Improving Mental Health in Pregnancy for Refugee Women: Protocol for the Implementation and Evaluation of a Screening Program in Melbourne, Australia.
Identifying mental health disorders in migrant and refugee women during pregnancy provides an opportunity for interventions that may benefit women and their families. Evidence suggests that perinatal mental health disorders impact mother-infant attachment at critical times, which can affect child development. Postnatal depression resulting in suicide is one of the leading causes of maternal mortality postpartum. Routine screening of perinatal mental health is recommended to improve the identification of depression and anxiety and to facilitate early management. However, screening is poorly implemented into routine practice. This study is the first to investigate routine screening for perinatal mental health in a maternity setting designed for refugee women. This study will determine whether symptoms of depression and anxiety are more likely to be detected by the screening program compared with routine care and will evaluate the screening program's feasibility and acceptability to women and health care providers (HCPs). The objectives of this study are (1) to assess if refugee women are more likely to screen risk-positive for depression and anxiety than nonrefugee women, using the Edinburgh Postnatal Depression Scale (EPDS); (2) to assess if screening in pregnancy using the EPDS enables better detection of symptoms of depression and anxiety in refugee women than current routine care; (3) to determine if a screening program for perinatal mental health in a maternity setting designed for refugee women is acceptable to women; and (4) to evaluate the feasibility and acceptability of the perinatal mental health screening program from the perspective of HCPs (including the barriers and enablers to implementation). This study uses an internationally recommended screening measure, the EPDS, and a locally developed psychosocial questionnaire, both administered in early pregnancy and again in the third trimester. These measures have been translated into the most common languages used by the women attending the clinic and are administered via an electronic platform (iCOPE). This platform automatically calculates the EPDS score and generates reports for the HCP and woman. A total of 119 refugee women and 155 nonrefugee women have been recruited to evaluate the screening program's ability to detect depression and anxiety symptoms and will be compared with 34 refugee women receiving routine care. A subsample of women will participate in a qualitative assessment of the screening program's acceptability and feasibility. Health service staff have been recruited to evaluate the integration of screening into maternity care. The recruitment is complete, and data collection and analysis are underway. It is anticipated that screening will increase the identification and management of depression and anxiety symptoms in pregnancy. New information will be generated on how to implement such a program in feasible and acceptable ways that will improve health outcomes for refugee women. DERR1-10.2196/13271.


Phosphoenolpyruvate-sugar phosphotransferase transport system of Streptococcus mutans: purification of HPr and enzyme I and determination of their intracellular concentrations by rocket immunoelectrophoresis.
Enzyme I and HPr, the general proteins of the phosphoenolpyruvate-sugar phosphotransferase system, play a pivotal role in the control of sugar utilization in gram-negative and gram-positive bacteria. To determine whether growth conditions could modify the rate of biosynthesis of these proteins in Streptococcus mutans, we first purified to homogeneity enzyme I and HPr from S. mutans ATCC 27352. Using specific antibodies obtained against these proteins, we determined by rocket electrophoresis the intracellular levels of enzyme I and HPr in cells of S. mutans 27352 grown under various batch culture conditions and in a number of glucose-grown cells of other strains of S. mutans. HPr was purified by the procedure reported by Gauthier et al. (L. Gauthier, D. Mayrand, and C. Vadeboncoeur, J. Bacteriol. 160:755-763, 1984) and displayed a single band with a molecular weight of 6,650 when analyzed by sodium dodecyl sulfate-urea gel electrophoresis. Enzyme I was purified by DEAE-cellulose chromatography, affinity chromatography on an anti-Streptococcus salivarius column, and preparative electrophoresis. The protein migrated as a single band in native and denaturating gel electrophoresis. The subunit molecular weight of enzyme I determined by electrophoresis under denaturating conditions was 68,000. In gel filtration chromatography at 4 degrees C, the enzyme migrated as a 135,000- to 160,000-molecular-weight species, suggesting that enzyme I is a dimer. In double immunodiffusion experiments, antibodies against HPr reacted with several oral streptococci, Streptococcus lactis, Streptococcus faecium, and Lactobacillus casei, but not with Bacillus subtilis, Staphylococcus aureus, and Escherichia coli. Antibodies against enzyme I of S. mutans 27352 cross-reacted with enzyme I from all the other oral streptococci tested. No cross-reaction was observed with other gram-positive and gram-negative bacteria. The levels of enzyme I and HPr determined by rocket electrophoresis in S. mutans 27352 varied at the most by twofold, depending on the growth conditions. Glucose-grown cells of other S. mutans strains contained levels of enzyme I and HPr which were similar to those found in S. mutans 27352.


Assessment of causal associations between illness and criminal acts in those who are acquitted by reason of insanity.
The court proceedings after the terrorist attacks on 22 July 2011 reignited the debate on the justification for having a rule that regulates the insanity defence exclusively on the basis of a medical condition – the medical principle. The psychological principle represents an alternative that requires a causal relationship between the psychosis and the acts committed. In this article we investigate rulings made by the courts of appeal where the accused have been found legally insane at the time of the act, and elucidate the extent to which a causal relationship between the illness and the act appears to be in evidence. Data have been retrieved from rulings by the courts of appeal published at lovdata.no, which include anonymised rulings. Searches were made for cases under Section 39 (verdict of special sanctions) and Section 44 (acquittal by reason of insanity) of the General Civil Penal Code. Court rulings in which a possible causal relationship could be considered were included. The included rulings were carefully assessed with regard to whether a causal relationship existed between the mental disorder of the accused at the time and the criminal act. The search returned a total of 373 rulings, of which 75 were included. The vast majority of the charges referred to serious crimes. Diagnoses under ICD-10 category codes F20-29 (schizophrenia, schizotypal and delusional disorders) were the most frequently occurring type. In 17 of the 75 rulings (23%), it was judged that no causal relationship between the illness and the act existed. In 25 of 26 cases that involved homicide, a causal relationship between the illness and the act was judged to be evident. The data may indicate that the medical principle results in impunity in a considerable number of rulings where the illness of the accused apparently has had no effect on the acts committed.


Cell-based multiscale computational modeling of small molecule absorption and retention in the lungs.
For optimizing the local, pulmonary targeting of inhaled medications, it is important to analyze the relationship between the physicochemical properties of small molecules and their absorption, retention and distribution in the various cell types of the airways and alveoli. A computational, multiscale, cell-based model was constructed to facilitate analysis of pulmonary drug transport and distribution. The relationship between the physicochemical properties and pharmacokinetic profile of monobasic molecules was explored. Experimental absorption data of compounds with diverse structures were used to validate this model. Simulations were performed to evaluate the effect of active transport and organelle sequestration on the absorption kinetics of compounds. Relating the physicochemical properties to the pharmacokinetic profiles of small molecules reveals how the absorption half-life and distribution of compounds are expected to vary in different cell types and anatomical regions of the lung. Based on logP, pK(a) and molecular radius, the absorption rate constants (K(a)) calculated with the model were consistent with experimental measurements of pulmonary drug absorption. The cell-based mechanistic model developed herein is an important step towards the rational design of local, lung-targeted medications, facilitating the design and interpretation of experiments aimed at optimizing drug transport properties in lung.


Early toxicity and patient reported quality-of-life in patients receiving proton therapy for localized prostate cancer: a single institutional review of prospectively recorded outcomes.
We report prospectively captured clinical toxicity and patient reported outcomes in a single institutional cohort of patients treated for prostate cancer with proton beam therapy (PBT). This is the largest reported series of patients treated mostly with pencil beam scanning PBT. We reviewed 231 patients treated on an IRB approved institutional registry from 2013 to 2016; final analysis included 192 patients with > 1-year of follow-up. Toxicity incidence was prospectively captured and scored using CTCAE v4.0. International Prostate Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) score, and Expanded Prostate Cancer Index Composite (EPIC) bowel domain questionnaires were collected at each visit. Univariate Cox regression was used to explore associations of grade 2+ toxicity with clinical, treatment, and dosimetric variables. Median follow-up was 1.7 years. Grade 3 toxicity was seen in 5/192 patients. No grade 4 or 5 toxicity was seen. Patient reported quality-of-life showed no change in urinary function post-radiation by IPSS scores. Median SHIM scores declined by 3.7 points at 1-year post-treatment without further decrease beyond year 1. On univariate analysis, only younger age (HR = 0.61, p = 0.022) was associated with decreased sexual toxicity. EPIC bowel domain scores declined from 96 at baseline (median) by an average of 5.4 points at 1-year post-treatment (95% CI: 2.5-8.2 points, p < 0.001), with no further decrease over time. Bowel toxicity was mostly in the form of transient rectal bleeding and was associated with anticoagulation use (HR = 3.45, p = 0.002). Grade 3 or higher toxicity was rare at 2-years after treatment with PBT for localized prostate cancer. Longer follow-up is needed to further characterize late toxicity and biochemical control. NCT, NCT01255748 . Registered 1 January 2013.


