS with changes in BMI (P interaction = 0.001) and waist circumference (P interaction < 0.001). Results were consistent and significant in female cohorts rather than in male cohorts. Among women, higher AMY1-GRS was associated with more increases in adiposity if dietary carbohydrate food intake was high, while higher AMY1-GRS was associated with less gains in adiposity when the dietary intake was low. Also, in a 2-year randomized dietary intervention trial, associations of AMY1-GRS with changes in weight (P interaction = 0.023) and waist circumference (P interaction = 0.037) were significantly modified by carbohydrate intake. Our results suggest the importance of precision nutrition strategies considering participants' genetic adaptation to carbohydrate-rich diets in regulating general and central adiposity.


Barriers and drivers to capacity-building in global mental health projects.
The global shortage of mental health workers is a significant barrier to the implementation and scale-up of mental health services. Partially as a result of this shortage, approximately 85% of people with mental, neurological and substance-use disorders in low- and middle-income countries do not receive care. Consequently, developing and implementing scalable solutions for mental health capacity-building has been identified as a priority in global mental health. There remains limited evidence to inform best practices for capacity building in global mental health. As one in a series of four papers on factors affecting the implementation of mental health projects in low- and middle-income countries, this paper reflects on the experiences of global mental health grantees funded by Grand Challenges Canada, focusing on the barriers to and drivers of capacity-building. Between June 2014 and May 2017, current or former Grand Challenges Canada Global Mental Health grantees were recruited using purposive sampling. N = 29 grantees participated in semi-structured qualitative interviews, representing projects in Central America and the Caribbean (n = 4), South America (n = 1), West Africa (n = 4), East Africa (n = 6), South Asia (n = 11) and Southeast Asia (n = 3). Based on the results of a quantitative analysis of project outcomes using a portfolio-level Theory of Change framework, six key themes were identified as important to implementation success. As part of a larger multi-method study, this paper utilized a framework analysis to explore the themes related to capacity-building. Study participants described barriers and facilitators to capacity building within three broad themes: (1) training, (2) supervision, and (3) quality assurance. Running throughout these thematic areas were the crosscutting themes of contextual understanding, human resources, and sustainability. Additionally, participants described approaches and mechanisms for successful capacity building. This study demonstrates the importance of capacity building to global mental health research and implementation, its relationship to stakeholder engagement and service delivery, and the implications for funders, implementers, and researchers alike. Investment in formative research, contextual understanding, stakeholder engagement, policy influence, and integration into existing systems of education and service delivery is crucial for the success of capacity building efforts.


Pulmonary cavitation following pulmonary infarction.
Cavitation following bland pulmonary infarction is not commonly considered in the differential diagnosis of cavitary lung disease. In a 4-year period we have found 10 cases of cavitating pulmonary infarction (CPI) by reviewing serial chest radiographs from autopsies with pulmonary infarction and in all cases with positive ventilation-perfusion lung scans. We have compared these cases to 31 previously reported cases in the English literature that met our criteria for CPI. In our 10 patients, there were 12 radiographic cavities; 5 in the upper lobes, 5 in the lower lobes and 2 in the middle lobe. This distribution was consistent with a relative upper-lobe predominance in the literature review. In nine patients the cavitation appeared rapidly (mean, 5 days) and was associated with fever, purulent sputum, and leukocytosis. Sputum cultures were obtained in eight patients, revealing Pseudomonas aeruginosa and Escherichia coli in three each and Proteus species in two. In four patients, pulmonary infarction was not considered and the diagnosis was made at autopsy, a situation also common in previously reported cases. We have seen a high incidence of CPI in a retrospective review of patients with pulmonary infarction, and we believe that it is important to consider this diagnosis when evaluating cavitary lesions.


Genotype-phenotype complexity of the TR46/Y121F/T289A cyp51A azole resistance mechanism in Aspergillus fumigatus.
The Aspergillus fumigatus cyp51A gene TR46/Y121F/T289A mutation is a new emerging resistance mechanism with high-level voriconazole (VOR) resistance, and elevated MICs to all other medical azoles. This is highly worrisome as VOR is the primary drug for the treatment of many aspergillus diseases. The 46 base pair tandem repeat (TR46) is positioned at the same location of the cyp51A gene promoter region as has been described for other tandem repeats. The exact role of the TR46 in combination with the two amino acid changes (Y121F and T289A) in the CYP51A protein is unknown. In this study this azole resistance mechanism was investigated by recombinant analysis study combined with homology modelling. MICs of the TR46/Y121F/T289A recombinant corresponded to the MICs of the original clinical isolates containing the same mutations with high-level resistance to VOR. The TR46 or Y121F by itself has only a moderate effect on azole susceptibility. The combination of TR46/Y121F, however, appears to be highly resistant not only for VOR but also for itraconazole (ITZ). The genetic change of T289A in combination with TR46 or by itself has no significant effect on the phenotype but moderates the phenotype of the ITZ resistance only in the presence of Y121F. The striking resistant phenotype of the TR46/Y121F mutant is supported by the structural analysis of the CYP51A homology model. The A. fumigatus CYP51A Y121 residue forms an H-bond with the heme centre of the enzyme. Disruption of the H-bond by the Y121F substitution destabilizes the active centre of CYP51A which appears to be essential with respect to azole resistance. In CYP51A-azole complexes, residue T289 is in close proximity of the azole moiety of VOR. Replacement of the polar amino acid threonine by the more hydrophobic amino acid alanine might promote more stable drug-protein interactions and has thereby an impact on ITZ susceptibility, which is confirmed by the MICs of the genetic recombinants.


Doublethink and scale mismatch polarize policies for an invasive tree.
Mismatches between invasive species management policies and ecological knowledge can lead to profound societal consequences. For this reason, natural resource agencies have adopted the scientifically-based density-impact invasive species curve to guide invasive species management. We use the density-impact model to evaluate how well management policies for a native invader (Juniperus virginiana) match scientific guidelines. Juniperus virginiana invasion is causing a sub-continental regime shift from grasslands to woodlands in central North America, and its impacts span collapses in endemic diversity, heightened wildfire risk, and crashes in grazing land profitability. We (1) use land cover data to identify the stage of Juniperus virginiana invasion for three ecoregions within Nebraska, USA, (2) determine the range of invasion stages at individual land parcel extents within each ecoregion based on the density-impact model, and (3) determine policy alignment and mismatches relative to the density-impact model in order to assess their potential to meet sustainability targets and avoid societal impacts as Juniperus virginiana abundance increases. We found that nearly all policies evidenced doublethink and policy-ecology mismatches, for instance, promoting spread of Juniperus virginiana regardless of invasion stage while simultaneously managing it as a native invader in the same ecoregion. Like other invasive species, theory and literature for this native invader indicate that the consequences of invasion are unlikely to be prevented if policies fail to prioritize management at incipient invasion stages. Theory suggests a more realistic approach would be to align policy with the stage of invasion at local and ecoregion management scales. There is a need for scientists, policy makers, and ecosystem managers to move past ideologies governing native versus non-native invader classification and toward a framework that accounts for the uniqueness of native species invasions, their anthropogenic drivers, and their impacts on ecosystem services.


Research opportunities for medications to treat alcohol dependence: addressing stakeholders' needs.
During the past decade, significant advances have been made in the development of medications to treat alcohol dependence. Four medications have been approved by the U.S. Food and Drug Administration for treating alcohol dependence-naltrexone, injectable naltrexone, acamprosate, and disulfiram-and several others show promise. The fact remains, however, that because of the heterogeneity of alcohol dependence, these medications will not work for all people, in all circumstances. Moreover, clinicians are not routinely prescribing these medications for alcohol treatment. This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking. These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers. Addressing these issues will not only help to improve treatment but, as further described, will also open up many new research opportunities for alcohol investigators in the coming decade.


A Cross-Sectional Analysis of Telomere Length and Sleep in the Women's Health Initiative.
Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a subpopulation of 3,145 postmenopausal women (1,796 European-American (EA) and 1,349 African-American (AA)) enrolled in the Women's Health Initiative in 1993-1998 with data on Southern blot-measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AAs + EAs; adjusted for race/ethnicity) and in racial/ethnic strata, since LTL differs by ancestry. After adjustment for covariates, each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair (95% confidence interval (CI): 6, 48) longer LTL in the entire sample. Associations between sleep duration and LTL were strongest among AAs (adjusted β = 37, 95% CI: 4, 70); a similar, nonsignificant association was observed for EAs (adjusted β = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms: P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.


