Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation.
Kallistatin is an inhibitor of tissue kallikrein and also inhibits the Wnt pathway. Its role in diabetic nephropathy (DN) is uncertain. Here we reported that serum kallistatin levels were significantly increased in diabetic patients with DN compared to those in diabetic patients without DN and healthy controls, and positively correlated with urinary albumin excretion. In addition, renal kallistatin levels were significantly upregulated in mouse models of type 1 (Akita, OVE26) and type 2 diabetes (db/db). To unveil the effects of kallistatin on DN and its underlying mechanism, we crossed transgenic mice overexpressing kallistatin with OVE26 mice (KS-tg/OVE). Kallistatin overexpression exacerbated albuminuria, renal fibrosis, inflammation, and oxidative stress in diabetes. Kallikrein activity was inhibited while the renin-angiotensin system (RAS) upregulated in the kidney of KS-tg/OVE mice compared to WT/OVE mice, suggesting a disturbed balance between the RAS and kallikrein-kinin systems. As shown by immunostaining of endothelial makers, renal vascular densities were decreased accompanied by increased HIF-1α and erythropoietin levels in the kidneys of KS-tg/OVE mice. Taken together, high levels of kallistatin exacerbate DN at least partly by inducing RAS overactivation and hypoxia. The present study demonstrated a positive correlation between kallistatin levels and DN, suggesting a potential biomarker for prognosis of DN.


Knowledge and self-care practices regarding diabetes among patients with Type 2 diabetes in Rural Sullia, Karnataka: A community-based, cross-sectional study.
Diabetes is a lifestyle disease which requires a multipronged approach for its management, wherein patient has an important role to play in terms of self-care practices, which can be taught to them by educational programs. To develop such an educational program, a baseline assessment of knowledge and self-care practices of patients, needs to be made. The two objectives of the study were to estimate the knowledge of diabetic patients regarding the disease and its complications, and to estimate the knowledge and adherence to self-care practices concerned with Type 2 diabetes mellitus. The study was conducted in rural Sullia, Karnataka, from January 2014 to May 2015. The sample size was calculated to be 400, and the sampling method was probability proportionate to sampling size. Majority of them were married males of Hindu religion and belonged to upper middle class. Only 24.25% of them had good knowledge. Among the self-care practices, foot care was the most neglected area. Only one-fourth of the study population had a good knowledge toward diabetes. Adherence to some of the self-care practices was also poor. Government policies may help in creating guidelines on diabetes management, funding community programs for public awareness, availability of medicines, and diagnostic services to all sections of the community. Continuing education programs for health-care providers and utilization of mass media to the fullest potential may also help in creating awareness.


The female inferior hypogastric (= pelvic) plexus: anatomical and radiological description of the plexus and its afferences--applications to pelvic surgery.
We wanted to determine the anatomical features of the inferior hypogastric plexus (IHP), and the useful landmarks for a safe surgical approach during pelvic surgery. We dissected the IHP in 22 formolized female anatomical subjects, none of which bore any stigmata of subumbilical surgery. The inferior hypogastric plexus (IHP) is a triangle with a posterior base and an anterior inferior top. It can be described as having three edges and three angles; its inferior edge stretches constantly from the fourth sacral root to the ureter's point of entry into the posterior layer of the broad ligament; its cranial edge is strictly parallel to the posterior edge of the hypogastric artery, along which it runs at a distance of 10 mm; its posterior (dorsal) edge is at the point of contact with the sacral roots, from which it receives its afferences. They most frequently originate from S3 or S4 (60%) and then, in one or two branches, often from S2 (40%), never from S1 and in exceptional cases from S5 (20%). There are sympathetic afferences in 30% of cases, usually through a single branch of the second, third or fourth sacral ganglion. All IHPs have at least one sacral afference and sometimes there may be up to three afferences from the same sacral root. Its dorsal cranial angle, which is superior, comes after the SHP (hypogastric nerve or presacral nerve filament); its anterior inferior angle is located exactly at the ureter's point of entry into the posterior layer of the broad ligament. This is the top of the IHP; its posterior inferior angle is located at the point of contact with the fourth sacral root. At its entrance at the base of the parametrium the pelvic ureter is the anterior, fundamental positional reference for the IHP. The vaginal efferences come out of the top of the IHP through branches leading to the bladder, the vagina and the rectum, which originate through two trunks exactly underneath the crossing point of the ureter and the uterine artery: (i) one trunk leading to the bladder runs along and underneath the ureter and divides into two groups, which are lateral and medial, trigonal. (ii) the trunk leading to the vagina runs along the inferior edge of the uterine artery. At the point of contact with the lateral edge of the vagina, it splits into two groups: anterior thin and posterior voluminous. Some of its branches perforate the posterior wall of the vagina and are distributed to the rectovaginal septum in a tooth comb pattern. The inferior branches, which emerge from the inferior edge of the IHP, reach the rectum directly. The dissection of the 22 specimens allowed us to describe three efferent plexuses: a vaginal rectal plexus, a vesical plexus and a inferior rectal plexus. So the IHP's anterior, fundamental positional reference is the pelvic ureter at the point where it enters at the base of the parametrium, then at the crossing point of the uterine artery. The ureter is the vector for vesical efferences, the uterine artery is the vector for vaginal efferences, which are thus sent into the vesicovaginal septum and the rectovaginal septum. This surgical point of reference is of vital importance in nerve sparing during the course of a simple or extended hysterectomy. Any dissection carried out underneath and outside of the ureter inevitably carries a risk of lesions to its efferent, lateral vesical or medial, rectovaginal fibres.