Effect of a cleavage-resistant collagen mutation on left ventricular remodeling.
Matrix metalloproteinase-mediated degradation of type I collagen may play a role in cardiac remodeling after strain or injury. To explore this hypothesis, we used mice homozygous (r/r) for a targeted mutation in Col1a1; these mice synthesize collagen I that resists collagenase cleavage at Gly975-Leu976. A total of 64 r/r and 84 littermate wild-type mice (WT) underwent experimental pressure overload by transverse aortic constriction (TAC) or myocardial infarction (MI). Echocardiographic, hemodynamic, and histological parameters were evaluated up to 12 weeks after TAC or 21 days after MI. At 4 weeks after TAC, collagen levels, wall thickness, and echocardiographic parameters were similar in the 2 groups. At 12 weeks after TAC, r/r mice had smaller LV dimensions (ESD: 2.7+/-0.2 mm WT versus 1.7+/-0.2 mm r/r, P<0.013; EDD: 3.8+/-0.2 mm WT versus 3.1+/-0.1 mm r/r, P<0.013); better fractional shortening (30+/-2% WT versus 46+/-4% r/r; P<0.013); and lower LV/body weight ratios (7.3+/-0.6 WT and 5.1+/-0.5 r/r; P<0.013). Surprisingly, these differences were not accompanied by differences in collagen accumulation, myocyte cross-sectional areas, wall thickness, or microvessel densities. Furthermore, no differences in LV remodeling assessed by echocardiography, fibrosis, or hemodynamic parameters were found between r/r and WT mice after MI. Thus, a mutation that encodes a collagenase cleavage-resistant collagen I does not affect early LV remodeling after TAC or MI, suggesting that collagen cleavage at this site is not the mechanism by which metalloproteinases mediate LV remodeling. Collagen cleavage could, however, have a role in preservation of cardiac function in late remodeling by mechanisms independent of collagen accumulation. We were not able to detect collagen cleavage fragments, and could not, therefore, rule out the possibility of collagen cleavage at additional sites.


Sulfur globule oxidation in green sulfur bacteria is dependent on the dissimilatory sulfite reductase system.
Green sulfur bacteria (GSB) oxidize sulfide and thiosulfate to sulfate, with extracellular globules of elemental sulfur as an intermediate. Here we investigated which genes are involved in the formation and consumption of these sulfur globules in the green sulfur bacterium Chlorobaculum tepidum. We show that sulfur globule oxidation is strictly dependent on the dissimilatory sulfite reductase (DSR) system. Deletion of dsrM/CT2244 or dsrT/CT2245, or the two dsrCABL clusters (CT0851-CT0854, CT2247-2250), abolished sulfur globule oxidation and prevented formation of sulfate from sulfide, whereas deletion of dsrU/CT2246 had no effect. The DSR system also seems to be involved in the formation of thiosulfate, because thiosulfate was released from wild-type cells during sulfide oxidation, but not from the dsr mutants. The dsr mutants incapable of complete substrate oxidation oxidized sulfide and thiosulfate about twice as fast as the wild-type, while having only slightly lower growth rates (70-80 % of wild-type). The increased oxidation rates seem to compensate for the incomplete substrate oxidation to satisfy the requirement for reducing equivalents during growth. A mutant in which two sulfide : quinone oxidoreductases (sqrD/CT0117 and sqrF/CT1087) were deleted exhibited a decreased sulfide oxidation rate (~50 % of wild-type), yet formation and consumption of sulfur globules were not affected. The observation that mutants lacking the DSR system maintain efficient growth suggests that the DSR system is dispensable in environments with sufficiently high sulfide concentrations. Thus, the DSR system in GSB may have been acquired by horizontal gene transfer as a response to a need for enhanced substrate utilization in sulfide-limiting habitats.


Gender differences in the influence of economic, lifestyle, and psychosocial factors on later-life health.
Gender differences in exposure to social resources play a significant role in influencing gender inequalities in health. A related question--and our focus--asks whether these inequalities are also influenced by gendered vulnerabilities to social forces. Specifically, this paper examines the differential impact of social forces on the health of elderly (65+) men and women. Multiple linear regression analysis is used to estimate gender differences in the influence of socioeconomic, lifestyle, and psychosocial factors on both self-rated health and overall functional health using data from the 1994-1995 National Population Health Survey. Key findings include: 1) the relationship between income and health is significant for older women only, whereas the converse holds for education; 2) having an acceptable body weight is positively associated with health for elderly women only; and 3) stress-related factors are stronger determinants of health for older women. Our findings shed light on the processes of healthy aging for men and women, and suggest that interventions to improve the health of elderly Canadians need to be gender-specific.


Revisiting the pathobiology of scurvy: a review of the literature in the context of a challenging case.
Scurvy is a nutritional disorder resulting from vitamin C deficiency. Although rare in developing countries, scurvy continues to develop in settings of limited dietary intake such as post-gastrointestinal surgery and restrictive dietary habits. The disease primarily affects the skin and soft tissue. As the state of deficiency persists, hematological and immunological sequelae may develop. The classic signs of scurvy are not always present and can be altered by the presence of other comorbidities. In this article, we present a challenging case of scurvy in an older male from an urban tertiary healthcare setting. We review the atypical and uncommon clinical and pathological findings of scurvy including those seen in the skin, blood, and bone marrow. We also review contemporary research findings that provide a better understanding of the pathogenicity and clinical manifestations of vitamin C deficiency.


THz time-domain spectroscopy modulated with semiconductor plasmonic perfect absorbers.
Terahertz time-domain spectroscopy (THz-TDS) at room temperature and standard atmosphere pressure remains so far the backbone of THz photonics in numerous applications for civil and defense levels. Plasmonic microstructures and metasurfaces are particularly promising for improving THz spectroscopy techniques and developing biomedical and environmental sensors. Highly doped semiconductors are suitable for replacing the traditional plasmonic noble metals in the THz range. We present a perfect absorber structure based on semiconductor III-Sb epitaxial layers. The insulator layer is GaSb while the metal-like layers are Si doped InAsSb (∼ 5·1019 cm-3). The doping is optically measured in the IR with polaritonic effects at the Brewster angle mode. Theoretically, the surface can be engineered in frequency selective absorption array areas of an extensive THz region from 1.0 to 6.0 THz. The technological process is based on a single resist layer used as hard mask in dry etching defined by electron beam lithography. A wide 1350 GHz cumulative bandwidth experimental absorption is measured in THz-TDS between 1.0 and 2.5 THz, only limited by the air-exposed reflectance configuration. These results pave the way to implement finely tuned selective surfaces based on semiconductors to enhance light-matter interaction in the THz region.


Preparation and anticancer activity evaluation of an amorphous drug nanocomposite by simple heat treatment.
The solubility of drug molecules is closely related to its bioactivity as it affects the dissolution rate and bioavailability, especially in the case of BCS IV drugs like camptothecin (CPT), a potential broad-spectrum anticancer agent. In this study, we construct a novel boric acid (BA)-coated CPT nanocomposite by means of a simple heat-treatment approach, which combines nanoscale size range and amorphous solid state together to improve the overall dissolution rate of CPT. This new CPT formulation showed a rod-like structure with nanoscale size and amorphous solid nature. These BA-coated CPT nanocomposites exhibited a dramatically improved dissolution rate, water dispersion property, and long-term chemical and physical stability. More importantly, the specific reactivity of BA groups to diols in the cell glycocalyx facilitated a rapid cross-membrane translocation of the drug nanocomposite, leading to efficient intracellular drug delivery. When tested on A549 cells and SKBR3 cells, this formulation demonstrated a much higher anticancer activity in comparison with free CPT, naked amorphous CPT nanoparticles, and control CPT nanocrystals. This formulation has great potential for clinical application; it is easy to scale up and be applied on other hydrophobic drugs.


Genetic Diversity Analysis of Coxsackievirus A8 Circulating in China and Worldwide Reveals a Highly Divergent Genotype.
Coxsackievirus A8 (CV-A8) is one of the pathogens associated with hand, foot and mouth disease (HFMD) and herpangina (HA), occasionally leading to severe neurological disorders such as acute flaccid paralysis (AFP). Only one study aimed at CV-A8 has been published to date, and only 12 whole-genome sequences are publicly available. In this study, complete genome sequences from 11 CV-A8 strains isolated from HFMD patients in extensive regions from China between 2013 and 2018 were determined, and all sequences from GenBank were retrieved. A phylogenetic analysis based on a total of 34 complete VP1 sequences of CV-A8 revealed five genotypes: A, B, C, D and E. The newly emerging genotype E presented a highly phylogenetic divergence compared with the other genotypes and was composed of the majority of the strains sequenced in this study. Markov chain Monte Carlo (MCMC) analysis revealed that genotype E has been evolving for nearly a century and somehow arose in approximately 2010. The Bayesian skyline plot showed that the population size of CV-A8 has experienced three dynamic fluctuations since 2001. Amino acid residues of VP1100N, 103Y, 240T and 241V, which were embedded in the potential capsid loops of genotype E, might enhance genotype E adaption to the human hosts. The CV-A8 whole genomes displayed significant intra-genotypic genetic diversity in the non-capsid region, and a total of six recombinant lineages were detected. The Chinese viruses from genotype E might have emerged recently from recombining with European CV-A6 strains. CV-A8 is a less important HFMD pathogen, and the capsid gene diversity and non-capsid recombination variety observed in CV-A8 strains indicated that the constant generation of deleterious genomes and a constant selection pressure against these deleterious mutations is still ongoing within CV-A8 quasispecies. It is possible that CV-A8 could become an important pathogen in the HFMD spectrum in the future. Further surveillance of CV-A8 is greatly needed.