Fucoxanthin: A Promising Phytochemical on Diverse Pharmacological Targets.
Fucoxanthin (FX) is a special carotenoid having an allenic bond in its structure. FX is extracted from a variety of algae and edible seaweeds. It has been proved to contain numerous health benefits and preventive effects against diseases like diabetes, obesity, liver cirrhosis, malignant cancer, etc. Thus, FX can be used as a potent source of both pharmacological and nutritional ingredient to prevent infectious diseases. In this review, we gathered the information regarding the current findings on antimicrobial, antioxidant, anti-inflammatory, skin protective, anti-obesity, antidiabetic, hepatoprotective, and other properties of FX including its bioavailability and stability characteristics. This review aims to assist further biochemical studies in order to develop further pharmaceutical assets and nutritional products in combination with FX and its various metabolites.


Plasma concentration and lipoprotein distribution of ApoC-I is dependent on ApoE genotype rather than the Hpa I ApoC-I promoter polymorphism.
An Hpa I restriction site located 317 bp upstream of the transcription initiation site of the apoC-I gene has been shown to increase apoC-I gene transcription in vitro. The aim of the present study was to determine whether this genetic polymorphism was associated in vivo with increased plasma levels of apoC-I. In a cohort of French-Canadians (n=391) recruited for a family study, we found strong linkage disequilibrium between the genes for apoC-I and apoE (as reported before for European-Americans), such that the apoC-I Hpa I-negative (H1) allele was strongly associated with apoE epsilon 3, whereas the apoC-I Hpa I-positive (H2) allele was strongly associated with apoE epsilon 2 and epsilon 4. ApoC-I and apoE were measured by ELISA in total plasma and in very low-density lipoproteins (VLDL) separated by ultracentrifugation (d<1.006 g/ml), and then by difference for the non-VLDL fraction (d>1.006 g/ml), in a subset of families selected for their diverse apoE genotypes. Subjects were divided into normolipidemic (NL, n=89, TG<2.3 mmol/l, LDL-C<3.8 mmol/l) and hyperlipidemic groups (HL, n=88, TG>2.3 mmol/l and/or LDL-C>3.8 mmol/l). In NL subjects, apoC-I levels were not significantly associated with apoC-I genotype (H1/H1, H1/H2 or H2/H2). They were, however, related to apoE genotype, such that apoE3/2 subjects tended to have higher and apoE4/3 subjects tended to have lower concentrations of total plasma and non-VLDL apoC-I and apoE. Total plasma, VLDL and non-VLDL apoC-I and E levels were also higher in HL subjects with an apoE2/2 or apoE3/2 genotype. These results suggest that plasma levels of apoC-I are more strongly influenced by apoE genotype than by the Hpa I apoC-I promoter polymorphism, which probably reflects an effect of different apoE isoforms on plasma lipoprotein and plasma apoC-I metabolism, rather than a direct effect of apoE alleles on apoC-I transcription.


Enhanced immunogenicity of HPV16E7 accompanied by Gp96 as an adjuvant in two vaccination strategies.
Human papillomavirus, particularly type 16 (HPV16) is present in more than 99% of cervical cancers. E7 is the major oncogenic protein produced in cervical cancer-associated HPV16. An efficient vaccine against viral infection requires induction of strong humoral and cellular responses against viral proteins. Heat shock proteins (HSPs) like Gp96 have been described as potent tumor vaccines in animal models and are currently studied in human clinical trials. In this study, we investigated the utility of HPV16 E7 along with Gp96 as an adjuvant in C57BL/6 mice model. We compared the level of humoral and cellular immune responses by E7+Gp96 co-injection as DNA/DNA and prime-boost (DNA/protein) immunization strategies. In prime-boost immunization strategies, we first immunized C57BL/6 mice with the complete open-reading frame of E7 and Gp96 (pcDNA-E7 and pcDNA-Gp96) and then boosted with rE7, rNT-gp96 (N-terminal extension of Gp96) and rCT-gp96 (C-terminal extension of Gp96) mixed with Montanide 720 in different formulations. The humoral immune responses against rE7 and the different truncated forms of rGp96 suggested a mixed Th1/Th2 response with high intensity toward Th2. Assessment of lymphoproliferative and cytokine responses against rE7 and the different fragments of Gp96, showed that DNA vaccination including E7 and Gp96 induced Th1 response. We concluded that co-delivery of naked DNA E7+Gp96 plasmid was immunologically more effective than E7 alone. Our study demonstrated that co-delivery of E7+Gp96 as DNA/DNA and E7+CT-gp96 as DNA/protein could be an effective approach to induce E7-specific immune responses as a potential vaccine candidate for cervical cancer.


Single-Center Experience in Pre-transplant Hepatitis C Virus (HCV) Treatment Among Living Donor Liver Transplant Candidates: Bridging the Direct-Acting Antivirals (DAA).
BACKGROUND Treatment with DAAs before deceased donor liver transplantation has been shown to be an effective strategy to prevent post-transplant HCV recurrence, with a 95% cure-rate among individuals who achieve undetectable HCV VL for ≥30 days pre- transplant. This strategy has not been evaluated in LDLT. MATERIAL AND METHODS We evaluated outcomes in LDLT recipients treated with DAAs pre-transplant and bridged with 4 weeks of post-transplant SOF. All cases of LDLT at Johns Hopkins (1/1/2014-3/1/15) were retrospectively reviewed. RESULTS There were 4 HCV+ LDLT cases treated with DAAs pre- and post-transplant. Pre-transplant DAA regimens included SOF plus SIM in 2 cases of HCC and SOF plus RBV in 2 cases of ESLD. All patients achieved negative VL by week 7 of treatment and all patients had at least 30 days of HCV RNA negativity at the time of LDLT. Patient 4 had a delay in LDLT due to uncontrolled pulmonary hypertension, and experienced viral breakthrough because of treatment interruption. Due to concerns for SOF resistance, a salvage regimen of LDV-SOF and SIM was used. Post-LDLT patients 1-3 received 4 weeks of SOF monotherapy and patient 4 received 14 weeks of LDV-SOF. Three patients achieved SVR12. One died from non-HCV related complications at 4 months post-LDLT. CONCLUSIONS Our preliminary experience suggests that bridging DAAs pre- and post-LDLT is an effective strategy to prevent HCV recurrence. With delays in transplant and prolonged use of SOF/RBV, there is a risk of viral breakthrough, but a salvage strategy of triple DAA therapy can be effective.


Demonstration of Complement Fixing Antibody in the Sera of Cattle Vaccinated with Combined Living Blackleg-anthrax Vaccine.
Complement fixing antibodies could be detected in the sera of cattle vaccinated with combined living blackleg-anthrax vaccine by modified complement fixation tests. Conventional direct complement fixation tests with bovine antibody-antigen systems often caused false negative reactions; however, in the modified test, when guinea pig complement was supplemented with fresh unheated normal rabbit serum, positive reactions were obtained and the sensitivity of the test was increased without loss of specificity.


In vitro regulation of granulopoiesis in human leukemia: application of an assay for colony-inhibiting cells.
We describe two assays to detect the action of colony-inhibiting cells. In the first assay, we used a simple density separation technique to remove dense neutrophils (PMN) from suspensions of blood and of bone marrow cells prior to culture in semisolid agar. Conditions were arranged to ensure that control suspensions of unseparated cells and test suspensions of buoyant mononuclear cells differed only in their content of neutrophils. The control and test suspensions contained equal numbers of mononuclear cells (and granulocyte precursors). Colony (and cluster) formation was invariably enhanced in neutrophil-depleted cultures of normal cells. In the second assay, dense PMN, treated by an adherence separation procedure, were recovered, and the non-adherent dense PMN were added back to PMN-depleted cultures. A reproducible dose-related decrease in colony (and cluster) formation to basal levels resulted. The inhibitory effect was identical when the PMN were added directly to the culture (overlayer) or to the underlayer. In PMN-depleted cultures obtained from patients with leukemia and other hemopoietic disorders, neither colony nor cluster formation was enhanced, and sometimes it was reduced. When we compared the effect of adding patient and normal non-adherent PMN to target cultures of normal and patient PMN-depleted cells, some leukemic PMN were noninhibitory. Our results suggest that abnormalities of cellular interactions in vitro detected in the first assay may have more than one explanation, as shown when they are subjected to the closer scrutiny possible with the second assay.