Untangling the R2* contrast in multiple sclerosis: A combined MRI-histology study at 7.0 Tesla.
T2*-weighted multi-echo gradient-echo magnetic resonance imaging and its reciprocal R2* are used in brain imaging due to their sensitivity to iron content. In patients with multiple sclerosis who display pathological alterations in iron and myelin contents, the use of R2* may offer a unique way to untangle mechanisms of disease. Coronal slices from 8 brains of deceased multiple sclerosis patients were imaged using a whole-body 7.0 Tesla MRI scanner. The scanning protocol included three-dimensional (3D) T2*-w multi-echo gradient-echo and 2D T2-w turbo spin echo (TSE) sequences. Histopathological analyses of myelin and iron content were done using Luxol fast blue and proteolipid myelin staining and 3,3'-diaminobenzidine tetrahydrochloride enhanced Turnbull blue staining. Quantification of R2*, myelin and iron intensity were obtained. Variations in R2* were found to be affected differently by myelin and iron content in different regions of multiple sclerosis brains. The data shall inform clinical investigators in addressing the role of T2*/R2* variations as a biomarker of tissue integrity in brains of MS patients, in vivo.


Effects of culture density on the kinetics of germ tube formation in Candida albicans.
The relationship between culture density or phase of growth at 24.5 degrees C and the ability of Candida albicans to form germ tubes when shifted to 37 degrees C was investigated. Evidence is presented demonstrating germ tube production from liquid synthetic medium cultures at all phases of growth. Previous studies reported that only cells from stationary phase cultures were competent to form germ tubes. Comparisons between exponential and stationary phase cultures indicate more rapid and more synchronous germ tube production from cells growing in the exponential phase.


Optimization of confocal laser induced fluorescence in a plasma.
Laser Induced Fluorescence (LIF) provides measurements of flow speed, temperature, and density of ions or neutrals in a plasma. Traditionally, a LIF measurement requires two ports on a plasma device; one for laser injection and one for emission collection. Proper alignment of LIF optics is time consuming and sensitive to mechanical vibration. We describe a confocal configuration for LIF that requires a single port and requires no alignment. The measurement location is scanned radially by physically moving the entire optical structure. Confocal LIF measurements are compared to traditional LIF measurements over the same radial range.


Transient Focal Neurologic Symptoms Correspond to Regional Cerebral Hypoperfusion by MRI: A Stroke Mimic in Children.
Children who present with acute transient focal neurologic symptoms raise concern for stroke or transient ischemic attack. We present a series of 16 children who presented with transient focal neurologic symptoms that raised concern for acute stroke but who had no evidence of infarction and had unilateral, potentially reversible imaging features on vascular and perfusion-sensitive brain MR imaging. Patients were examined with routine brain MR imaging, MRA, perfusion-sensitive sequences, and DWI. Fourteen (88%) children had lateralized MRA evidence of arterial tree pruning without occlusion, all had negative DWI findings, and all showed evidence of hemispheric hypoperfusion by susceptibility-weighted imaging or arterial spin-labeling perfusion imaging at presentation. These findings normalized following resolution of symptoms in all children who had follow-up imaging (6/16, 38%). The use of MR imaging with perfusion-sensitive sequences, DWI, and MRA can help to rapidly distinguish children with conditions mimicking stroke from those with acute stroke.


Inhibition kinetics and affinity labeling of bacterial squalene:hopene cyclase by thia-substituted analogues of 2, 3-oxidosqualene.
Five sulfur-containing analogues of 2,3-oxidosqualene (OS) were evaluated as inhibitors of squalene:hopene cyclase (SHC) from Alicyclobacillus acidocaldarius. In these analogues, sulfur replaces carbons at C-6, C-10, C-14, C-18, or C-19 of OS. Each analogue was a submicromolar inhibitor of SHC with IC50 values ranging from 60 to 570 nM. Enzyme inhibition kinetic analysis was performed using homogeneous recombinant A. acidocaldarius SHC. While analogues 9 (S-14, Ki = 109 nM, kinact = 0.058 min-1) and 11 (S-19, Ki = 83 nM, kinact = 0.054 min-1) were time-dependent inhibitors of SHC, analogues 7 (S-6, Ki = 127 nM) and 8 (S-10, Ki = 971 nM) showed no time dependency with SHC. Analogue 10 (S-18) was the most potent inhibitor and showed time-dependent irreversible inhibition (Ki = 31 nM, kinact = 0.071 min-1). Kinetic analysis for the five analogues with purified rat liver OSLC was conducted to compare the vertebrate and prokaryotic enzymes. Affinity labeling experiments, using either [17-3H]10 or [22-3H]10 with crude and with pure recombinant SHC, clearly showed specific labeling. A single major radioactive band at 72 kDa on SDS-PAGE indicated that irreversible covalent modification of SHC had occurred. These results suggest that the presence of sulfur at C-18 of OS can interrupt the cyclization and that an intermediate partially cyclized cation may be captured by a nucleophilic residue of the SHC active site.