Tissue-specific oxidative imbalance and mitochondrial dysfunction during Trypanosoma cruzi infection in mice.
In this study, we examined the tissue specificity of inflammatory and oxidative responses and mitochondrial dysfunction in mice infected by Trypanosoma cruzi. In acute mice, parasite burden and associated inflammatory infiltrate was detected in all tissues (skeletal muscle>heart>stomach>colon). The extent of oxidative damage and mitochondrial decay was in the order of heart>stomach>skeletal muscle>colon. In chronic mice, a low level of parasite burden and inflammation continued in all tissues; however, oxidant overload and mitochondrial inefficiency mainly persisted in the heart tissue (also detectable in stomach). Further, we noted an unvaryingly high degree of oxidative stress, compromised antioxidant status, and decreased mitochondrial respiratory complex activities in peripheral blood of infected mice. A pair-wise log analysis showed a strong positive correlation in the heart-versus-blood (but not other tissues) levels of oxidative stress markers (malonyldialdehyde, glutathione disulfide), antioxidants (superoxide dismutase, MnSOD, catalase), and mitochondrial inhibition of respiratory complexes (CI/CIII) in infected mice. T. cruzi-induced acute inflammatory and oxidative responses are widespread in different muscle tissues. Antioxidant/oxidant status and mitochondrial function are consistently attenuated in the heart, and reflected in the peripheral-blood of T. cruzi-infected mice. Our results provide an impetus to investigate the peripheral-blood oxidative responses in relation to clinical severity of heart disease in chagasic human patients.


Rural-urban variation in breast-conserving surgery in Kentucky.
Recently researchers from the University of Kentucky published a study showing that, in the early 1990s, Appalachian women were less likely to receive breast-conserving surgery (BCS) in the treatment of early stage cancer, than other Kentucky women diagnosed with early stage breast cancer, and that poverty was the only predictor of lowered probability of receiving BCS. In that study, analyses were performed on a dataset of Kentucky Medicare beneficiary claims of treatment information that had been linked with data from the Kentucky Cancer Registry for staging information. County-level data were also used, from the 1990 census and other sources, on poverty and education rates for women, and hospital bed and physician ratios per population. While the findings of the study are significant, the study is generalizable only to women aged 65 years and older because a Medicare dataset was used. In addition, the study represented Kentucky practice seven to ten years ago, from 1992 through 1995, which raises interest in obtaining BCS rates for more current practice. In this article, we update the previous study with the most recent data on BCS, and include women of all ages, not just those over age 64 years. Access was obtained to the Kentucky Cancer Registry, which contains records of the initial treatment for breast cancer, as well as staging information about the extent of disease at diagnosis. Data from the 2000 census were not available for this analysis, however.


Assessement of serum amyloid A levels in the rehabilitation setting in the Florida manatee (Trichechus manatus latirostris).
The acute phase protein serum amyloid A (SAA) has been previously shown to have value as a biomarker of inflammation and infection in many species, including manatees (Trichechus manatus latirostris). In the current study, results from an automated assay for SAA were used in a rehabilitation setting. Reference intervals were established from clinically normal manatees using the robust method: 0-46 mg/L. More than 30-fold higher mean SAA levels were observed in manatees suffering from cold stress and boat-related trauma. Poor correlations were observed between SAA and total white blood count, percentage of neutrophils, albumin, and albumin/globulin ratio. A moderate correlation was observed between SAA and the presence of nucleated red blood cells. The sensitivity of SAA testing was 93% and the specificity was 98%, representing the highest combined values of all the analytes. The results indicate that the automated method for SAA quantitation can provide important clinical data for manatees in a rehabilitation setting.


Smad8 mediates the signaling of the ALK-2 [corrected] receptor serine kinase.
Smad proteins are critical intracellular mediators of signaling by growth and differentiation factors of the transforming growth factor beta superfamily. We have isolated a member of the Smad family, Smad8, from a rat brain cDNA library and biochemically and functionally characterized its ability to transduce signals from serine kinase receptors. In Xenopus embryo, Smad8 is able to transcriptionally activate a subset of mesoderm target genes similar to those induced by the receptor serine kinase, activin receptor-like kinase (ALK)-2. Smad8 can be specifically phosphorylated by a constitutively active ALK-2 but not the related receptor serine kinase, ALK-4. In response to signaling from ALK-2, Smad8 associates with a common regulatory molecule, Smad4, and this association leads to a synergistic effect on gene transcription. Furthermore, Smad8 is able to rescue the expression of mesoderm genes blocked by truncated ALK-2 in the embryo. These results indicate that Smad8 can function as a downstream signaling mediator of ALK-2.


Patients view of the anaesthetist in a developing country.
The objective of this study was to assess patients regarding their knowledge and perception of the anaesthetists' role in patient care in a developing country. The audit was conducted at the Aga Khan University Hospital, Karachi. Two hundred surgical and 102 medical out-patients were included in the audit prospectively who filled a detailed questionnaire. Fifty-six percent of the patients knew that anaesthetists were medically qualified but only 20% and 27% had an idea about their role in the intraoperative and immediate postoperative period. 14.6% were aware of the anaesthetists role outside the operating room. No difference was observed between the two groups of patients except that a higher percentage of surgical patients were interested in having more information regarding anaesthesia and wanted to choose their anaesthetist if the need arose. Gender difference was observed in answer to two questions only. A higher percentage of males know the role of anaesthetist in the recovery room whereas a greater number of females who had surgery before remembered their anaesthetist postoperatively. The results of this audit show a poor perception of the anaesthetists role both inside and outside the operating room. Although public knowledge surveys have been carried out in developed countries there is a pressing need to repeat these in developing countries since the image as perceived by public may have a direct bearing on the recruitment of young doctors into an already shortage specialty in these less affluent countries.


Bipolar disorder with comorbid cluster B personality disorder features: impact on suicidality.
Because of their overlapping phenomenology and mutually chronic, persistent nature, distinctions between bipolar disorder and cluster B personality disorders remain a source of unresolved clinical controversy. The extent to which comorbid personality disorders impact course and outcome for bipolar patients also has received little systematic study. One hundred DSM-IV bipolar I (N = 73) or II (N = 27) patients consecutively underwent diagnostic evaluations with structured clinical interviews for DSM-IV Axis I and cluster B Axis II disorders, along with assessments of histories of childhood trauma or abuse. Cluster B diagnostic comorbidity was examined relative to lifetime substance abuse, suicide attempt histories, and other clinical features. Thirty percent of subjects met DSM-IV criteria for a cluster B personality disorder (17% borderline, 6% antisocial, 5% histrionic, 8% narcissistic). Cluster B diagnoses were significantly linked with histories of childhood emotional abuse (p = .009), physical abuse (p = .014), and emotional neglect (p = .022), but not sexual abuse or physical neglect. Cluster B comorbidity was associated with significantly more lifetime suicide attempts and current depression. Lifetime suicide attempts were significantly associated with cluster B comorbidity (OR = 3.195, 95% CI = 1.124 to 9.088), controlling for current depression severity, lifetime substance abuse, and past sexual or emotional abuse. Cluster B personality disorders are prevalent comorbid conditions identifiable in a substantial number of individuals with bipolar disorder, making an independent contribution to increased lifetime suicide risk.


Interaction Between Memory Load and Experimental Design on Brain Connectivity and Network Topology.
The conventional approach to investigating functional connectivity in the block-designed study usually concatenates task blocks or employs residuals of task activation. While providing many insights into brain functions, the block design adds more manipulation in functional network analysis that may reduce the purity of the blood oxygenation level-dependent signal. Recent studies utilized one single long run for task trials of the same condition, the so-called continuous design, to investigate functional connectivity based on task functional magnetic resonance imaging. Continuous brain activities associated with the single-task condition can be directly utilized for task-related functional connectivity assessment, which has been examined for working memory, sensory, motor, and semantic task experiments in previous research. But it remains unclear how the block and continuous design influence the assessment of task-related functional connectivity networks. This study aimed to disentangle the separable effects of block/continuous design and working memory load on task-related functional connectivity networks, by using repeated-measures analysis of variance. Across 50 young healthy adults, behavioral results of accuracy and reaction time showed a significant main effect of design as well as interaction between design and load. Imaging results revealed that the cingulo-opercular, fronto-parietal, and default model networks were associated with not only task activation, but significant main effects of design and load as well as their interaction on intra- and inter-network functional connectivity and global network topology. Moreover, a significant behavior-brain association was identified for the continuous design. This work has extended the evidence that continuous design can be used to study task-related functional connectivity and subtle brain-behavioral relationships.


Utilization of glutamate accumulating bacterial cells for production of ribonucleotides.
Corynebacterium glutamicum cells are industrially used for glutamate production. However, the waste that contains microbial cells, cellular debris, residual sugars, ammonia and metabolites seriously pollutes the environment. The cells are recovered and utilized for ribonucleotide production so that the pollution caused by the cells is eliminated. Nucleic acid is extracted from the cells and is hydrolyzed with nuclease P1 from Penicillium citrinum. The hydrolysate is fractionated with Dowex-50 and Dowex-1 into 5'-CMP, 5'-UMP, 5'-GMP and 5'-AMP. The products are characterized by electrophoresis, ultraviolet light absorbance, and 5'-nucleotidase.


Left atrial remodeling in adolescents with obesity evaluated by speckle-tracking echocardiography.
In adolescents with obesity, a left atrial (LA) enlargement has been reported. However, data regarding its function and its stiffness are missing. The aim of this study was to describe LA morphology and function, using speckle-tracking echocardiography (STE) and to explore their potential determinants in adolescents with obesity. Twenty-eight adolescent women with obesity (13.2 ± 1.4 yr) with an illness duration of 130 ± 27 months and 33 controls (14.1 ± 2.0 yr) underwent a resting echocardiography including an analysis of left ventricular (LV) and LA morphologies and strains. A fasting venous blood sample was performed to biochemical determinations including inflammation markers. LA volume and stiffness index were increased in adolescents with obesity compared to controls. LA reservoir, conduit and booster pump functions were not different between groups. By stepwise forward multivariate regression analyses, systolic blood pressures, cardiac output and sedimentation rate were the independent determinants of LA volume (p < 0.0001, β-coefficient = 0.460) whereas only the body mass index was an independent determinant of LA stiffness (p = 0.003, β-coefficient = 0.413). In adolescents with obesity, we observed a specific LA remodeling, including higher volume and lower stiffness, which could constitute early signs of an altered LV diastolic function.