[Subtotal and total colectomy with formation of primary anastomosis for left colonic ileus of tumoral genesis].
The one-staged subtotal/total colectomy with formation of primary ileo-sigmoanastomosis or ileo-rectal anastomosis is applied in tumoral left colonic ileus. There were estimated immediate results and the role of the method in the treatment of 46 patients with left colonic obstructive tumor. Postoperative complications had occurred in 52% of the patients, postoperative mortality had constituted 10.9%. Performance of subtotal/total colectomy with formation of primary anastomosis constitutes the alternative and preferable method of treatment of patients with left colonic obstructive tumor.


Overexpression of interleukin-6 in human basal cell carcinoma cell lines increases anti-apoptotic activity and tumorigenic potency.
Interleukin-6 (IL-6) is a pleiotropic cytokine that is capable of modulating the diverse functions of cells such as acute phase responses and inflammation. Excessive or insufficient production of IL-6 may contribute to certain diseases of the skin. The aim of this study was to investigate the possible role of IL-6 in the tumorigenesis of basal cell carcinoma (BCC). Initially, we transfected IL-6 expression vector, under the control of a CMV promoter, into human BCC cells and successfully obtained IL-6-overexpressing clones (BCC/IL-6-c1 and BCC/IL-6-c2) and a mixture (BCC/IL-6). DNA synthesis assay determined using (3)H-thymidine pulse incorporation revealed that IL-6-expressing BCC cells exhibited a much higher DNA synthesis rate than the neo control or parental BCC cells. We also detected a greater abundance of IL-6-expressing cell colonies formed in soft agar than in the vector control cells. Furthermore, BCC/IL-6 cells, but not vector control cells, were resistant to UV and photodynamic therapy (PDT)-induced apoptosis, as confirmed using DNA fragmentation and morphologic change analyses. Immunoblot analysis showed that Mcl-1, an anti-apoptotic protein, was specifically up-regulated IL-6 transfectants but not in the control cells. Transient transfection of IL-6 transfectants with antisense mcl-1 greatly enhanced their apoptosis frequency by UV treatment. In tumorigenesis assay, IL-6 transfected clones formed tumors in nude mice more rapidly than the control cells. These tumors appeared to be highly vascularized using pathological examination. Supportive of this finding, we found that IL-6 transfected cells expressed elevated levels of two angiogenic factors, cyclooxygenase (Cox)-2 and vascular endothelial growth factor (VEGF). These results suggest that overexpression of IL-6 enhances the tumorigenic activity of BCC cells by both suppressing apoptosis and actively promoting angiogenesis.


[Effects of dauricine on slow action potentials in myocardium].
The effects of dauricine were examined on the slow action potentials induced by both high K+ (24 mmol/L) or TTX (40 mumol/L) in guinea pig papillary muscles and in sinoatrial node cells of rabbit. Dauricine 40 mumol/L decreased the maximal upstroke velocity (Vmax) of slow action potentials and prolonged the action potential duration at 50% repolarization (APD50). Bay K 8644 (50 nmol/L) increased the amplitude and Vmax of slow action potentials, which were antagonized by dauricine (40 mumol/L). An inhibitory influence of dauricine on the action potential amplitude was observed in papillary muscles superfused with Tyrode's solution containing high K+ and in rabbit sinoatrial node cells, but it was not with TTX. The resting potentials of the 3 slow action potentials were not affected by dauricine. The results suggest that dauricine possesses calcium-antagonistic effect.


InGaN light emitting solar cells with a roughened N-face GaN surface through a laser decomposition process.
InGaN-based light-emitting solar cell (LESC) structure with an inverted pyramidal structure at GaN/sapphire interface was fabricated through a laser decomposition process and a wet crystallographic etching process. The highest light output power of the laser-treated LESC structure, with a 56% backside roughened-area ratio, had a 75% enhancement compared to the conventional device at a 20 mA operating current. By increasing the backside roughened area, the cutoff wavelength of the transmittance spectra and the wavelength of the peak photovoltaic efficiency had a redshift phenomenon that could be caused by increasing the light absorption at InGaN active layer.


The microbiota of the surface, dermis and subcutaneous tissue of dog skin.
Studies using highly sensitive molecular techniques have detected bacterial communities below the human epidermis. Depending on their abundance and composition, this finding could be clinically relevant. The aim of this study was to determine if bacteria can be detected in the dermis and subcutaneous tissue of dogs without cutaneous disease using two different approaches: traditional cultures and DNA sequencing of the V4 region of bacterial 16S rRNA gene using next-generation sequencing (NGS). Seven healthy dogs were included in the study, and two sets of samples were collected from each subject. Sample sets were composed of a 6-mm abdominal skin biopsy, including epidermis, dermis, and subcutis, a skin surface swab, and an environmental blank sample for contamination control. One set of samples from each dog was submitted for bacterial culture and the other one for bacterial DNA amplification and sequencing. Five different bacterial genera (Staphylococcus, Bacillus, Corynebacterium, Streptococcus, and Enterococcus) were isolated in five out of the seven skin surface swab samples with aerobic microbiological culture methods, while no growth was obtained from the other two samples. Although some DNA could be amplified from epidermal, dermal, and subcutaneous tissue samples, the results of the NGS were similar to those of the blanks. When investigated with aerobic microbiological culture methods, the dermis and subcutaneous tissue of dogs are sterile. NGS techniques lead to the detection of some bacterial DNA, similar to the signal detected in blanks, which does not support the presence of a microbiota in dermis or subcutaneous tissue.


Distal splenorenal shunt for portal hypertension.
A distal splenorenal shunt was performed electively in 25 patients with bleeding oesophageal varices. Early postoperative mortality was 16%. During the follow-up period (mean 41 months) three patients died, one of liver insufficiency and two of cardiac complications. Two patients of 17 survivors (12%) had endoscopically demonstrable varices. One of these patients had one upper gastrointestinal rebleeding period. The actual three year survival was 71%. Reverse portal blood flow was demonstrated postoperatively in eight of 17 patients (47%). In these cases the distal splenorenal shunt had in fact slowly turned to a total shunt. Even though in certain patients the original selectivity of the shunt is lost it gives a good long-term variceal decompression and certainly is a useful alternative in the treatment of selected good risk patients for bleeding oesophageal varices.


Comparative proteomic analysis reveals proteins putatively involved in toxin biosynthesis in the marine dinoflagellate Alexandrium catenella.
Alexandrium is a neurotoxin-producing dinoflagellate genus resulting in paralytic shellfish poisonings around the world. However, little is known about the toxin biosynthesis mechanism in Alexandrium. This study compared protein profiles of A. catenella collected at different toxin biosynthesis stages (non-toxin synthesis, initial toxin synthesis and toxin synthesizing) coupled with the cell cycle, and identified differentially expressed proteins using 2-DE and MALDI-TOF-TOF mass spectrometry. The results showed that toxin biosynthesis of A. catenella occurred within a defined time frame in the G1 phase of the cell cycle. Proteomic analysis indicated that 102 protein spots altered significantly in abundance (P < 0.05), and 53 proteins were identified using database searching. These proteins were involved in a variety of biological processes, i.e., protein modification and biosynthesis, metabolism, cell division, oxidative stress, transport, signal transduction, and translation. Among them, nine proteins with known functions in paralytic shellfish toxin-producing cyanobacteria, i.e., methionine S-adenosyltransferase, chloroplast ferredoxin-NADP+ reductase, S-adenosylhomocysteinase, adenosylhomocysteinase, ornithine carbamoyltransferase, inorganic pyrophosphatase, sulfotransferase (similar to), alcohol dehydrogenase and arginine deiminase, varied significantly at different toxin biosynthesis stages and formed an interaction network, indicating that they might be involved in toxin biosynthesis in A. catenella. This study is the first step in the dissection of the behavior of the A. catenella proteome during different toxin biosynthesis stages and provides new insights into toxin biosynthesis in dinoflagellates.