High Glucose Induces Mitochondrial Dysfunction in Retinal Müller Cells: Implications for Diabetic Retinopathy.
To investigate whether high glucose (HG) induces mitochondrial dysfunction and promotes apoptosis in retinal Müller cells. Rat retinal Müller cells (rMC-1) grown in normal (N) or HG (30 mM glucose) medium for 7 days were subjected to MitoTracker Red staining to identify the mitochondrial network. Digital images of mitochondria were captured in live cells under confocal microscopy and analyzed for mitochondrial morphology changes based on form factor (FF) and aspect ratio (AR) values. Mitochondrial metabolic function was assessed by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a bioenergetic analyzer. Cells undergoing apoptosis were identified by differential dye staining and TUNEL assay, and cytochrome c levels were assessed by Western blot analysis. Cells grown in HG exhibited significantly increased mitochondrial fragmentation compared to those grown in N medium (FF = 1.7 ± 0.1 vs. 2.3 ± 0.1; AR = 2.1 ± 0.1 vs. 2.5 ± 0.2; P < 0.01). OCR and ECAR were significantly reduced in cells grown in HG medium compared to those grown in N medium (steady state: 75% ± 20% of control, P < 0.02; 64% ± 22% of control, P < 0.02, respectively). These cells also exhibited a significant increase (∼2-fold) in the number of apoptotic cells compared to those grown in N medium (P < 0.01), with a concomitant increase in cytochrome c levels (247% ± 94% of control, P < 0.05). Findings indicate that HG-induced mitochondrial morphology changes and subsequent mitochondrial dysfunction may contribute to retinal Müller cell loss associated with diabetic retinopathy.


Culturally-tailored interventions for chronic disease self-management among Chinese Americans: a systematic review.
Objectives: Literature review evaluating the effectiveness and cultural surface and deep structures of interventions designed to improve Chinese Americans' chronic disease self-management.Method: PubMed, PsycINFO, CINAHL, and Health Source databases were searched for research conducted from 1990 to 2016 on self-management interventions for Chinese Americans with chronic disease.Results: Ten articles comprised eight interventions, which each addressed a dimension of cultural surface structure, all providing linguistically appropriate messages delivered via bilingual staff. Five interventions also addressed cultural deep structure dimensions by providing culturally congruent counsellors or educators, or incorporating Chinese cultural values and social customs. Six interventions resulted in significant improvements in major outcome variables. Participants also reported high satisfaction and retention rates were high.Conclusion: Culturally-tailored interventions that incorporate surface and deep structural elements of culture are sensitive and generally effective for Chinese Americans to improve access to health care, disease awareness, social environment, and participants' ability to practice self-management skills.


Global media framing, COVID-19 and the issue of vaccination: An empirical inquisition.
Background: This study examined global media framing on issues of vaccination for COVID-19. The framing and media dependency theories were used to understand the potential influence of global media outlets as suppliers of health messages during pandemics. Methods: Content analysis was used to generate qualitative and quantitative data to answer the research questions. The qualitative data provided rich descriptive data about the themes and types of news frames on issues of vaccination for COVID-19, while the quantitative data provided statistical details about the frequency, viewership level and types of news frames on issues of vaccination for COVID-19. Results: The findings of this study showed that conflict and responsibility frames were the predominant frames used to report issues of vaccination for COVID-19. Also, the findings of this study indicated that vaccine safety was the overriding media theme on vaccination issue for COVID-19. Conclusion: The global media serve as suppliers of health communication in developed and developing countries. This study recommended that the global media can spearhead an information campaign to correct misconceptions, misrepresentations and misinformation on issues of vaccination for COVID-19.


Benzodiazepines II: Waking Up on Sedatives: Providing Optimal Care When Inheriting Benzodiazepine Prescriptions in Transfer Patients.
This review discusses risks, benefits, and alternatives in patients already taking benzodiazepines when care transfers to a new clinician. Prescribers have the decision-sometimes mutually agreed-upon and sometimes unilateral-to continue, discontinue, or change treatment. This decision should be made based on evidence-based indications (conditions and timeframes), comorbidities, potential drug-drug interactions, and evidence of adverse effects, misuse, abuse, dependence, or diversion. We discuss management tools involved in continuation (e.g., monitoring symptoms, laboratory testing, prescribing contracts, state prescription databases, stages of change) and discontinuation (e.g., tapering, psychotherapeutic interventions, education, handouts, reassurance, medications to assist with discontinuation, and alternative treatments).


Breakpoint chlorination curves of greywater.
A study on chlorination of raw greywater with hypochlorite is reported in this paper. Samples were chlorinated in a variety of conditions, and residual chlorine (Cl2) was measured spectrophotometrically. For each sample, the chlorination curve (chlorine residuals versus chlorine dose) was obtained. Curves showed the typical hump-and-dip profile attributable to the formation and destruction of chloramines. It was observed that, after reactions with strong reductants and chloramines-forming compounds, the remaining organic matter exerted a certain demand of chlorine. The evolution of chlorination curves with addition of ammonia and dodecylbencene sulfonate sodium salt and with dilution of the greywater sample were studied. In addition, chlorination curves at several contact times have been obtained, resulting in slower chlorine decay in the hump zone than in the dip zone. In addition, the decay of coliforms in chlorinated samples was also investigated. It was found that, for a chlorination dosage corresponding to the maximum of the hump zone (average 8.9 mg Cl2/ L), samples were negative in coliforms after 10 to 30 minutes of contact time. After-growth was not observed within 3 days after chlorination. Implications in chlorination treatments of raw greywater can be derived from these results.