Lower gastrointestinal symptoms and quality of life in patients with systemic sclerosis: a population-based study.
To investigate the frequency and nature of bowel symptoms in a population-based cohort of patients with systemic sclerosis (SSc), compared with healthy controls, and to relate these symptoms to health-related quality of life (HR-QOL). Seventy-nine SSc patients and 158 matched controls answered a validated questionnaire on gastrointestinal (GI) symptoms and Medical Outcomes Study Short Form Health Survey (SF-36). Modified Miller Score, a composite score measuring faecal incontinence, was computed. Abnormal stool consistency, bloating, a feeling of incomplete evacuation, faecal incontinence and rectal bleeding were more frequently reported by SSc patients than controls. The ability for anorectal discrimination, and deferring defecation was diminished in SSc patients. Bowel function affected general well being in 30% of patients and social life in 20%. Patients had lower SF-36 scores, that is, worse HR-QOL than controls. Modified Miller Score did not correlate to the SF-36 scores in patients, but other lower GI symptoms, especially abdominal pain and bloating, were associated with diminished HR-QOL. Lower GI symptoms, including faecal incontinence, are more common in patients with SSc than in healthy controls and are of consequence to the individual patient's life. The lower prevalence of anorectal discrimination in the SSc patients suggests a neuronal defect in these patients. Increased awareness of these symptoms might stimulate a search for new diagnostic and therapeutic strategies.


Antimicrobial effects of Turkish propolis, pollen, and laurel on spoilage and pathogenic food-related microorganisms.
The antimicrobial activities of propolis extract, pollen extract, and essential oil of laurel (Laurus nobilis L.) at concentrations from 0.02% to 2.5% (vol/vol) were investigated on bacteria (Bacillus cereus, Bacillus subtilis, Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, Yersinia enterocolitica, Enterococcus faecalis, and Listeria monocytogenes), yeasts (Saccharomyces cerevisiae and Candida rugosa), and molds (Aspergillus niger and Rhizopus oryzae). Pollen has no antimicrobial effects on the bacteria and fungi tested in the concentrations used. Propolis showed a bactericidal effect at 0.02% on B. cereus and B. subtilis, at 1.0% on S. aureus and E. faecalis, and at 0.2% on L. monocytogenes. The minimum inhibitory concentration of propolis for fungi was 2.5%. Propolis and laurel were ineffective against E. coli and S. typhimurium at the concentrations tested. The results showed that the antimicrobial activity were concentration dependent. Propolis and essential oil of laurel may be used as biopreservative agents in food processing and preservation.


Nosocomial outbreak of infections by Proteus mirabilis that produces extended-spectrum CTX-M-2 type beta-lactamase.
Nineteen multidrug-resistant Proteus mirabilis strains were isolated from 19 patients suffering from infections probably caused by P. mirabilis. These strains were recovered from urine or other urogenital specimens of 16 inpatients and three outpatients with a hospitalization history in a urology ward of Funabashi Medical Center, from July 2001 to August 2002. These strains demonstrated resistance to cefotaxime, ceftriaxone, cefpodoxime, and aztreonam, while they were highly susceptible to ceftazidime (MIC, </=0.5 micro g/ml). The resistance level of these strains to cefotaxime was decreased by the presence of clavulanic acid. Therefore, the strains were speculated to produce extended-spectrum class A beta-lactamases. These strains were later found to carry bla(CTX-M-2) genes by both PCR and sequencing analyses. The profiles of SmaI-digested genomic DNA of 19 isolates were distinguished into five different clusters by biased sinusoidal field gel electrophoresis. Four of them, consisting of 18 isolates, were suggested to be a clonal expansion. These findings suggested that a nosocomial outbreak of infections by CTX-M-2-producing P. mirabilis had occurred in our medical center. Most patients suffered from urogenital malignancies with long-term catheterization. Cefazolin, cefoperazone-sulbactam, and/or levofloxacin were mostly administered to the patients, but these agents seemed ineffective for eradication of CTX-M-2 producers. Early recognition and rapid identification of colonizing antimicrobial-resistant bacteria, including CTX-M-2-producing P. mirabilis, would be the most effective measures to cope with further spread of this kind of hazardous microorganism in clinical environments.


Defining potency: a comparison of the International Index of Erectile Function short version and the Expanded Prostate Cancer Index Composite.
Both the 5-item short version of the International Index of Erectile Function (IIEF-5) and the Expanded Prostate Cancer Index Composite (EPIC) have been used to assess erectile function. In this study, the authors compared various definitions of potency according to the IIEF-5 and the EPIC. Patients with prostate cancer who had completed the IIEF-5 and the EPIC within 7 days of each other were included. The Spearman correlation coefficient (rho) was calculated to assess the relation between IIEF-5 and EPIC sexual domain scores. Concordance of potency rates by IIEF-5 and EPIC was assessed in cross-tabulations. By calculating the area under the receiver operator characteristics (ROC) curve (AUC), the authors ascertained the discriminative ability of the IIEF-5 score to identify potent men as defined by the EPIC. Analyzing 102 questionnaire pairs, IIEF-5 and EPIC domain scores were found to be highly correlated (rho = 0.776). EPIC sexual domain scores > or =60 had high concordance with IIEF-5 scores > or =17 (98%) and with nearly all single-item definitions of potency (> or =71%). However, an EPIC sexual domain score > or =80 was a very strict definition of potency, and only 54% of patients with IIEF-5 scores > or =22 met this threshold. On the basis of ROC analysis (AUC = 0.90), an IIEF-5 score > or =20 was identified as the ideal cutoff for defining potency and corresponded with an EPIC sexual domain score > or =60. IIEF-5 and EPIC scores were highly correlated, but potency rates varied widely, depending on the definition of potency. The current results help with the interpretation of sexual function outcomes data in patients with prostate cancer.


Role of BMP family members during kidney development.
Members of the Bone morphogenetic protein (BMP) family have been shown to be important signaling molecules throughout mouse development. Accordingly, many BMPs are also expressed during organogenesis of the metanephric kidney. However, only BMP7 has been shown to be absolutely required for proper formation of the kidney, thus the majority of information known involves this family member. BMP7 is expressed in both the ureteric epithelium and the mesenchyme throughout embryonic development and has been shown to function as a survival factor for the nephrogenic mesenchyme. However, there has been some controversy over the role of BMP7 as an inducing molecule for the metanephric mesenchyme. Recent studies have shown that BMP7 functions as an anti-differentiation factor for this mesenchyme cell population. The function of BMPs in the ureter and in the more differentiated epithelial structures of the nephron is less well understood.


Changes in socioeconomic mortality inequalities at adult and old ages in Lithuania, 2001-05 to 2011-15.
This article provides evidence about changes in mortality inequalities by education and economic activity status among adults aged 30-64 and older adults aged 65 and over in Lithuania between 2001-05 and 2011-15. The study shows that the overall mortality decline in Lithuania was not homogeneous across socio-economic groups. The inequitable progress resulted in a widening in absolute and relative mortality inequalities among older adults and notable increases in relative mortality inequalities among adults aged 30-64. The total public health burden of mortality inequalities remained very pronounced or even increased further.


The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis.
The current systematic review and meta-analysis provides an extended and comprehensive overview of the associations between neurocognitive and social cognitive functioning and different types of functional outcome. Literature searches were conducted in MEDLINE and PsycINFO and reference lists from identified articles to retrieve relevant studies on cross-sectional associations between neurocognition, social cognition and functional outcome in individuals with non-affective psychosis. Of 285 studies identified, 52 studies comprising 2692 subjects met all inclusion criteria. Pearson correlations between cognition and outcome, demographic data, sample sizes and potential moderator variables were extracted. Forty-eight independent meta-analyses, on associations between 12 a priori identified neurocognitive and social cognitive domains and 4 domains of functional outcome yielded a number of 25 significant mean correlations. Overall, social cognition was more strongly associated with community functioning than neurocognition, with the strongest associations being between theory of mind and functional outcomes. However, as three-quarters of variance in outcome were left unexplained, cognitive remediation approaches need to be combined with therapies targeting other factors impacting on outcome.


High-field magnetic resonance imaging in patients with moyamoya disease.
The purpose of this study was to assess the utility of high-field magnetic resonance (MR) imaging as a quantitative tool for estimating cerebral circulation in patients with moyamoya disease. Eighteen patients with moyamoya disease who were scheduled to undergo revascularization surgery and 100 healthy volunteers were examined using T2-reversed MR imaging performed using a 3-tesla system. Ten of the 18 patients underwent a second study between 1 year and 3 years after revascularization. Magnetic resonance images obtained in the patients with moyamoya disease were statistically analyzed and compared with those obtained in healthy volunteers. The MR imaging findings were also correlated with results of single-photon emission computerized tomography and conventional cerebral angiography studies. Transverse lines in the white matter (medullary streaks) were observed in almost all persons. In healthy volunteers, the diameter sizes of the medullary streaks increased significantly with age (p < 0.001). Multiple logistic regression analysis revealed that age-adjusted medullary streak diameters were significantly larger in patients with moyamoya disease (p < 0.001). Diameter sizes also increased significantly with the increased severity of cerebral hypoperfusion (p < 0.001) and a higher angiographically determined stage of the disease (p < 0.001). Diameter sizes decreased significantly after surgery (p < 0.001). The increases in medullary streak diameters observed in patients with moyamoya disease appear to represent vessels dilated due to cerebral hypoperfusion. High-field T2-reversed MR imaging is useful in estimating cerebral circulation in patients with moyamoya disease.