Strain background effects and genetic modifiers of hearing in mice.
Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positional-candidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23(753A/G)). This variant also was shown to modify hearing loss associated with the Atp2b2(dfw-2J) and Mass1(frings) mutations. The hearing modifier (Moth1) of tubby (Tub(tub)) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans.


Relapse in patients with shifting RDC diagnoses treated with lithium alone.
After a research diagnostic interview with 60 chronic outpatients clinically diagnosed as schizophrenic, the authors identified four patients who by retrospective history had had affective episodes at one time in their life and schizophrenic episodes at another. Lithium was substituted for antipsychotic medications and the patients were followed for 13 months. Two patients relapsed on lithium alone, one relapsed on no medications and one did well on lithium alone. The phenomenology observed in the three relapsing cases included: 1) RDC mania; 2) rapid onset with confusion; 3) sexually regressive behavior; and 4) improvement with reinitiation of antipsychotic medication. Caution is advised in the use of lithium alone for patients fitting this diagnostic description.


Two new species of Pseudogymnoascus with Geomyces anamorphs and their phylogenetic relationship with Gymnostellatospora.
Two new psychrophilic Pseudogymnoascus species with Geomyces anamorphs are described from a Sphagnum bog in Alberta, Canada. Pseudogymnoascus appendiculatus has long, branched, orange appendages and smooth, fusoid to ellipsoidal ascospores with a faint longitudinal rim. Pseudogymnoascus verrucosus has short, subhyaline appendages and warty peridial hyphae and ascospores, and both smooth to asperulate and irregularly warty conidia. Both species produce asci in chains, a feature that supports the distinction between this group and Myxotrichum, which produces asci singly. The discovery of species intermediate between Pseudogymnoascus and Gymnostellatospora, in having both ornamented ascospores and Geomyces anamorphs, prompted a re-evaluation of the genera. Sequence analysis of the internal transcribed spacer regions (ITS) of the nuclear ribosomal DNA indicates that the two genera remain distinct and comprise a monophyletic group. Pseudogymnoascus species have smooth to warty or lobate-reticulate ascospores while species of Gymnostellatospora have walnut-shaped spores with distinct longitudinal crests and striations. Anamorphs assignable to the form genus Geomyces are allied with both genera. A key is provided to the four species and varieties of Pseudogymnoascus.


Hepatitis B and alcohol affect survival of hepatocellular carcinoma patients.
In the USA, Hawaii has the highest incidence of hepatocellular carcinoma (HCC) and a diverse population. It is an ideal place to characterize HCC in the context of ethnicity/risk factors. A total of 262 cases of HCC (1992-2003) were retrospectively reviewed for demographics, ethnicity, birthplace, viral hepatitis, alcohol use, diabetes, smoking and risk factors for viral hepatitis such as intravenous drug abuse (IVDA), transfusions, tattoos and vertical transmission. Tumor stage, Child's class, Cancer of the Liver Italian Program (CLIP) score, alpha-fetoprotein level, treatment and survival were recorded. Gender, age, viral hepatitis, alcohol, IVDA, and diabetes differed significantly in Asians, non-Asians and Pacific Islanders. There were also specific differences within Asian subgroups. Alpha-fetoprotein, smoking, transfusions, stage and resectability did not differ between groups. Asians were more likely to have hepatitis B, while non-Asians were more likely to have hepatitis C. Factors that decreased survival included hepatitis B, alcohol, elevated alpha-fetoprotein, CLIP>2 and increased Child's class. When Asians were combined with Pacific Islanders, median survival (1.52 years vs 3.54 years), 1- and 3-year survival was significantly worse than those for non-Asians. After Cox regression analysis for hepatitis B and alcohol, there was no difference in survival by ethnicity. Various ethnicities have different risk factors for HCC. Hepatitis B, alcohol, and alpha-fetoprotein are more important factors for survival than ethnicity.


Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders.
Interactions between genetic and environmental risk factors underlie a number of neuropsychiatric disorders, including schizophrenia (SZ) and autism (AD). Due to the complexity and multitude of the genetic and environmental factors attributed to these disorders, recent research strategies focus on elucidating the common molecular pathways through which these multiple risk factors may function. In this study, we examine the combined effects of a haplo-insufficiency of glutamate carboxypeptidase II (GCPII) and dietary folic acid deficiency. In addition to serving as a neuropeptidase, GCPII catalyzes the absorption of folate. GCPII and folate depletion interact within the one-carbon metabolic pathway and/or of modulate the glutamatergic system. Four groups of mice were tested: wild-type, GCPII hypomorphs, and wild-types and GCPII hypomorphs both fed a folate deficient diet. Due to sex differences in the prevalence of SZ and AD, both male and female mice were assessed on a number of behavioral tasks including locomotor activity, rotorod, social interaction, prepulse inhibition, and spatial memory. Wild-type mice of both sexes fed a folic acid deficient diet showed motor coordination impairments and cognitive deficits, while social interactions were decreased only in males. GCPII mutant mice of both sexes also exhibited reduced social propensities. In contrast, all folate-depleted GCPII hypomorphs performed similarly to untreated wild-type mice, suggesting that reduced GCPII expression and folate deficiency are mutually protective. Analyses of folate and neurometabolite levels associated with glutamatergic function suggest several potential mechanisms through which GCPII and folate may be interacting to create this protective effect.


Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.
Bacterial infections caused by multi-drug-resistant Gram-negative pathogens pose a serious threat to public health. Gram-negative bacteria are characterized by the enrichment of lipid A-anchored lipopolysaccharide (LPS) or lipooligosaccharide (LOS) in the outer leaflet of their outer membrane. Constitutive biosynthesis of lipid A via the Raetz pathway is essential for bacterial viability and fitness in the human host. The inhibition of early-stage lipid A enzymes such as LpxC not only suppresses the growth of Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter spp., and other clinically important Gram-negative pathogens but also sensitizes these bacteria to other antibiotics. The inhibition of late-stage lipid A enzymes such as LpxH is uniquely advantageous because it has an extra mechanism of bacterial killing through the accumulation of toxic lipid A intermediates, rendering LpxH inhibition additionally lethal to Acinetobacter baumannii. Because essential enzymes of the Raetz pathway have never been exploited by commercial antibiotics, they are excellent targets for the development of novel antibiotics against multi-drug-resistant Gram-negative infections.This Account describes the ongoing research on characterizing the structure and inhibition of LpxC and LpxH, the second and fourth enzymes of the Raetz pathway of lipid A biosynthesis, in the laboratories of Dr. Pei Zhou and Dr. Jiyong Hong at Duke University. Our studies have elucidated the molecular basis of LpxC inhibition by the first broad-spectrum inhibitor, CHIR-090, as well as the mechanism underlying its spectrum of activity. Such an analysis has provided a molecular explanation for the broad-spectrum antibiotic activity of diacetylene-based LpxC inhibitors. Through the structural and biochemical investigation of LpxC inhibition by diacetylene LpxC inhibitors and the first nanomolar LpxC inhibitor, L-161,240, we have elucidated the intrinsic conformational and dynamics difference in individual LpxC enzymes near the active site. A similar approach has been taken to investigate LpxH inhibition, leading to the establishment of the pharmacophore model of LpxH inhibitors and subsequent structural elucidation of LpxH in complex with its first reported small-molecule inhibitor based on a sulfonyl piperazine scaffold.Intriguingly, although our crystallographic analysis of LpxC- and LpxH-inhibitor complexes detected only a single inhibitor conformation in the crystal lattice, solution NMR studies revealed the existence of multiple ligand conformations that together delineate a cryptic ligand envelope expanding the ligand-binding footprint beyond that observed in the crystal structure. By harnessing the ligand dynamics information and structural insights, we demonstrate the feasibility to design potent LpxC and LpxH inhibitors by merging multiple ligand conformations. Such an approach has enabled us to rationally design compounds with significantly enhanced potency in enzymatic assays and outstanding antibiotic activities in vitro and in animal models of bacterial infection. We anticipate that continued efforts with structure and ligand dynamics-based lead optimization will ultimately lead to the discovery of LpxC- and LpxH-targeting clinical antibiotics against a broad range of Gram-negative pathogens.