Creating groups with similar expected behavioural response in randomized controlled trials: a fuzzy cognitive map approach.
Controlling bias is key to successful randomized controlled trials for behaviour change. Bias can be generated at multiple points during a study, for example, when participants are allocated to different groups. Several methods of allocations exist to randomly distribute participants over the groups such that their prognostic factors (e.g., socio-demographic variables) are similar, in an effort to keep participants' outcomes comparable at baseline. Since it is challenging to create such groups when all prognostic factors are taken together, these factors are often balanced in isolation or only the ones deemed most relevant are balanced. However, the complex interactions among prognostic factors may lead to a poor estimate of behaviour, causing unbalanced groups at baseline, which may introduce accidental bias. We present a novel computational approach for allocating participants to different groups. Our approach automatically uses participants' experiences to model (the interactions among) their prognostic factors and infer how their behaviour is expected to change under a given intervention. Participants are then allocated based on their inferred behaviour rather than on selected prognostic factors. In order to assess the potential of our approach, we collected two datasets regarding the behaviour of participants (n = 430 and n = 187). The potential of the approach on larger sample sizes was examined using synthetic data. All three datasets highlighted that our approach could lead to groups with similar expected behavioural changes. The computational approach proposed here can complement existing statistical approaches when behaviours involve numerous complex relationships, and quantitative data is not readily available to model these relationships. The software implementing our approach and commonly used alternatives is provided at no charge to assist practitioners in the design of their own studies and to compare participants' allocations.


Comparing methods to predict baseline mortality for excess mortality calculations.
The World Health Organization (WHO)'s excess mortality estimates presented in May 2022 stirred controversy, due in part to the high estimate provided for Germany, which was later attributed to the spline model used. This paper aims to reproduce the problem using synthetic datasets, thus allowing the investigation of its sensitivity to parameters, both of the mortality curve and of the used method, thereby shedding light on the conditions that gave rise to this error and identifying possible remedies. A negative binomial model was used accounting for long-term change, seasonality, flu seasons, and heat waves. Simulated mortality curves from this model were then analysed using simple methods (mean, linear trend), the WHO method, and the method of Acosta and Irizarry. The performance of the WHO's method with its original parametrization was indeed very poor, however it can be profoundly improved by a better choice of parameters. The Acosta-Irizarry method outperformed the WHO method despite being also based on splines, but it was also dependent on its parameters. Linear extrapolation could produce very good results, but was highly dependent on the choice of the starting year, while the average was the worst in almost all cases. Splines are not inherently unsuitable for predicting baseline mortality, but caution should be taken. In particular, the results suggest that the key issue is that the splines should not be too flexible to avoid overfitting. Even after having investigated a limited number of scenarios, the results suggest that there is not a single method that outperforms the others in all situations. As the WHO method on the German data illustrates, whatever method is chosen, it remains important to visualize the data, the fit, and the predictions before trusting any result. It will be interesting to see whether further research including other scenarios will come to similar conclusions.


Regioselective synthesis, biological evaluation, and molecular docking of dihydropyrimidin-4-ols as acetylcholinesterase inhibitors.
A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4-fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC50 2.2 ± 0.9 μm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π-π stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated.


Reduction of genetic diversity in 'Alalā (Hawaiian crow; Corvus hawaiiensis) between the late 1800s and the late 1900s.
Genetic and genomic data are increasingly used to aid conservation management of endangered species by providing insights into evolutionary histories, factors associated with extinction risks, and potential for future adaptation. For the 'Alalā, or Hawaiian crow (Corvus hawaiiensis), genetic concerns include negative correlations between inbreeding and hatching success. However, it is unclear if low genetic diversity and inbreeding depression are consequences of a historical population bottleneck, or if 'Alalā had historically low genetic diversity that predated human influence, perhaps as a result of earlier declines or founding events. In this study, we applied a hybridization-based sequence capture to generate a genome-wide single nucleotide polymorphism (SNP) dataset for comparing historical specimens collected in the 1890s, when 'Alalā were more numerous, to samples taken between 1973 and 1998, when 'Alalā population densities were near the lowest documented levels in the wild, prior to all individuals being collected for captive rearing. We found low genome-wide diversity in both sample groups, however, the modern sample group (1973-1998 cohort) exhibited relatively fewer polymorphic alleles, a lower proportion of polymorphic loci, and lower observed heterozygosity, consistent with a population decline and potential bottleneck effects. These results combined with a current low population size highlight the importance of continued efforts by conservation managers to mitigate inbreeding and maintain founder representation to preserve what genetic diversity remains.