Use of monoclonal antibodies to culture rat proximal tubule cells.
Current renal cell culture techniques are limited by either a low yield of cells or by heterogeneity of cell types. We have used monoclonal antibodies to microvillus membrane proteins to isolate and culture a pure population of proximal tubule cells. The cells were characterized as proximal tubule cells by phase microscopy, enzyme histochemistry for alkaline phosphatase, butyrate esterase, and gamma-glutamyltransferase, electron microscopy, and specific reactivity with a variety of monoclonal antibodies for proximal tubule cells. Growth over 2-7 days yielded cell numbers up to 1,000-fold greater than obtained by single tubule microdissection. Dome formation was observed, suggesting intact fluid transport. In addition, Na+-H+ exchange and Na+-dependent D-hexose transport, known transport processes of the proximal tubule, were demonstrated by microfluorimetry of single cells and methyl-alpha-D-glucopyranoside uptake, respectively. Our results indicate that large numbers of homogeneous, cultured rat proximal tubule cells that maintain characteristics of in vivo proximal tubule cells can be obtained using a monoclonal antibody technique of isolation.


Technical note: An improved tool to insert lines for abomasal infusion in rumen cannulated cattle.
An improved tool was tested that facilitates the insertion of abomasal infusion lines in ruminally cannulated cattle for postruminal infusion studies. The insertion device was made from a 68 × 25 mm section of 20-mm i.d. stainless steel device with a weight of 125 g. The general procedure to place the tool is to pass the insertion device with the infusion line through the rumen cannula, through the sulcus omasi (reticulo-omasal orifice), and finally into the abomasum. Once inside the omasum, the insertion device is placed inside the abomasum by gently shifting the infusion line from the flexible polyvinyl chloride tubing fitted to the insertion device. The insertion device places itself by self-moving down through the abomasal orifice into the abomasum by means of its own weight. After device placement, its position can be verified by palpating through the wall of the rumen. This way, an infusion line can easily be inserted into the abomasum by any person without introducing the hand into the omasum, avoiding possible injuries to the animal and tool being expulsed of its desired position.


Severity of upper and lower extremity functional limitation: scale development and validation with self-report and performance-based measures of physical function. WHAS Research Group. Women's Health and Aging Study.
To better understand disablement and transitions from impairment to disability, discrete valid measures of functional limitation are needed. This study reports the development and criterion-related validity of scales that quantify severity of upper and lower extremity functional limitation. Data are from 3,635 cognitively intact community-dwelling women aged 65 years and older and 1,002 moderately to severely disabled participants in the Women's Health and Aging Study. Scales assessing severity of upper and lower extremity functional limitation were constructed from commonly available questions on functional difficulty. Criterion-related validity was evaluated with self-report and performance-based measures. The upper and lower extremity scales range from 0 to 6 and 0 to 9, respectively. Scale scores were well distributed in the disabled group and discriminated limitations in the broader community. For both scales, rates of difficulty for all ADL and IADL increased (p<.001) with increasing severity score, and percent able and mean performance on respective upper and lower extremity tasks decreased (p<.01). These scales, constructed from commonly used self-report measures of function, provide discrete measures of upper and lower functional limitation. Because these scales are distinct from measures of disability and impairment, their use should facilitate increased understanding of the disablement process.


Lactiplantibacillus plantarum dfa1 Outperforms Enterococcus faecium dfa1 on Anti-Obesity in High Fat-Induced Obesity Mice Possibly through the Differences in Gut Dysbiosis Attenuation, despite the Similar Anti-Inflammatory Properties.
Fat reduction and anti-inflammation are commonly claimed properties of probiotics. Lactiplantibacillus plantarum and Enterococcus faecium were tested in high fat-induced obesity mice and in vitro experiments. After 16 weeks of probiotics, L. plantarum dfa1 outperforms E. faecium dfa1 on the anti-obesity property as indicated by body weight, regional fat accumulation, serum cholesterol, inflammatory cytokines (in blood and colon tissue), and gut barrier defect (FITC-dextran assay). With fecal microbiome analysis, L. plantarum dfa1 but not E. faecium dfa1 reduced fecal abundance of pathogenic Proteobacteria without an alteration in total Gram-negative bacteria when compared with non-probiotics obese mice. With palmitic acid induction, the condition media from both probiotics similarly attenuated supernatant IL-8, improved enterocyte integrity and down-regulated cholesterol absorption-associated genes in Caco-2 cell (an enterocyte cell line) and reduced supernatant cytokines (TNF-α and IL-6) with normalization of cell energy status (extracellular flux analysis) in bone-marrow-derived macrophages. Due to the anti-inflammatory effect of the condition media of both probiotics on palmitic acid-activated enterocytes was neutralized by amylase, the active anti-inflammatory molecules might, partly, be exopolysaccharides. As L. plantarum dfa1 out-performed E. faecium dfa1 in anti-obesity property, possibly through the reduced fecal Proteobacteria, with a similar anti-inflammatory exopolysaccharide; L. plantarum is a potentially better option for anti-obesity than E. faecium.


Approaches for assessing the role of household socioeconomic status on child anthropometric measures in urban South Africa.
The objectives of this article were to compare the variance explained in anthropometric outcomes when using individual measures of socioeconomic status (SES) versus different approaches to create SES indices within the urban African context, and to examine the influence of SES measured during infancy on child anthropometric outcomes at 7/8 years. Data from the 1990 Birth-to-Twenty cohort study set in Johannesburg-Soweto, South Africa, were used (n = 888). Linear regression models were used to investigate the association between SES (individual and index measures) during infancy and anthropometric measures at age 7/8 years, controlling for sex, age, and population group. Both individual and index measures of SES explained similar proportions of the variance for each anthropometric outcome. SES measured during infancy influenced weight more than height at age 7/8 years in Johannesburg-Soweto. Positive associations were found between SES and the anthropometric measures--ownership of a car, telephone, and having an inside flush toilet were the most significant SES variables. The similarities observed in the variance explained relating to the anthropometric outcomes suggest that researchers who want to adjust for SES in analyses could use an SES index to make statistical models more parsimonious. However, using such indices loses information relating to the specific socioeconomic factors that are important for explaining child anthropometrics. If the purpose of the research is to make policy recommendations for the improvement of child growth, individual SES variables would provide more specific information to target interventions.


[Reinterventions in late failures of femorodistal grafts].
In this retrospective study of 195 patients treated for late failure of a previous femoral-distal reconstruction, there were 178 men and 17 women ranging in age from 42 to 79 years. The graft material utilised for initial operation was an autoenous vein (reversed saphenous vein (75), in situ (1) and arm veins (4) in 80, polytetrafluoroethylene in 51, Dacron in 46, Biografts in 12 and composite grafts in 6 patients. The previous site for distal anastomosis was above the knee in 70 and tibial or peroneal arteries in 18 cases. The most common cause of graft failure was late thrombosis (95), progression of the underlying disease (64), deterioration of the graft (15), pseudoaneurysms (8), and rerelly perigraft reactions, hemodynamic insufficiency, late infection, etc. The aim of the reoperation was: graft extension for distal disease (68) desobstruction and patch angioplasty (21), thrombectomy (9) exchange of the graft (17), local repair of the graft (3). Seventeen patients required inflow procedures. Other reinterventions (sympathectomy, catheterisation and prostaglandin perfusion, were used in patients with no chance for reconstructive arterial surgery. Secondary reoperations were performed in 12, tertiary operations in 7 patients. Major amputations rate, operation mortality, wound morbidity and hemodynamic success rates with limb salvage in reoperated patients support usefulness of repeated revascularisation when femoro-distal bypass failure occurs.


[The heterogeneity of neurospecific S-100 protein].
A modified method is described of the isolation of neuro-specific S-100 protein from bovine brain tissue by means of thermal denaturation, ammonium sulphate fractionation, chromatography on DEAE-Sephadex A-50 and gel filtration through Sephadex G-100. Considerable heterogeneity of S-100 protein is discovered: it produces 4 fractions (f1--f4) under fractionation on DEAE-Sephadex A-50. The constant elution from the column of the main fraction, eluted with 0.325--0.35 M NaCl, and minor S-100 protein fractions, eluted with more high NaCl concentrations, is registered. At the same time, considerable variation in the quantitative yield of the main component of S-100 protein and in the relative content of main and minor components of S-100 protein is developed. Fast- (in f1 and f4 fractions) and slow-migrating (in f2 and f3 fractions) components are revealed under polyacrylamide gel electrophoresis. The f1 fraction is found to consist mainly of the component with molecular weight of 20 000 while fz, f3 and f4 fractions contain two components having molecular weight of 32 000 and 71 000. Antiserum to S-100 protein produced a positive immunodiffusion reaction with f1 and f2, and not with f3 and f4 fractions.


The fitness and functionality of culturally evolved communication systems.
This paper assesses whether human communication systems undergo the same progressive adaptation seen in animal communication systems and concrete artefacts. Four experiments compared the fitness of ad hoc sign systems created under different conditions when participants play a graphical communication task. Experiment 1 demonstrated that when participants are organized into interacting communities, a series of signs evolve that enhance individual learning and promote efficient decoding. No such benefits are found for signs that result from the local interactions of isolated pairs of interlocutors. Experiments 2 and 3 showed that the decoding benefits associated with community evolved signs cannot be attributed to superior sign encoding or detection. Experiment 4 revealed that naive overseers were better able to identify the meaning of community evolved signs when compared with isolated pair developed signs. Hence, the decoding benefits for community evolved signs arise from their greater residual iconicity. We argue that community evolved sign systems undergo a process of communicative selection and adaptation that promotes optimized sign systems. This results from the interplay between sign diversity and a global alignment constraint; pairwise interaction introduces a range of competing signs and the need to globally align on a single sign-meaning mapping for each referent applies selection pressure.