Boosting the Performance of the Nickel Anode in the Oxygen Evolution Reaction by Simple Electrochemical Activation.
The development of cost-effective and active water-splitting electrocatalysts that work at mild pH is an essential step towards the realization of sustainable energy and material circulation in our society. Its success requires a drastic improvement in the kinetics of the anodic half-reaction of the oxygen evolution reaction (OER), which determines the overall system efficiency to a large extent. A simple electrochemical protocol has been developed to activate Ni electrodes, by which a stable NiOOH phase was formed, which could weakly bind to alkali-metal cations. The electrochemically activated (ECA) Ni electrode reached a current of 10 mA at <1.40 V vs. the reversible hydrogen electrode (RHE) at practical operation temperatures (>75 °C) and a mild pH of ca. 10 with excellent stability (>24 h), greatly surpassing that of the state-of-the-art NiFeOx electrodes under analogous conditions. Water electrolysis was demonstrated with ECA-Ni and NiMo, which required an iR-free overall voltage of only 1.44 V to reach 10 mA cmgeo-2 .


The evaluation of suspected ulnar neuropathy at the elbow. Normal conduction study values.
Local compression of the ulnar nerve occurs at several points, with the elbow region being the most common. Nerve conduction studies can be useful in identifying and localizing such lesions; however, the specifics of the technique, including normal values, have not been firmly established. We evaluated the effect of elbow position on segmental conduction velocities (CVs), the influence of elbow, nerve segment length on CV calculations, the change in compound action potential amplitude at sites along the nerve, and the use of performing segmental sensory CVs. Conductions done with the elbow flexed produced less segment-to-segment CV variation than those obtained with the elbow extended. The influence of using overlapping nerve segments compared with short adjacent ones for segmental CV comparison is discussed.


Determination of Polycyclic Aromatic Hydrocarbons in Commercial Parenteral Formulations and Medications Using High-Performance Liquid Chromatography with Diode Array Detection.
HPLC coupled to UV diode array detection (DAD) is proposed for the determination of polycyclic aromatic hydrocarbons (PAHs) in pharmaceutical products for parenteral administration. Because rubber is a possible source of PAHs for these products, samples stored in containers with rubber parts were selected for the analysis. The basis for method optimization was EPA Method 8310, which determines 16 priority PAHs in ground water and wastewater by HPLC using both UV and fluorescence detection. Using DAD, two channels were selected for detection, with one operating at 254 nm for the detection of nine PAHs and the other at 225 nm for the detection of seven PAHs. This method allowed for the detection of PAHs using external calibration with LODs and LOQs ranging from 0.001 to 0.060 µg/mL and from 0.003 to 0.167 µg/mL, respectively. Within-day precision, expressed as RSD, varied from 1.24 to 7.76% for PAH concentrations from 0.05 to 0.50 µg/mL, and intraday precision varied from 3.10 to 9.40% for the same concentration range. Method accuracy was confirmed by recoveries of 75-120% of the spiked samples. This method was applied for the determination of PAHs in three commercial infusion solutions and in nine different medications stored in syringes prior to administration to patients. Twelve of 16 PAHs were found in these samples. Total PAH concentrations varied from 0.13 to 13.50 µg/mL. Pyrene was the most prevalent contaminant, being present in 11 of 12 samples in concentrations ranging from 0.17 to 4.80 µg/mL. This method presented good sensitivity for the measurement of PAH in the target samples, allowing for the determination of the 16 priority PAHs in one run and in 30 min.


PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients.
EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients. Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18). Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.


Developmental genes targeted for epigenetic variation between twin-twin transfusion syndrome children.
Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. The unequal flow results in reciprocal hypo- and hypervolemia in the affected twins, striking growth differences and physiologic adaptations in response to this significant stressor. The donor twin in the TTTS syndrome can be profoundly growth restricted and there is likely a nutritional imbalance between the twins. The consequences of TTTS on fetal programming are unknown. This condition can now be effectively treated through the use of fetal laparoscopic procedures, but the potential for lifelong morbidity related to this condition during development is apparent. As this condition and the resulting uteroplacental discordance can play a role in the epigenetic process, we sought to investigate the DNA methylation profiles of childhood survivors of TTTS (n = 14). We focused on differences in both global measures and genome-wide CpG specific DNA methylation between donor and recipient children in this pilot study in order to generate hypotheses for further research. We identified significant hypomethylation of the LINE1 repetitive element in the peripheral blood of donor children and subtle variation in the genome-wide profiles of CpG specific methylation most prominent at CpG sites which are targets for polycomb group repressive complexes. These preliminary results suggest that coordinated epigenetic alterations result from the intrauterine environment experienced by infants with TTTS and may, at least in part, be responsible for downstream health conditions experienced by individuals surviving this condition.


Acknowledging Patient Heterogeneity in Economic Evaluations in Schizophrenia: A Systematic Review.
Schizophrenia is a severe mental illness with heterogeneous etiology, range of symptoms, and course of illness. Cost-effectiveness analysis often applies averages from populations, which disregards patient heterogeneity even though there are a range of methods available to acknowledge patient heterogeneity. This review evaluates existing economic evaluations of interventions in schizophrenia to understand how patient heterogeneity is currently reflected in economic evaluation. Electronic searches of MEDLINE, Embase, and PsycINFO via Ovid and the Health Technology Assessment database were run to identify full economic evaluations of interventions aiming to reduce the symptoms associated with schizophrenia. Two levels of screening were used, and explicit inclusion criteria were applied. Prespecified data extraction and critical appraisal were performed. Seventy-six relevant studies were identified. More than half (41 of 76) of the articles acknowledged patient heterogeneity in some way through discussion or methods. There was a range of patient characteristics considered, including demographics and socioeconomic factors (eg, age, educational level, ethnicity), clinical characteristics (eg, symptom severity, comorbidities), and preferences (eg, preferences related to outcomes or symptoms). Subgroup analyses were rarely reported (8 of 76). Patient heterogeneity was frequently mentioned in studies but was rarely thoroughly investigated in the identified economic evaluations. When investigated, included patient characteristics and methods were found to be heterogeneous. Understanding and acknowledging patient heterogeneity may alter the conclusions of cost-effectiveness evaluations; subsequently, we would encourage further research in this area.


Influence of atmospheric oxygen concentration on acetylene reduction and efficiency of nitrogen fixation in intact Klebsiella pneumoniae.
Oxygen-limited (N2-fixing) chemostat cultures of Klebsiella pneumoniae supplied with a N-free medium were established by introducing low atmospheric O2 concentrations into the gas supply of anaerobic glucose-limited N2-fixing chemostat cultures; the molar growth yield for glucose and the efficiency of N2 fixation (mug N fixed/mg glucose consumed) were increased (by up to 82%) from the anaerobic values. Acetylene-reducing activity was inhibited reversibly by O2 in samples from O2-limited and anaerobic glucose-limited chemostat cultures. Oxygen uptake rates in samples from these chemostat cultures were similar, but C2-H2-reducing activity in samples from O2-limited chemostat cultures was more tolerant of low atmospheric O2 concentrations, in part because of a higher population density. In the absence of glucose, O2 was required at a low atmospheric concentration for C2H2 reduction in samples from either O2-limited or anaerobic glucose-limited chemostat cultures. The possibility is discussed that ATP generated from oxidative phosphorylation can be used for N2 fixation in K. pneumoniae.


Underestimation of acute pancreatitis: patients with only a small increase in amylase/lipase levels can also have or develop severe acute pancreatitis.
In most treatment studies on acute pancreatitis, pancreatologists base their diagnosis on amylase/lipase levels more than three times above the upper limit of normal (>3n) and thus exclude patients with smaller enzyme level increases. The recommendations derived from the results of treatment studies do not take into account such patients. Non-pancreatologists frequently believe that only patients with high enzyme levels have a serious prognosis. To question the assumption that high enzyme levels indicate severe, and conversely low enzyme levels indicate mild, acute pancreatitis. This retrospective study includes 284 consecutive patients with a first attack of acute pancreatitis. The cause was biliary in 114 (40%) patients, alcoholism in 83 (29%), other in 21 (7%), and unknown in 66 (23%). Patients were divided into two groups according to their serum enzyme levels (amylase: </=3n, n = 88; >3n, n = 196; lipase: </=3n, n = 51; >3n, n = 233). Renal impairment, indication for dialysis and artificial ventilation, development of pseudocysts, necessity for surgery, and mortality were taken as parameters of severity. The incidence of severity was the same for both the </=3n and >3n groups. The severity of acute pancreatitis is independent of the elevation in serum amylase/lipase level (</=3n or >3n) on admission. Patients with only a slight increase can also have or develop severe acute pancreatitis. Patients with </=3n elevated enzyme levels on admission represent a substantial group that treatment studies have frequently overlooked. This is especially true for patients with alcohol induced acute pancreatitis whose amylase levels are lower than in other aetiological groups.