Utilization of agricultural residues for poly(3-hydroxybutyrate) production by Halomonas boliviensis LC1.
Utilization of cheap and readily available agricultural residues as cheap carbon sources for poly(3-hydroxybutyrate) (PHB) production by Halomonas boliviensis. Wheat bran was hydrolysed by a crude enzyme preparation from Aspergillus oryzae NM1 to provide a mixture of reducing sugars composed mainly of glucose, mannose, xylose and arabinose. Growth of H. boliviensis using a mixture of glucose (0.75% w/v) and xylose (0.25% w/v) in the medium led to a PHB content and concentration of 45 wt% and 1 g l(-1), respectively, after 30 h. A similar PHB concentration was attained when H. boliviensis was grown on wheat bran hydrolysate but with a lower PHB content, 34 wt%. In a batch cultivation mode in a fermentor, using 1.8% (w/v) reducing sugars, the maximum PHB accumulation by H. boliviensis was attained in 20 h, but was reduced to about 30 wt%. By adding butyric acid (0.8% v/v), sodium acetate (0.8% w/v) and decreasing the reducing sugars concentration to 1 x 0% w/v in the medium, PHB accumulation and concentration were increased to 50 wt% and 4 g l(-1), respectively, after 20 h. Butyric acid and sodium acetate for PHB production could also be provided by anaerobic digestion of solid potato waste. Cheap and readily available agricultural residues can be used as substrates to produce PHB. The production of PHB by H. boliviensis using wheat bran hydrolysate as source of carbon is expected to reduce the production cost and motivates further studies. Large-scale commercial utilization of PHB is mainly hampered by its high production cost. Carbon source for PHB production accounts up to 50% of the total production costs. Thus, the use of waste agricultural residues can substantially reduce the substrate cost (and in turn even provide value to the waste), and can downsize the production costs. This improves the market competitiveness. Studies on PHB production by moderate halophiles were recently initiated with H. boliviensis and findings show that it has potential for commercial exploitation. PHB production by H. boliviensis using wheat bran and potato waste is hence interesting.


lncRNA-ES3/miR-34c-5p/BMF axis is involved in regulating high-glucose-induced calcification/senescence of VSMCs.
Vascular calcification/aging is common in diabetes and is associated with increased morbidity and mortality of patients. MiR-34c-5p, not miR-34c-3p, was suppressed significantly in calcification/senescence of human aorta vascular smooth muscle cells (HA-VSMCs) induced by high glucose, which was proven by the formation of mineralized nodules and staining of senescence associated-β-galactosidase staining (SA β-gal) positive cells. Overexpression of miR-34c-5p alleviated calcification/senescence of HA-VSMCs, whereas inhibition of miR-34c-5p received the opposite results. Bcl-2 modifying factor (BMF) was a functional target of miR-34c-5p and it was involved in the process of calcification/senescence of HA-VSMCs. Besides, lncRNA-ES3 acted as a competing endogenous RNAs (ceRNA) of miR-34c-5p to enhance BMF expression. Further, lncRNA-ES3 inhibited miR-34c-5p expression by direct interaction and its knockdown suppressed the calcification/senescence of HA-VSMCs. Our results showed for the first time that the calcification/senescence of VSMCs was regulated by lncRNA-ES3 /miR-34c-5p/BMF axis.


Transthoracic aspiration cytology of pulmonary lesions.
In a seven-year period (1974 to 1981), 1,390 patients had transthoracic aspiration biopsy for radiologically suspected pulmonary neoplasms. Of the 1,209 proven malignant neoplasms, 1,059 (88%) were cytologically diagnosed as malignant. There were only two (0.2%) false-positive diagnoses both due to florid bronchoalveolar hyperplasia associated with granulomatous disease. Cytologic and histologic correlations for primary lung cancers were 92% for adenocarcinoma, 87% for oat cell (small cell) carcinoma, and 83% for epidermoid carcinoma. Characteristic cytomorphology of pulmonary carcinomas, some metastatic neoplasms, and inflammatory lesions are described.


The association between a statewide stay-at-home order and motor vehicle injury rates among population sub-groups in West Virginia.
Little is known about the relationship between Stay-At-Home orders issued by state governments due to the COVID-19 pandemic and their impacts on motor vehicle-related injuries. The purpose of this study was to determine whether the presence of a Stay-At-Home order was associated with lower rates of motor vehicle-related injuries requiring emergency medical treatment among population sub-groups in West Virginia (i.e., males, females, 0-17, 18-25, 26-45, 46-65, ≥66 years old). A Stay-At-Home order was in effect in West Virginia from March 23-May 4, 2020. Counts of individuals who incurred motor-vehicle-related injuries that required emergency medical treatment were obtained from the Centers for Disease Control and Prevention's National Syndromic Surveillance Program from January 1 thru September 6 of 2019 and 2020. Counts were obtained by week-year and by population sub-group in West Virginia. The presence of the Stay-At-Home order was binary coded by week. Negative binomial regression was used to assess the relationship between the presence of a Stay-At-Home and injury rates. 2019 population sub-group estimates were obtained from the United States Census Bureau and used as offsets in the models. Models were also adjusted for year and vehicle miles traveled by week-year. There were 23,418 motor-vehicle related injuries during the study period. The presence of the Stay-At-Home order was associated with 44% less injuries overall [Incident Rate Ratio (IRR)=0.56, 95% CI 0.48, 0.64]. Females experienced fewer injuries than males (IRR = 0.49 vs 0.63, respectively) and the number of injuries decreased with age (p-value 0.031) when comparing time periods when the Stay-At-Home was in effect compared to times when it was not. West Virginia's Stay-At-Home order was associated with lower motor-vehicle injury rates requiring medical treatment across all population sub-groups. Most population sub-groups likely altered their travel behaviors which resulted in lower motor-vehicle injury rates. These findings may inform future policies that impose emergency travel restrictions in populations.