New progress in CT and MRI examination and diagnosis of small intestinal tumors.
Precise examination and diagnosis of small intestinal tumors is difficult because of the curved course and overlapping canal of the small intestine. Traditional technology for intestinal canal examination and endoscopy cannot exhibit the intestinal wall and extra-luminal structure well. With the development and advancement of multi-slice spiral computed tomography and magnetic resonance imaging (MRI), computed tomography enteroclysis (CTE) and magnetic resonance enteroclysis (MRE) are widely used in the examination and diagnosis of small intestinal tumors. CTE and MRE, with three-dimensional imaging capabilities and excellent soft-tissue contrast, can analyze the abnormalities of peripheral intestinal structure as well as the tunica mucosa. In addition, these two technologies can clearly reveal the localization, appearance, degree of mesenteric infiltration and remote tumor metastasis, which increases our cognition of the imaging diagnosis for intestinal tumors. Here we review recent progress in imaging (CT and MRI) examination and diagnosis of small intestinal tumors.


The auditory startle reaction in parkinsonian disorders.
The auditory startle reaction to an unexpected loud stimulus is regarded as a brainstem reflex originating in the nucleus reticularis pontis caudalis and being distributed up the brainstem and down the spinal cord along slowly conducting pathways. Auditory startle responses (ASR) have been reported absent or reduced in progressive supranuclear palsy (PSP), and delayed in Parkinson's disease (PD), but normal in multiple-system atrophy (MSA). For the first time we studied ASR in patients fulfilling the clinical criteria of dementia with Lewy bodies (DLB) (n = 8), a neurodegenerative disorder characterized by cortical and subcortical depositions of Lewy bodies resulting in parkinsonism and progressive cognitive decline. For comparison, we also investigated patients with PD (n = 10), MSA (n = 7), PSP (n = 10), and age-matched healthy controls (n = 10). ASR were elicited by binaural high-intensity auditory stimuli. Surface electromyographic activity was simultaneously recorded from facial, upper, and lower extremity muscles. For each muscle, we assessed response probability and measured latency, amplitude, duration, and habituation rate. Patients with DLB had fewer and abnormally delayed ASR of low amplitude and short duration in extremity muscles compared to healthy controls. Furthermore, we confirm and extend previous findings of abnormal ASR in PSP and PD, and also demonstrate exaggerated ASR in extremity muscles of MSA patients. The different patterns of ASR abnormalities may reflect distinct types of brainstem dysfunction in DLB.


Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors.
Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. In this 6-month randomized, placebo-controlled, double-blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire-Disability Index (HAQ-DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis. At 3 months, the rates of ACR20 response were 50% with the 5-mg dose of tofacitinib and 47% with the 10-mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ-DI score were -0.39 and -0.35, as compared with -0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5-mg dose of tofacitinib continuously and in 6% who received the 10-mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib. In this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439 .).


High intensity strength training improves strength and functional performance after stroke.
To evaluate the effects of a progressive resistance strength training program on changes in muscle strength, gait, and balance in older individuals 1 yr after stroke, seven individuals were recruited who were greater than 60-yr-old, 1 yr after stroke, living at home, and able to follow verbal commands. Subjects participated in a 12-wk 2x per wk resistance training program at 70% of 1 repetition maximum. Lower limb strength improved 68% on the affected side and 48% on the intact side during training, with the largest increases observed for hip extension (affected side: 88%, P < 0.01; intact side: 103%, P < 0.001). Repeated chair stand time decreased 21% (P < 0.02). Motor performance assessed by the Motor Assessment Scale improved 9% (P < 0.04) and static and dynamic balance (Berg balance scale) improved 12% (P < 0.004). Progressive resistance training in individuals 1 yr after stroke improves affected and intact side lower limb strength and was associated with gains in chair stand time, balance, and motor performance. These results support the concept that strength training is an appropriate intervention to improve the quality of physical function in older community dwelling stroke survivors.


A Team for the Low-Temperature Bulk Depolymerization of Polymethacrylates.
This invited Team Profile was created by Athina Anastasaki of the Laboratory of Polymeric Materials at ETH Zurich, Switzerland. They recently published an article developing a low-temperature and solvent-free method to depolymerize polymers made by atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The key to the success of the approach was an efficient end-group transformation of the polymers to macromonomer, which allowed up to 90 % monomer regeneration at low temperatures. "Solvent-Free Chemical Recycling of Polymethacrylates Made by ATRP and RAFT Polymerization: High-Yielding Depolymerization at Low Temperatures", R. Whitfield, G. R. Jones, N. P. Truong, L. E. Manring, A. Anastasaki, Angew. Chem. Int. Ed. 2023, 62, e202309116.


Inhibition of the primary lesion of adjuvant. induced polyarthritis in rats (18-hour arthritis test) for specific detection of clinically effective anti-arthritic drugs.
Adjuvant-induced polyarthritis can be induced in rats 14 to 21 days after subplantar injection of 0.1 ml of a 0.5% suspension of Mycobacterium tuberculosis in heavy mineral oil into a hind paw. However, edema volume of the injected pay (primary lesion) developed rapidly and reached a peak in 18 hours after injection and persisted at this level for up to 90 hours. A single oral dose of 25 clinically effective or experimental antiarthritic agents given 1 hour prior to M. tuberculosis injection and tested 18 hours later significantly inhibited edema formation in a dose-related fashion. Only D-penicillamine and azathioprine which are clinically effected, gave false-negative responses in this test. However, cyclophosphamide, another immunosuppressive like azathioprine, was effective. The ED50 values for most drugs in this test were at least 2-fold greater than in the carrageenan edema test. On the other hand, of the 17 drugs considered as false-positives in the carrageenan test only the antihistaminic agent, chlorpheniramine maleate, was effective in the 18-hour arthritis test, whereas several other agents with this activity but different chemical structure proved ineffective. In addition, 18 other agents from various classes of therapeutic agents were also tested and found ineffective in each test. These data suggest that the 18-hour arthritis test in rats is highly specific and a more reliable screening procedure than carrageenan-induced edema for detecting potentially useful antiarthritic agents. The practical advantages of this method are also discussed.


Accumulation of heavy metals in four grasses grown on lead and zinc mine tailings.
A field experiment was conducted to compare the growth and metal accumulation of Vetiveria zizanioides, Paspalum notatum, Cynodon dactylon and Imperata cylindraca var. major on the tailings, amended with 10 cm domestic refuse + complex NPK fertilizer(Treatment A), 10 cm domestic refuse(Treatment B) and complex NPK fertilizer (Treatment C) respectively, and without any amendment used as control (Treatment D). The results indicated that V. zizanioides was a typical heavy metal excluder, because the concentrations in shoots of the plants were the lowest among the four plants tested. The most of metal accumulated in V. zizanioides distributed in its root, and transportation of metal in this plant from root to shoot was restricted. Therefore, V. zizanioides was more suitable for phytostabilization of toxic mined lands than P. notatum and C. dactylon, which accumulated a relatively high level of metals in their shoots and roots. It was also found that I. cylindraca var. major accumulated lower amounts of Pb, Zn and Cu than C. dactylon and P. notatum, and could also be considered for phytostalilisaton of tailings. Although the metal(Pb, Zn and Cu) concentrations in shoots and roots of V. zizanioides were the lowest, the total amounts of heavy metals accumulated in shoots of V. zizanioides were the highest among the four tested plants due to the highest dry weight yield of it. The results indicated that V. zizanioides was the best choice among the four species used for phytoremediation (for both phytostabilization and phytoextraction) of metal contaminated soils.


SLC5A1 Mutations in Saudi Arabian Patients With Congenital Glucose-Galactose Malabsorption.
Congenital glucose-galactose malabsorption (cGGM) is a rare autosomal recessive disorder, caused by mutations in the SLC5A1 gene, encoding the sodium/glucose cotransporter 1, which may result in severe life-threatening osmotic diarrhea due to the accumulation of unabsorbed sugars in the intestinal lumen. If treated early with elimination of glucose and galactose from the diet, patients usually recover and develop normally. We present clinical and molecular data from 16 unrelated cGGM diagnosed Saudi patients from consanguineous families with majority of them having previous positive family history of cGGM. Sanger sequencing for the full coding regions of SLC5A1 for all patients resulted in the identification of 4 allelic variants in a homozygous state. Two mutations are novel; c.265G>A (p.G89R) and c.1304 G>A (p.G435D), and 2 have been previously reported to cause cGGM, c.765 C>G (p.C255W) and c.1136 G>A (p.R379Q). This is the first report delineating the clinical and molecular basis of cGGM in patients from this region.


Increased FGFR1 copy number in lung squamous cell carcinomas.
The basic fibroblast growth factor (bFGF), via activation of its receptor, FGFR1, has been postulated to be an important inducer of host stromal response and angiogenesis. More recently, FGFR1 amplifications were investigated using large-scale single nucleotide polymorphism arrays in lung cancer. We hypothesized that FGFR1 overexpression may be correlated with the clinicopathological features of lung cancers. The increased copy number of the FGFR1 gene was analyzed by real-time polymerase chain reaction amplifications in 100 surgically treated non-small cell lung cancer cases from Nagoya City University Hospital. Sixty-five squamous cell carcinoma cases were included. An increased FGFR1 gene copy number was found in 32 (32%) lung cancer patients. The increased FGFR1 copy number status significantly correlated with gender (females 13.8% vs. males 39.4%, p=0.0173), smoking status (never smoker 4.2% vs. smoker 40.8%, p=0.0004) and pathological subtypes (squamous cell carcinoma 41.5% vs. non-squamous cell carcinoma 14.3%, p=0.0066). However, within the squamous cell carcinomas the FGFR1 copy number status did not significantly correlate with gender, smoking status, pathological stages and differentiation status of the lung cancers. Thus, the FGFR1 copy number is common within squamous cell carcinoma.