Primary systemic amyloidosis of tongue with chondroid metaplasia.
Amyloid is a pathologic proteinaceous substance deposited between cells in various tissues in a variety of clinical conditions. We report a case of amyloidosis of tongue with extensive chondroid metaplasia diagnosed on incisional biopsy in a multiple myeloma patient, who underwent autologous peripheral blood stem cell transplant for the same in 2010 and now presented with disease relapse after 2 years.


[Primary angiitis of the central nervous system: an infrequent form of presentation].
Primary angiitis of the central nervous system (CNS) is a rare disease. Clinical signs and symptoms include headache and cognitive disorders associated to multifocal neurological deficits. A definitive diagnosis can only be achieved by means of a cerebromeningeal biopsy. We describe the case of a 15-year-old male who first reported lower back pain and progressive paresis of the right lower limb, later followed by laterocollis on the right side. Magnetic resonance (MR) scanning of the brain and spinal cord revealed a pseudotumoral lesion in the right cerebellum and two lesions in the spinal cord. Dexamethasone was administered and surgical resection of the cerebellar lesion was performed. Following surgery, the patient received corticoid treatment with progressive withdrawal. Full clinical recovery of the patient was achieved. A year later, the same patient was admitted to hospital again because of headaches and diplopia. A new MR brain scan showed a right frontotemporal lesion. Dexamethasone was administered and the patient recovered. Thirteen months later, he reported dysarthria and right-side hemiparesis. An MR brain scan revealed the presence of a number of bilateral lesions in the white matter. Results of a lumbar puncture showed lymphocytic pleocytosis and raised protein levels in cerebrospinal fluid. The laminae from the cerebromeningeal biopsy were reviewed and the results confirmed the hypothetical diagnosis of angiitis of the CNS. Treatment was established with intravenous cyclophosphamide in association with oral prednisone. Primary angiitis of the CNS is an infrequent disease and its pathogenesis remains unknown. The definitive diagnosis of these patients is histological. It courses spontaneously and generally has a fatal outcome. Treatment, which consists in an association of cyclophosphamide and prednisone, must be started as early as possible.


Poor survival with wild-type TP53 ovarian cancer?
The objective of this study is to investigate whether wild-type TP53 status in high-grade serous ovarian carcinoma is associated with poorer survival. Clinical and genomic data of 316 sequenced samples from The Cancer Genome Atlas (TCGA) ovarian high-grade serous carcinoma study were downloaded from TCGA data portal. Association between wild-type TP53 and survival was analyzed with Kaplan Meier method and Cox regression. The diagnosis of high-grade serous carcinomas was evaluated by reviewing pathological reports and high-resolution hematoxylin and eosin (H&E) images from frozen sections. The authenticity of wild-type TP53 in these tumor samples was assessed by analyzing SNP array data with ASCAT algorithm, reverse phase protein array (RPPA) data and RNAseq data. Fifteen patients with high grade serous ovarian carcinomas were identified to have wild-type TP53, which had significantly shorter survival and higher chemoresistance than those with mutated TP53. The authenticity of wild-type TP53 status in these fifteen patients was supported by SNP array, RPPA, and RNAseq data. Except four cases with mixed histology, the classification as high grade serous carcinomas was supported by pathological reports and H&E images. Using RNAseq data, it was found that EDA2R gene, a direct target of wild-type TP53, was highly up-regulated in samples with wild-type TP53 in comparison to samples with either nonsense or missense TP53 mutations. Although patients with wild-type TP53 ovarian cancer were rare in the TCGA high grade ovarian serous carcinomas cohort, these patients appeared to have a poorer survival and were more chemoresistant than those with mutated TP53. Differentially expressed genes in these TP53 wild-type tumors may provide insight in the molecular mechanism in chemotherapy resistance.


Antimicrobial resistance in Shiga toxin-producing Escherichia coli other than serotype O157 : H7 in England, 2014-2016.
Introduction. Despite many ongoing surveillance projects and the recent focus on the veterinary and clinical 'One Health' aspects of antimicrobial resistance (AMR), evidence of the extent of any public health risk posed by animal reservoirs with respect to the transmission of resistant strains of Escherichia coli to humans remains varied and contentious. In the UK, the main zoonotic reservoir for the foodborne pathogen Shiga toxin-producing E. coli (STEC) is cattle and sheep. In this study, we adopt an alternative approach to the risk assessment of transmission of AMR E. coli from animals to humans, involving monitoring AMR in isolates of STEC, an established zoonotic, foodborne pathogen, from human cases of gastrointestinal disease.Aim. The aim of this study was to determine the genome-derived AMR profiles for STEC from human cases to assess the risk of transmission of multidrug-resistant STEC from ruminants to humans.Methodology. STEC belonging to 10 different clonal complexes (CCs) (n=457) isolated from human faecal specimens were sequenced and genome-derived AMR profiles were determined. Phenotypic susceptibility testing was undertaken on all isolates (n=100) predicted to be resistant to at least one class of antimicrobial.Results. Of the 457 isolates, 332 (72.7 %) lacked identifiable resistance genes and were predicted to be fully susceptible to 11 classes of antimicrobials; 125/332 (27.3 %) carried 1 or more resistance genes, of which 83/125 (66.4 %) were resistant to 3 or more classes of antibiotic. The percentage of isolates harbouring AMR determinants varied between CCs, from 4% in CC25 to 100% in CC504. Forty-six different AMR genes were detected, which conferred resistance to eight different antibiotic classes. Resistance to ampicillin, streptomycin, tetracyclines and sulphonamides was most commonly detected. Four isolates were identified as extended-spectrum β-lactamase producers. An overall concordance of 97.7 % (n=1075/1100) was demonstrated between the phenotypic and genotypic methods.Conclusion. This analysis provided an indirect assessment of the risk of transmission of AMR gastrointestinal pathogens from animals to humans, and revealed a subset of human isolates of the zoonotic pathogen STEC were resistant to the antimicrobials used in animal husbandry. However, this proportion has not increased over the last three decades, and thismay provide evidence that guidancepromoting responsible practice has been effective.


Soil aggregation and associated microbial communities modify the impact of agricultural management on carbon content.
Soil carbon (C) stabilisation is known to depend in part on its distribution in structural aggregates, and upon soil microbial activity within the aggregates. However, the mechanisms and relative contributions of different microbial groups to C turnover in different aggregates under various management practices remain unclear. The aim of this study was to determine the role of soil aggregation and their associated microbial communities in driving the responses of soil organic matter (SOM) to multiple management practices. Our results demonstrate that higher amounts of C inputs coupled with greater soil aggregation in residue retention management practices has positive effects on soil C content. Our results provide evidence that different aggregate size classes support distinct microbial habitats which supports the colonisation of different microbial communities. Most importantly our results indicate that the effects of management practices on soil C is modulated by soil aggregate sizes and their associated microbial community and are more pronounced in macro-aggregate compared with micro-aggregate sizes. Based on our findings we recommend that differential response of management practices and microbial control on the C turnover in macro-aggregates and micro-aggregate should be explicitly considered when accounting for management impacts on soil C turnover.


Magnetism and perfect spin filtering in pristine MgCl2 nanoribbons modulated by edge modification.
The search for new materials, with ideal electronic and magnetic properties for potential applications in nanoelectronics, has been extremely successful so far, and has paved the way for us to reimagine all technological devices. In the present work, we study the design of MgCl2 nanoribbons for applications in nanoelectronics and spintronics, by employing first-principles calculations based on density functional theory (DFT) and non-equilibrium Greens function techniques. Our results show that the properties of MgCl2 nanoribbons depend strongly not only on their geometrical form (armchair or zigzag) but also on the atoms at their edges. The armchair MgCl2 nanoribbon is a semiconductor and the zigzag nanoribbons vary from semiconducting, to metallic, to ferromagnetic, and to half-metallic, depending on the edge terminations. All these nanoribbons are very stable, with a relatively low cohesive energy per atom, and their attributes are not affected by the width of the nanoribbon. From transport calculations, we observed partial spin filtering in the ferromagnetic nanoribbon and perfect spin filtering in the two half-metallic nanoribbons. Moreover, we show how the current versus voltage curves can be fully understood by analysing the alignment of the energy levels of the electrodes. Our results corroborate the promising use of single-layer MgCl2 for the development of spintronics devices.