Ferrocene and cobaltocene derivatives for non-aqueous redox flow batteries.
Ferrocene and cobaltocene and their derivatives are studied as new redox materials for redox flow cells. Their high reaction rates and moderate solubility are attractive properties for their use as active materials. The cyclability experiments are carried out in a static cell; the results showed that these materials exhibit stable capacity retention and predictable discharge potentials, which agree with the potential values from the cyclic voltammograms. The diffusion coefficients of these materials are 2 to 7 times higher than those of other non-aqueous materials such as vanadium acetylacetonate, iron tris(2,2'-bipyridine) complexes, and an organic benzene derivative.


The yydFGHIJ operon of Bacillus subtilis encodes a peptide that induces the LiaRS two-component system.
The Bacillus subtilis LiaRS two-component system (TCS) responds to perturbations of the cell envelope induced by lipid II-interacting antibiotics, such as vancomycin, ramoplanin, nisin, and bacitracin. Here, we characterize Tn7-generated mutations that induce the liaRS TCS. In addition to insertions in liaF, a known negative regulator of the LiaRS TCS, we identified two disruptions in the last two genes of the yydFGHIJ operon. This operon is predicted to encode a 49-amino-acid peptide (YydF), a modification enzyme (YydG), a membrane-embedded protease (YydH), and an ATP-binding cassette (ABC) transporter (YydIJ). Genome sequence comparisons suggest that the yydFGHIJ operon may have been acquired by horizontal transfer. Inactivation of the YydIJ transporter resulted in increased expression from the LiaR-dependent P(liaI) promoter only in the presence of the yydFGH genes. Cells harboring the complete yydFGHIJ operon induced LiaR activity in cocultured cells lacking either this transporter or the complete operon. These results suggest that this operon is involved in the synthesis and export of a modified peptide (YydF*) that elicits cell envelope stress sensed by the LiaRS TCS.


Interpretation of microbial bioassays using kinetic parameters.
A method analogous to that used for enzyme kinetics was applied to estimate maximum growth rates and oxygen depletion rates as measures of microbial toxicity. Selected toxicants including phenol, formalin and CuSO4 were tested against an axenic culture of E. coli and a mixed culture derived from soil to determine reproducibility of the test procedures. Optical density was used as a measure of growth over time. Oxygen uptake over a short term (less than 20 min.) and over extended time (greater than 4 hrs.) was also monitored. Microbial growth rate constants (g) and oxygen depletion rate constants (k) were calculated and the EC50 values for toxicity were taken as one half the maximum growth rate or oxygen depletion rates, respectively. The method proved a reasonable and reliable measure of toxicity.


Acute retrobulbar optic neuritis and macular detachment associated with morning glory optic disc anomaly.
A 31-year-old woman with morning glory optic disc anomaly (MGDA) developed acute retrobulbar optic neuritis and a bullous macular detachment. MRI demonstrated truncation of the perineural space of the affected optic nerve as well as focal optic nerve enhancement. Optical coherence tomography (OCT) showed retinoschisis associated with the macular detachment. The MRI and OCT findings support the vitreous as the source of the subretinal fluid. This is the first reported case of optic neuritis in MGDA.


Current knowledge and availability of machine learning across the spectrum of trauma science.
Recent technological advances have accelerated the use of Machine Learning in trauma science. This review provides an overview on the available evidence for research and patient care. The review aims to familiarize clinicians with this rapidly evolving field, offer perspectives, and identify existing and future challenges. The available evidence predominantly focuses on retrospective algorithm construction to predict outcomes. Few studies have explored actionable outcomes, workflow integration, or the impact on patient care. Machine Learning and data science have the potential to simplify data capture and enhance counterfactual causal inference research from observational data to address complex issues. However, regulatory, legal, and ethical challenges associated with the use of Machine Learning in trauma care deserve particular attention. Machine Learning holds promise for actionable decision support in trauma science, but rigorous proof-of-concept studies are urgently needed. Future research should assess workflow integration, human-machine interaction, and, most importantly, the impact on patient outcome. Machine Learning enhanced causal inference for observational data carries an enormous potential to change trauma research as complement to randomized studies. The scientific trauma community needs to engage with the existing challenges to drive progress in the field.


d-Amino Acid Position Influences the Anticancer Activity of Galaxamide Analogs: An Apoptotic Mechanism Study.
Galaxamide, an extract from Galaxaura filamentosa, is a cyclic pentapeptide containing five l-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present work, we synthesized six Galaxamide analogs by replacing one of the l-leucines with phenylalanine and varying the d-amino acid position. The anticancer effect of the synthesized Galaxamide analogs was tested against four in vitro human cancer cell lines, human hepatocellular cells (HepG₂), human breast cancer cell (MCF-7), human breast adenocarcinoma cells (MDA-MB-435) and a human cervical carcinoma cell line (Hela). Results showed that Galaxamide analogs with different d-amino acid positions displayed distinct anticancer potential. The Galaxamide analog containing d-amino acid at position 5 (Analog-6) presented the strongest anticancer activity. The mechanism study revealed that Analog-6 could cause the early apoptosis of HepG₂ cells by inhibiting their growth in the sub-G1 stage of the cell cycle and induce the chromatin condensation and fragmentation, which can be seen as 68% of HepG₂ cells inhibited in the sub-G1 stage. Moreover, a mitochondria-mediated pathway was found to be involved in the apoptotic process of Analog-6 on HepG₂ cells.