Memory for acute stress disorder symptoms: a two-year prospective study.
The present study aimed to index the accuracy of memory for acute trauma symptoms by comparing the symptoms reported by motor vehicle accident (MVA) victims within 1 month posttrauma with the recall of these symptoms at 2 years posttrauma. Ninety-two consecutive MVA admissions were assessed for the presence of acute stress disorder (ASD) within 1 month posttrauma. At 2 years posttrauma, 61% (N = 56) of the sample were reassessed for posttraumatic stress disorder (PTSD) and for accuracy of recall of the symptoms reported during the first assessment. At least one of the four ASD diagnostic clusters was recalled inaccurately by 75% of patients. High levels of posttraumatic stress severity and high subjective ratings of injury severity at 2 years posttrauma were associated with errors of addition (i.e., recalling the presence of acute symptoms 2 years posttrauma that were not reported during the first assessment). Low levels of posttraumatic stress severity and low subjective ratings of injury severity at 2 years posttrauma were associated with errors of omission (i.e., omitting to recall acute symptoms 2 years posttrauma that were reported during the first assessment). These results suggest that retrospective reports of acute stress symptoms should be interpreted cautiously because of the influence of current symptoms on recall of acute symptoms.


Transcatheter aortic valve implantation and four-year follow up in a 99-year-old patient.
Transcatheter aortic valve implantation (TAVI) has emerged as a life-saving therapy in patients with severe aortic valve stenosis who are considered to be high-risk surgical candidates. However, there is a paucity of data on the long-term survival and quality-of-life in very old patients undergoing TAVI. Here, the case is reported of a now 104-year-old patient who underwent percutaneous transfemoral TAVI with a CoreValve prosthesis at the age of 99 years; details of his four-year outcome data are also provided. To best of the authors' knowledge, this patient is the oldest reported to have undergone TAVI, and is currently living with good functional status more than four years after the intervention.


Organizing collective cell migration through guidance by followers.
Morphogenesis, wound healing, and some cancer metastases rely on the collective migration of groups of cells. In these processes, guidance and coordination between cells and tissues are critical. While strongly adherent epithelial cells have to move collectively, loosely organized mesenchymal cells can migrate as individual cells. Nevertheless, many of them migrate collectively. This article summarizes how migratory reactions to cell-cell contacts, also called "contact regulation of locomotion" behaviors, organize mesenchymal collective cell migration. It focuses on one recently discovered mechanism called "guidance by followers", through which a cell is oriented by its immediate followers. In the gastrulating zebrafish embryo, during embryonic axis elongation, this phenomenon is responsible for the collective migration of the leading tissue, the polster, and its guidance by the following posterior axial mesoderm. Such guidance of migrating cells by followers ensures long-range coordination of movements and developmental robustness. Along with other "contact regulation of locomotion" behaviors, this mechanism contributes to organizing collective migration of loose populations of cells.


Small strokes causing severe vertigo: frequency of false-negative MRIs and nonlacunar mechanisms.
Describe characteristics of small strokes causing acute vestibular syndrome (AVS). Ambispective cross-sectional study of patients with AVS (acute vertigo or dizziness, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with at least one stroke risk factor from 1999 to 2011 at a single stroke referral center. Patients underwent nonquantitative HINTS "plus" examination (head impulse, nystagmus, test-of-skew plus hearing), neuroimaging to confirm diagnoses (97% by MRI), and repeat MRI in those with initially normal imaging but clinical signs of a central lesion. We identified patients with diffusion-weighted imaging (DWI) strokes ≤10 mm in axial diameter. Of 190 high-risk AVS presentations (105 strokes), we found small strokes in 15 patients (median age 64 years, range 41-85). The most common vestibular structure infarcted was the inferior cerebellar peduncle (73%); the most common stroke location was the lateral medulla (60%). Focal neurologic signs were present in only 27%. The HINTS "plus" battery identified small strokes with greater sensitivity than early MRI-DWI (100% vs 47%, p < 0.001). False-negative initial MRIs (6-48 hours) were more common with small strokes than large strokes (53% [n = 8/15] vs 7.8% [n = 7/90], p < 0.001). Nonlacunar stroke mechanisms were responsible in 47%, including 6 vertebral artery occlusions or dissections. Small strokes affecting central vestibular projections can present with isolated AVS. The HINTS "plus" hearing battery identifies these patients with greater accuracy than early MRI-DWI, which is falsely negative in half, up to 48 hours after onset. We found nonlacunar mechanisms in half, suggesting greater risk than might otherwise be assumed for patients with such small infarctions.


Prohibitin overexpression in adipocytes induces mitochondrial biogenesis, leads to obesity development, and affects glucose homeostasis in a sex-specific manner.
Adipocytes are the primary cells in the body that store excess energy as triglycerides. To perform this specialized function, adipocytes rely on their mitochondria; however, the role of adipocyte mitochondria in the regulation of adipose tissue homeostasis and its impact on metabolic regulation is not understood. We developed a transgenic mouse model, Mito-Ob, overexpressing prohibitin (PHB) in adipocytes. Mito-Ob mice developed obesity due to upregulation of mitochondrial biogenesis in adipocytes. Of note, Mito-Ob female mice developed more visceral fat than male mice. However, female mice exhibited no change in glucose homeostasis and had normal insulin and high adiponectin levels, whereas male mice had impaired glucose homeostasis, compromised brown adipose tissue structure, and high insulin and low adiponectin levels. Mechanistically, we found that PHB overexpression enhances the cross talk between the mitochondria and the nucleus and facilitates mitochondrial biogenesis. The data suggest a critical role of PHB and adipocyte mitochondria in adipose tissue homeostasis and reveal sex differences in the effect of PHB-induced adipocyte mitochondrial remodeling on whole-body metabolism. Targeting adipocyte mitochondria may provide new therapeutic opportunities for the treatment of obesity, a major risk factor for type 2 diabetes.


Influenza Virus Hemagglutinin Glycoproteins with Different N-Glycan Patterns Activate Dendritic Cells In Vitro.
Influenza virus hemagglutinin (HA) N-glycans play important regulatory roles in the control of virus virulence, antigenicity, receptor-binding specificity, and viral escape from the immune response. Considered essential for controlling innate and adaptive immune responses against influenza virus infections, dendritic cells (DCs) trigger proinflammatory and adaptive immune responses in hosts. In this study, we engineered Chinese hamster ovary (CHO) cell lines expressing recombinant HA from pandemic H1, H5, and H7 influenza viruses. rH1HA, rH5HA, and rH7HA were obtained as wild-type proteins or in the presence of kifunensine (KIF) or further with endo-β-N-acetylglucosaminidase-treated KIF (KIF+E) to generate single-N-acetylglucosamine (GlcNAc) N-glycans consisting of (i) terminally sialylated complex-type N-glycans, (ii) high-mannose-type N-glycans, and (iii) single-GlcNAc-type N-glycans. Our results show that high-mannose-type and single-GlcNAc-type N-glycans, but not complex-type N-glycans, are capable of inducing more active hIL12 p40, hIL12 p70, and hIL-10 production in human DCs. Significantly higher HLA-DR, CD40, CD83, and CD86 expression levels, as well reduced endocytotic capacity in human DCs, were noted in the high-mannose-type rH1HA and single-GlcNAc-type rH1HA groups than in the complex-type N-glycan rH1HA group. Our data indicate that native avian rHA proteins (H5N1 and H7N9) are more immunostimulatory than human rHA protein (pH1N1). The high-mannose-type or single-GlcNAc-type N-glycans of both avian and human HA types are more stimulatory than the complex-type N-glycans. HA-stimulated DC activation was accomplished partially through a mannose receptor(s). These results provide more understanding of the contribution of glycosylation of viral proteins to the immune responses and may have implications for vaccine development. Influenza viruses trigger seasonal epidemics or pandemics with mild-to-severe consequences for human and poultry populations. DCs are the most potent professional antigen-presenting cells, which play a crucial role in the link between innate and adaptive immunity. In this study, we obtained stable-expression CHO cells to produce rH1HA, rH5HA, and rH7HA proteins containing distinct N-glycan patterns. These rHA proteins, each with a distinct N-glycan pattern, were used to investigate interactions with mouse and human DCs. Our data indicate that native avian rHA proteins (H5N1 and H7N9) are more immunostimulatory than human rHA protein (pH1N1). High-mannose-type and single-GlcNAc-type N-glycans were more effective than complex-type N-glycans in triggering mouse and human DC activation and maturation. We believe these results provide some useful information for influenza vaccine development regarding how influenza virus HA proteins with different types of N-glycans activate DCs.