The association of highly processed food consumption with food choice values and food literacy in Japanese adults: a nationwide cross-sectional study.
Highly processed food (HPF) consumption is increasing globally and has become a prominent public health concern. However, the relationship between HPF consumption and food choice values and food literacy is unknown. This study aimed to examine the association of HPF consumption with food choice values and food literacy. This cross-sectional study used data from a nationwide questionnaire survey conducted in 2018 among 2232 Japanese adults aged 18-80 years. We assessed eight food choice values (accessibility, convenience, health/weight control, tradition, sensory appeal, organic, comfort, and safety) using a 25-item scale, and food literacy characterised by nutrition knowledge (using a validated 143-item questionnaire), cooking and food skills (using 14- and 19-item scales, respectively), and eight eating behaviours (hunger, food responsiveness, emotional overeating, enjoyment of food, satiety responsiveness, emotional undereating, food fussiness, and slowness in eating, using the 35-item Adult Eating Behavior Questionnaire). HPF consumption was estimated using a validated brief diet history questionnaire. The associations between HPF consumption and age, body mass index, energy intake, and each score on food choice values and food literacy were evaluated by multiple linear regression. In males, one standard deviation increase in scores for cooking skill and satiety responsiveness was associated with an increase in HPF consumption by 22.1 g/4184 kJ (95% confidence interval (CI): 6.6 to 37.5) and 15.4 g/4184 kJ (95% CI: 6.0 to 24.7), respectively. In females, one standard deviation increase in age and scores for safety and nutrition knowledge corresponded to a decrease in HPF consumption by - 16.4 g/4184 kJ (95% CI: - 23.4 to - 9.3), - 9.9 g/4184 kJ (95% CI: - 19.1 to - 0.7), and - 11.1 g/4184 kJ (95% CI: - 17.0 to - 5.3), whereas one standard deviation increase in the satiety responsiveness score corresponded to an increase in HPF consumption by 13.1 g/4184 kJ (95% CI: 6.8 to 19.4). This cross-sectional study suggests that several aspects of food choice values and food literacy were associated with HPF consumption in Japanese adults. Further studies are needed to confirm our findings in a broader context.


Characterization of a monoclonal antibody against the lymphoblast substance P receptor.
A murine monoclonal antibody to the IM-9 lymphoblast substance P (SP) receptor has been produced which recognizes the membrane-associated proteins of the SP receptor as demonstrated by immunoprecipitation of [125I]SP affinity-labeled and [35S]methionine biosynthetically labeled IM-9 soluble membranes. SP and anti-SP receptor binding to [35S]methionine-labeled IM-9 cell proteins were directly compared by attachment of each to affinity supports. Eluants from these affinity columns were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and revealed an equivalent 33-kDa protein in both cases. This protein corresponds to one of the previously described [125I]SP specifically affinity-labeled membrane-associated proteins. In addition, two-color fluorescence-activated cell sorter analysis with human peripheral blood T lymphocytes with fluorescein-SP and rhodamine-labeled antireceptor antibody revealed a distinct population of cells (20 to 30%) that were equally labeled by both the fluorescent peptide and antibody. This result indicates that the anti-SP receptor antibody recognizes an epitope of the receptor that is common to both human peripheral blood T lymphocytes and IM-9 lymphoblast cells.


Effective and efficient diagnosis of parkinsonism: the role of dopamine transporter SPECT imaging with ioflupane I-123 injection (DaTscan™).
Parkinson's disease (PD), the second-most common neurodegenerative disease, is characterized by motor and nonmotor symptoms. PD is often misdiagnosed; inappropriate treatment due to misdiagnosis has undesired consequences, as does delayed diagnosis. Unfortunately, most people with PD receive a diagnosis only after motor symptoms have emerged, by which time 40% to 60% of dopamine neurons have already been lost. Advances in imaging techniques have provided clinicians with increasingly sophisticated tools. In 2011, the US Food and Drug Administration approved ioflupane I-123 injection (DaTscanTM) for striatal dopamine transporter visualization using single-photon emission computed tomography (SPECT) imaging, which provides an effective tool for assessing striatal dopaminergic deficiency. Among patients with suspected parkinsonian syndromes, of which PD is one, the diagnostic sensitivity and specificity of DaTscan SPECT imaging are high. In clinical studies that were part of the DaTscan new drug application, no serious drug-related adverse events reported by the 1236 participants were attributed to DaTscan. The introduction of DaTscan imaging and its utility necessitate the development of clinical recommendations for appropriate use; thus, a multidisciplinary panel of experts was convened to develop clinical criteria and algorithms to help guide clinicians and managed care organizations in the application of DaTscan SPECT imaging. Based on the consensus of this expert panel, appropriate use of DaTscan SPECT imaging includes cases where: (1) PD diagnosis is uncertain; (2) tremor of uncertain etiology is present; and (3) nonmotor and/ or supportive symptoms and features associated with PD are present but the classical motor syndrome is absent or atypical.


Associations between birth kit use and maternal and neonatal health outcomes in rural Jigawa state, Nigeria: A secondary analysis of data from a cluster randomized controlled trial.
The burden of maternal and neonatal mortality remains persistently high in Nigeria. Sepsis contributes significantly to both maternal and newborn mortality, and safe delivery kits have long been promoted as a cost-effective intervention to ensure hygienic delivery practices and reduce sepsis. However, there is limited evidence on the effectiveness of home birth kit distribution by community health workers, and particularly the impact of this intervention on health outcomes. This paper reports a secondary analysis of data from a cluster randomized trial in rural northern Nigeria in which birth kits were distributed by community health workers to pregnant women in their homes, analyzing non-experimental variation in receipt and use of birth kits. More specifically, associations between pregnant women's baseline characteristics and receipt and use of birth kits, and associations between birth kit use, care utilization and maternal and newborn outcomes were assessed. Baseline, post-birth and endline data related to 3,317 births observed over a period of three years in 72 intervention communities in Jigawa state, Nigeria, were analyzed using hierarchical, logistic regression models. In total, 140 women received birth kits, and 72 women used the kits. There were no associations between baseline demographic characteristics, health history, and knowledge and attitudes and receipt of a kit, suggesting that community health workers did not systematically target the distribution of birth kits. However, women who used the kit reported reduced odds of past pregnancy complications (OR = 0.44, 95% CI: 0.19-1.00) as well as significantly higher odds of feeling generally healthy at baseline (OR = 2.00, 95% CI: 1.06-3.76), of exposure to radio media (OR = 1.97, 95% CI: 1.21-3.22), and of perceiving themselves as having a low-risk pregnancy (OR = 3.05, 95% CI:1.39-6.68). While there were no significant associations between birth kit use and facility based delivery, skilled birth attendance or post-natal care, women who used a kit exhibited significantly lower odds of completing four or more ANC visits (adjusted OR = 0.39, 95% CI: 0.18-0.85) and significantly higher odds of reporting prolonged labor (adjusted OR = 4.75, 95% CI: 1.36-16.59), and post-partum bleeding (adjusted OR = 3.25, 95% CI: 1.11-9.52). This evidence suggests that use of birth kits is low in a rural population characterized by minimal baseline utilization of maternal and neonatal health services, and the use of birth kits was not associated with reductions in maternal or neonatal morbidity. While further research is required to understand how the effectiveness of birth kits may be shaped by the mechanism through which women access and utilize the kits, our findings suggest that the provision of kits to women outside of the formal health system may be associated with increased risk of adverse outcomes.