Mössbauer study of the three-coordinate planar Fe(II) thiolate complex [Fe(SR)(3)](-) (R = C(6)H(2)-2,4,6-tBu(3)): model for the trigonal iron sites of the MoFe(7)S(9):homocitrate cofactor of nitrogenase.
The cofactor (M-center) of the MoFe protein of nitrogenase, a MoFe(7)S(9):homocitrate cluster, contains six Fe sites with a (distorted) trigonal sulfido coordination. These sites exhibit unusually small quadrupole splittings, Delta E(Q) approximately 0.7 mm/s, and isomer shifts, delta approximately 0.41 mm/s. Mössbauer and ENDOR studies have provided the magnetic hyperfine tensors of all iron sites in the S = 3/2 state M(N). To assess the intrinsic zero-field splittings and hyperfine parameters of the cofactor sites, we have studied with Mössbauer spectroscopy two salts of the three-coordinated Fe(II) thiolate complex [Fe(SR)(3)](-) (R = C(6)H(2)-2,4,6-tBu(3)). One of the salts, [Ph(4)P][Fe(SR)(3)] x 2MeCN x C(7)H(8), 1, has a planar geometry with idealized C(3h) symmetry. This S = 2 complex has an axial zero-field splitting with D = +10.2 cm(-1). The magnetic hyperfine tensor components A(x) = A(y) = -7.5 MHz and A(z) = -29.5 MHz reflect an orbital ground state with d(z(2)) symmetry. A(iso) = (A(x) +A(y) +A(z))/3 = -14.9 MHz, which includes the contact interaction (kappa P = -21.9 MHz) and an orbital contribution (+7 MHz), which is substantially smaller than A(iso) approximately -22 MHz of the tetrahedral Fe(II)(S-R)(4) sites of both rubredoxin and [PPh(4)](2)[Fe(II)(SPh)(4)]. The largest component of the electric field gradient (EFG) tensor is negative, as expected for a d(z(2)) orbital. However, Delta E(Q) = -0.83 mm/s, which is smaller than expected for a high-spin ferrous site. This reduction can be attributed to a ligand contribution, which in planar complexes provides a large positive EFG component perpendicular to the ligand plane. The isomer shift of 1, delta = 0.56 mm/s, approaches the delta-values reported for the six trigonal cofactor sites. The parameters of 1 and their importance for the cofactor cluster of nitrogenase are discussed.


Expression of hypoxia-inducible carbonic anhydrases in brain tumors.
Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel-Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-1alpha staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target.


An enteroendocrine cell-based model for a quiescent intestinal stem cell niche.
We have shown that the kinetics of conversion of intestinal crypt cell populations to a partially or wholly mutant phenotype are consistent with a model in which each crypt contains an infrequently dividing 'deep' stem cell that is the progenitor of several more frequently dividing 'proximate' stem cells. An assumption of our model is that each deep stem cell exists in a growth inhibitory niche. We have used information from the literature to develop a model for a quiescent intestinal stem cell niche. This niche is postulated to be primarily defined by an enteroendocrine cell type that maintains stem cell quiescence by secretion of growth inhibitory peptides such as somatostatin and guanylin/uroguanylin. Consistent with this model, there is evidence that the proteins postulated as defining a growth-inhibitory stem cell niche can act as intestinal tumour suppressors. Confirmation that a growth-inhibitory niche does exist would have important implications for our understanding of intestinal homeostasis and tumorigenesis.


Yeast Mon2p is a highly conserved protein that functions in the cytoplasm-to-vacuole transport pathway and is required for Golgi homeostasis.
Although the small Arf-like GTPases Arl1-3 are highly conserved eukaryotic proteins, they remain relatively poorly characterized. The yeast and mammalian Arl1 proteins bind to the Golgi complex, where they recruit specific structural proteins such as Golgins. Yeast Arl1p directly interacts with Mon2p/Ysl2p, a protein that displays some sequence homology to the large Sec7 guanine exchange factors (GEFs) of Arf1. Mon2p also binds the putative aminophospholipid translocase (APT) Neo1p, which performs essential function(s) in membrane trafficking. Our detailed analysis reveals that Mon2p contains six distinct amino acid regions (A to F) that are conserved in several other uncharacterized homologs in higher eukaryotes. As the conserved A, E and F domains are unique to these homologues, they represent the signature of a new protein family. To investigate the role of these domains, we made a series of N- and C-terminal deletions of Mon2p. Although fluorescence and biochemical studies showed that the B and C domains (also present in the large Sec7 GEFs) predominantly mediate interaction with Golgi/endosomal membranes, growth complementation studies revealed that the C-terminal F domain is essential for the activity of Mon2p, indicating that Mon2p might also function independently of Arl1p. We provide evidence that Mon2p is required for efficient recycling from endosomes to the late Golgi. Intriguingly, although transport of CPY to the vacuole was nearly normal in the Deltamon2 strain, we found the constitutive delivery of Aminopeptidase 1 from the cytosol to the vacuole to be almost completely blocked. Finally, we show that Mon2p exhibits genetic and physical interactions with Dop1p, a protein with a putative function in cell polarity. We propose that Mon2p is a scaffold protein with novel conserved domains, and is involved in multiple aspects of endomembrane trafficking.