Postpartum Depressive Symptoms as a Mediator Between Intimate Partner Violence During Pregnancy and Maternal-Infant Bonding in Japan.
Studies show that experiencing intimate partner violence (IPV) during pregnancy is related to poor maternal-infant bonding. However, the mechanisms underlying this relationship are unclear. This article aims to examine whether maternal postpartum depressive (PPD) symptoms mediate the association between pregnancy IPV and maternal-infant bonding, and whether the relationship differs by maternal-infant bonding subscales-lack of affection, anger/rejection. A survey was conducted among women who participated in a postpartum health check-up program in Aichi prefecture, Japan (N = 6,590) in 2012. We examined whether experiences of emotional and physical IPV were related to maternal-infant bonding and whether PPD symptoms mediated this relationship. Path analysis showed that emotional and physical IPV were associated with PPD symptoms, and PPD symptoms predicted poor bonding. The total effect of emotional IPV on poor bonding was significant, showing a marginally significant direct effect and statistically significant indirect effect. The total effect of physical IPV on poor bonding was not statistically significant. Emotional IPV was significantly associated with both lack of affection and anger/rejection bonding subscales, which were similarly mediated by PPD symptoms. Findings revealed a modest indirect association between IPV, emotional IPV in particular, and poor maternal-infant bonding, which was mediated by PPD symptoms. While prevention of IPV is the ultimate goal, the treatment of PPD symptoms among women who experience IPV during pregnancy may improve maternal-infant bonding and mitigate cross-generational effects of IPV. Identifying opportunities for detection of IPV and PPD symptoms, as well as prevention and early intervention, may improve maternal-infant bonding.


[Activity of NAD.H-generating enzymes and cytochrome content in mitochondria from rat liver and myocardium under artificial hypobiosis].
The modification particularities of the structural and functional state of the inner mitochondrial membrane of the rat liver and myocardium were observed in conditions of artificial hypobiosis, which was created using hypoxic and hypercapnic gas medium with a body temperature reduction. Under the artificial hypobiosis the activity of NAD.H-generating enzymes of the Krebs cycle of the liver mitochondria decreases. The established changes of the enzymes activity and cytochromes content of the inner mitochondrial membrane indicate the decrease of the oxidative activity of a respiratory chain, that can be limited on a terminal (cytochrome c oxidase) site and leads to the decrease (by 49% at an average) of the H+-ATPase activity of the liver mitochondria. Under the artificial hypobiosis the detected increase of the succinate-KoQ-oxidoreductase activity (by 65% at average) causes the maintaining of the functional activity of a mitochondrial respiratory chain, considering the high (relative to control) cytochrome c oxidase and H+-ATPase activities of the mitochondria of the rats' myocardium. The structural changes of the inner mitochondrial membrane of the liver and myocardium in experimental conditions are accompanied by the increase of hydrophobicity of tryptophan residues microenvironment and the intramolecular modifications of protein molecules.


Apoptosis in Rat Cornea After In Vivo Exposure to Ultraviolet Radiation at 300 nm.
Peak toxicity for in vivo ultraviolet radiation (UVR) exposure to the lens is in the 300-nm wavelength region. However, little is known about corneal cell damage at 300 nm. The purpose of the study was to determine the time evolution of apoptosis in the cornea after in vivo exposure to 300-nm UVR. Altogether, 16 Sprague Dawley rats were divided into 4 groups and unilaterally exposed to 5 kJ/m UVR (λmax: 300 nm; λ0.5: 10 nm) for 15 minutes. After a predetermined latency period of 1, 5, 24, and 120 hours, depending on the group, the animals were killed and eyes were enucleated. Eye globes were further cryosectioned in 10-μm thick midsagittal sections. For the detection of apoptosis, the TUNEL method was applied. TUNEL-positive signals were observed in the superficial epithelial cells in the exposed and control eyes at all latency periods. At 5 hours, TUNEL staining was detected in the exposed corneas in epithelial cells, keratocytes, and endothelial cells with a maximum signal at 24 hours. At 120 hours, no TUNEL staining was found in endothelial cells and only occasionally in keratocytes in exposed corneas. Signs of ulceration and stromal thinning were observed at 120 hours. UVR in the 300-nm wavelength region induces TUNEL staining in all 3 corneal layers. TUNEL staining of all 3 corneal layers is an early postexposure event observed after a 5-hour latency period. Corneal sterile keratolysis occurs in the time window of 24 to 120 hours probably induced by neutrophils.


Medical decision making in antipsychotic drug choice for schizophrenia.
The influence of patient and physician variables on antipsychotic drug choice for patients with schizophrenia was assessed. Interviews with 100 psychiatrists on drug choice for 200 patients suffering from schizophrenia were conducted. Data were analyzed by using multiple logistic regression. Older physicians were up to five times more likely to prescribe first-generation antipsychotics. Patient variables did not influence treatment decisions significantly. There is an urgent need for more research on clinical decision making and quality management.


Mucosal and hormonal adaptations after Roux-en-Y gastric bypass.
The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.


Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome.
Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected P<0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8+ T cells, CD4+ T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R, FASLG, and CCL18; P<5.9×10-4), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (Penrichment≤1×10-5). Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.


Antimicrobial Resistance in Africa-How to Relieve the Burden on Family Farmers.
Although currently available data indicate that Africa has the lowest usage of antimicrobials in animals in the world (adjusted by animal biomass), data show a high prevalence of antimicrobial resistance in foodborne pathogens isolated from animals and animal products. Apart from the lack of solid data on antimicrobial use in many countries in Africa, different hypotheses could explain this situation. Qualitative interviews of farmers show a lack of knowledge and uninformed use of antimicrobials. Considering the development of animal farming to meet an increasing demand for proteins, this deficiency represents a serious public health issue. We advocate for policies that consider the specific challenges faced by family farmers in Africa, to simultaneously improve access to veterinary drugs while strengthening the regulation of their use. We propose a global approach targeting the agri-food system, offering innovative social and technical interventions on antimicrobial usage, adapted to family farmers.


Efficacy of chlorhexidine rinses after periodontal or implant surgery: a systematic review.
Biofilm management and infection control are essential after periodontal and implant surgery. In this context, chlorhexidine (CHX) mouth-rinses are frequently recommended post-surgically. Despite its common use and many studies in this field, a systematic evaluation of the benefits after periodontal or implant surgery is-surprisingly-still missing. To evaluate the benefits of chlorhexidine rinsing after periodontal or implant surgery in terms of plaque and inflammation reduction potential. Furthermore, to screen whether the concentration changes or additives in CHX solutions reduce side effects associated with its use. A systematic literature search was performed for clinical trials, which compared CHX rinsing after periodontal or implant surgery with rinsing using placebo, non-staining formulations, or solutions with reduced concentrations of the active compound. Four databases (Medline, PubMed, Embase, Cochrane) were searched up to June 2018. Two reviewers independently identified and screened the literature. From 691 titles identified, only eleven publications met the inclusion criteria and were finally included. Mainly early publications assessed the benefits of CHX over placebo rinsing, whereas more recent publications focused more on the evaluation of new formulations with regard to effectiveness and side effects. The use of CHX after surgery showed in general significant reduction in plaque (means of 29-86% after 1 week) and bleeding (up to 73%) as compared to placebo. No consensus, however, was found regarding the most beneficial CHX formulation avoiding side effects. Chlorhexidine rinsing helps to reduce biofilm formation and gingival inflammation after surgery. However, no additional reduction of periodontal probing depth over any given placebo or control solution could be found irrespective of whether CHX was used or not. The use of additives such as antidiscoloration systems (ADS) or herbal extracts may reduce side effects while retaining efficacy. Within the limitations of this review, it can be concluded that CHX may represent a valuable chemo-preventive tool immediately after surgery, during the time period in which oral hygiene capacity is compromised. To reduce the side effects of CHX and maintain comparable clinical effects, rinsing with less concentrated formulations (e.g., 0.12%) showed the most promising results so far.


Haplotype frequency estimation error analysis in the presence of missing genotype data.
Increasingly researchers are turning to the use of haplotype analysis as a tool in population studies, the investigation of linkage disequilibrium, and candidate gene analysis. When the phase of the data is unknown, computational methods, in particular those employing the Expectation-Maximisation (EM) algorithm, are frequently used for estimating the phase and frequency of the underlying haplotypes. These methods have proved very successful, predicting the phase-known frequencies from data for which the phase is unknown with a high degree of accuracy. Recently there has been much speculation as to the effect of unknown, or missing allelic data - a common phenomenon even with modern automated DNA analysis techniques - on the performance of EM-based methods. To this end an EM-based program, modified to accommodate missing data, has been developed, incorporating non-parametric bootstrapping for the calculation of accurate confidence intervals. Here we present the results of the analyses of various data sets in which randomly selected known alleles have been relabelled as missing. Remarkably, we find that the absence of up to 30% of the data in both biallelic and multiallelic data sets with moderate to strong levels of linkage disequilibrium can be tolerated. Additionally, the frequencies of haplotypes which predominate in the complete data analysis remain essentially the same after the addition of the random noise caused by missing data. These findings have important implications for the area of data gathering. It may be concluded that small levels of drop out in the data do not affect the overall accuracy of haplotype analysis perceptibly, and that, given recent findings on the effect of inaccurate data, ambiguous data points are best treated as unknown.


Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid syndrome? A randomized, double-blind, placebo-controlled trial.
Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.


Determination of gibberellic acid residues on fruits by synchronous scanning derivative spectrofluorometry.
A synchronous derivative spectrofluorometric method is described for the determination of the plant growth regulator, gibberellic acid (GA3). The method is based on the formation of a fluorogen in concentrated sulfuric acid. The reaction is carried out at 85% sulfuric acid and in aqueous medium. The common fluorometric method with a linear dynamic range of 137-400 ppb, and a detection limit of 48 ppb is described. The synchronous first and second derivative method has linear dynamic ranges between 7.6-40 ppb and 12-40 ppb, with detection limits of 3.5 and 6.7 ppb, respectively. The influence of reaction variables and of other plant growth regulators present, and the application to residues on oranges, lemons, and grapes, are also described.