[Changes in the ultrastructure of the myocardium after fibrillation and in the process of autolysis].
Ultrastructure of the myocardium in the experiment was studied just after the heart ventricular fibrillation and 3 h after the animal death; the results were compared to those obtained by studying ultrastructure of human myocardium in patients dying from myocardial infarction complicated by ventricular fibrillation. The similarity of ultrastructural and autolytic changes was revealed in both series of observation. Overcontraction of myofibrils and redistribution of the mitochondria in cardiomyocytes, increase of the sarcoplasmic reticulum vesiculation, oedema of sarcoplasm, structural alterations of intercalative discs, later appearance of the symptoms of the irreversibility of lesions in the mitochondria and early penetration of colloidal lanthanum particles in rigor cells may serve ultrastructural diagnostic symptom of ventricular fibrillation. A better preservation of Purkinje's cells as compared to the contractile cardiomyocytes is also demonstrated.


Ewingana (Doreyana) baekelandae, sp. n., a parasite of molossid bats in Spain (Acari: Myobiidae).
Ewingana (Doreyana) baekelandae sp. n. (Acari: Myobiidae) is described on the basis of several adults and immatures collected on Tadarida (T.) teniotis from the province of Teruel, Spain. The species is a Palearctic representative of the evolutive line nanula Fain and digitata Fain. Differences within these species are observed in the female genito-anal area and in the shape and size of leg I, both in adults and in immatures.


Inositol 1,4,5-trisphosphate signaling regulates mating behavior in Caenorhabditis elegans males.
Complex behavior requires the coordinated action of the nervous system and nonneuronal targets. Male mating in Caenorhabditis elegans consists of a series of defined behavioral steps that lead to the physiological outcomes required for successful impregnation. We demonstrate that signaling mediated by inositol 1,4,5-trisphosphate (IP(3)) is required at several points during mating. Disruption of IP(3) receptor (itr-1) function results in dramatic loss of male fertility, due to defects in turning behavior (during vulva location), spicule insertion and sperm transfer. To elucidate the signaling pathways responsible, we knocked down the six C. elegans genes encoding phospholipase C (PLC) family members. egl-8, which encodes PLC-beta, functions in spicule insertion and sperm transfer. itr-1 and egl-8 are widely expressed in the male reproductive system. An itr-1 gain-of-function mutation rescues infertility caused by egl-8 RNA interference, indicating that egl-8 and itr-1 function together as central components of the signaling events controlling sperm transfer.


Vellus Hair Cyst of the Orbit.
Eruptive vellus hair cysts are a developmental abnormality of vellus hair follicles that result in small cystic papules occurring most frequently on the chest and proximal extremities. Lesions of the ocular adnexa are extremely rare, and to the best of the authors knowledge, involvement of the orbit has never been reported. The authors describe a patient with an eruptive vellus hair cyst involving the orbit.


Effects of propofol on conditioned place preference in male rats: Involvement of nitrergic system.
Drug-induced conditioned place preference (CPP) is linked to the addictive properties of the drug used. The number of studies that have investigated the effects of propofol on CPP is limited. Research findings suggest that nitric oxide (NO) might play an important role in substance use disorders. The present study sought to investigate the role of the nitrergic system on the rewarding effects of propofol by using the CPP protocol in rats. The experiment followed habituation, pre-conditioning, conditioning, and post conditioning sessions. Male Wistar albino rats weighing 240-290 g were divided into eight groups: control (saline), propofol (10, 20, and 40 mg/kg), the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) alone (30 and 60 mg/kg), and in combination with propofol (30 and 60 mg/kg L-NAME plus 40 mg/kg propofol) (n = 8 for each group). The CPP effects of propofol, L-NAME, saline, and their combinations were evaluated. All the drug and saline administrations were performed by intraperitoneal (ip) injections. Propofol (10-40 mg/kg) produced CPP that was statistically significant relative to saline. Propofol-induced CPP was significantly reversed by pretreatment with L-NAME. When administered alone, L-NAME did not produce CPP and also did not produce any significant change on locomotor activity of naïve rats. Our results suggest that propofol produces CPP effects in rats and that NO-related mechanisms may be responsible for propofol-induced CPP. Thus, propofol might have the potential to be addictive, and this possibility should be considered during clinical applications of this drug.


aRNApipe: a balanced, efficient and distributed pipeline for processing RNA-seq data in high-performance computing environments.
The wide range of RNA-seq applications and their high-computational needs require the development of pipelines orchestrating the entire workflow and optimizing usage of available computational resources. We present aRNApipe, a project-oriented pipeline for processing of RNA-seq data in high-performance cluster environments. aRNApipe is highly modular and can be easily migrated to any high-performance computing (HPC) environment. The current applications included in aRNApipe combine the essential RNA-seq primary analyses, including quality control metrics, transcript alignment, count generation, transcript fusion identification, alternative splicing and sequence variant calling. aRNApipe is project-oriented and dynamic so users can easily update analyses to include or exclude samples or enable additional processing modules. Workflow parameters are easily set using a single configuration file that provides centralized tracking of all analytical processes. Finally, aRNApipe incorporates interactive web reports for sample tracking and a tool for managing the genome assemblies available to perform an analysis. https://github.com/HudsonAlpha/aRNAPipe ; DOI: 10.5281/zenodo.202950. email@example.com. Supplementary data are available at Bioinformatics online.


Association between oral health and locomotive syndrome: a cross-sectional study in Japanese adults.
Many studies have examined the association between oral health, care needs, and physical function, but few have focused on the association between oral health and locomotive syndrome (LS). We examined the association between LS and oral-health status, such as the number of teeth and chewing function, in an adult population. The study included 2888 participants who underwent examinations of motor function and oral health. Individuals with LS stage 1 or higher were classified as having LS, while others were classified as not having it. Logistic regression analysis was performed using the presence or absence of LS as the dependent variable and age, sex, smoking status, drinking habit, exercise habit, walking speed, history of stroke, bone density, body mass index, metabolic syndrome, chewing function, and the number of teeth as independent variables to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for each independent variable. When the number of teeth and chewing function were included separately in multivariate analyses, the OR for LS was significantly higher for participants with 0-19 teeth than for those with 28 teeth, and for participants with poor chewing function than for those with good function (adjusted ORs, 1.47 [95% CI, 1.01-2.15] and 1.73 [95% CI, 1.37-2.18], respectively). In analyses that included tooth number and chewing function as a combined independent variable, relative to individuals with 28 teeth and good masticatory function, the adjusted ORs were 2.67 (95% CI, 1.57-4.52) for those with 28 teeth and poor chewing function, 1.63 (95% CI, 1.20-2.22) for those with 20-27 teeth and poor chewing function, and 1.83 (95% CI, 1.06-3.18) for those with 0-19 teeth and poor chewing function. Having fewer teeth and poor chewing function may be associated with LS. The maintenance of masticatory function may be important to prevent LS in adulthood.


Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations.
The pathophysiological concept of ischaemic stroke was recently expanded to a more comprehensive perspective, focussing on the vasculature as well as peri- and juxtavascular cells including astrocytes. Increasing evidence also supports a role of the vasculature in Alzheimer's disease (AD), but causal relationships are poorly understood. The purpose of this study was to examine vascular alterations due to cerebral ischaemia in aged wildtype (WT) mice and in the triple-transgenic (3xTg) mouse model of AD. Three- and 12-month-old WT and 3xTg mice underwent permanent middle cerebral artery occlusion. One day after ischaemia onset, expression of collagen IV and laminin as basement membrane constituents, and Solanum tuberosum lectin (STL) as endothelial marker was quantified in the ischaemic neocortex, striatum and hippocampus. Further, CD31- and aquaporin-4-immunoreactivity served for coverage of endothelium and astrocyte endfeet. Ischaemia resulted in strong upregulation of collagen IV and laminin in the neocortex of 3-month-old WT and 3xTg mice, while STL appeared unaffected. Quantification confirmed collagen IV upregulation in the ischaemic neocortex of 3- and 12-month-old WT and 3xTg mice, whereas striatal changes were limited to young WT mice. However, collagen IV expression in the hippocampus appeared nearly unaltered. Qualitative and quantitative data evidenced more severe degeneration of endothelial cells and astrocyte endfeet in 3xTg mice. In conclusion, this study supports the critical impact of the vasculature in the aged and AD brain by showing an age- and genetic background-dependent response of basement membranes to cerebral ischaemia, and a pronounced endothelial and astrocytic degeneration in the AD-like brain.