Kinetic and isothermal studies of lead ion adsorption onto palygorskite clay.
The use of a natural palygorskite clay for the removal of Pb(II) from aqueous solutions for different contact times, pHs of suspension, and amounts and particle sizes of palygorskite clay were investigated. The variations of the pH value of Pb(II) solutions on natural palygorskite in the adsorption process were determined. Batch adsorption kinetic experiments revealed that the adsorption of Pb(II) onto palygorskite clay involved fast and slow processes. It was found that the adsorption mechanisms in the lead/palygorskite system follow pseudo-second-order kinetics with a significant contribution from film diffusion. SEM observations demonstrated that an important interaction at the lead-granule interface occurred during the adsorption process. The adsorption isotherms were described by means of the Langmuir and Freundlich isotherms and the Langmuir model represents the adsorption process better than the Freundlich model. The maximum adsorption capacity of Pb(II) onto natural palygorskite was 104.28 mg g(-1).


Identification of a novel leukemic-specific splice variant of DNMT3B and its stability.
DNA methyltransferases make use of alternative splicing mechanism to generate various splice variants, but their role(s) in modulating DNA methylation patterns in the cells is unclear. Notably, DNMT3B alone contains nearly 40 different splice variants. In this study, we have identified a novel splice variant of DNMT3B, which lacks exon 7 and 10 from leukemic cell lines which we termed as DNMT3B9. The exon 7 codes for the major part of PWWP domain, and exon 10 inclusion serves as a pluripotent marker. By quantitative RT-PCR using exon-exon junction-specific primers, we showed higher level of DNMT3B9 transcripts in several leukemic cell lines. However, DNMT3B9 expression was less in other tested cancer cell lines indicating that DNMT3B9 might serve as a leukemic-specific biomarker. Surprisingly, endogenous protein for DNMT3B9 was not detected in leukemic cells suggesting the unidentified RNA-related function(s) for DNMT3B9. In addition, we showed that DNMT3B9 protein lacks PWWP domain is less stable compared to other DNMT3B variants which contain PWWP domain through computational predictions and by cycloheximide half-life experiment. Taken together, we demonstrated the existence of novel leukemic-specific splice variant of DNMT3B and provide the evidence for the role of PWWP domain in the stability of DNMT3B. The findings reported here have relevance in epigenetic therapy, which is aimed to target the DNMT3B in cancer cells.


Impact of Mineralocorticoid Receptor Antagonists in the Treatment of Heart Failure: Targeting the Heart Failure Cascade.
Epidemiological data from the Indian subcontinent on the burden of Heart failure (HF) is scarce. Mineralocorticoid receptor antagonists (MRAs) are usually used in the management of HF and hypertension. A consortium of experts reviewed and opined on the pathophysiological role of aldosterone in HF and its cascading effects on the heart in terms of cardiac fibrosis, cardiac hypertrophy, and remodeling, increased propensity to cause arrhythmias in addition to its effect on sodium and water retention. This expert opinion document highlights the various mechanisms of action of MRAs. It provides clinical experience and practice-based expert opinion on the use of spironolactone and eplerenone in patients with HF. The role of MRAs in diabetic patients with HF has also been profiled.


Of mothballs and old yellow enzymes.
Polycyclic aromatic hydrocarbons (PAHs) are persistent and toxic environmental pollutants that accumulate in anoxic habitats. With the exception of naphthalene, nothing is known about the microbial degradation of PAH in these environments. The challenge that must be met in anaerobic PAH degradation is the destabilization of the resonance energy of the aromatic ring system, which requires electrons with very negative redox potentials. Estelmann et al. (2014) identify two enzymes from sulphate-reducing bacteria that perform successive 2-electron reductions of a coenzyme A thioester derivative of naphthalene. The first reduces 2-naphthoyl-CoA to 5,6-dihydro-2-naphthoyl-CoA and the second generates 5,6,7,8-tetrahydro-2-naphthoyl-CoA. Surprisingly, both enzymes are members of the 'old yellow enzyme' (OYE) family of flavoproteins. Neither uses adenosine triphosphate to achieve reduction of the aromatic ring. Typically, OYEs have flavin mononucleotide as cofactor and use nicotinamide adenine dinucleotide (phosphate) as reductant. Both ring reductases have flavin adenine dinucleotide and an iron-sulphur cluster as additional cofactors. Evidence also suggests that in the sulphate-reducing bacteria, these enzymes form a complex, allowing substrate channeling. The findings of this superb study represent unprecedented biochemistry. This work sheds light on how microbes meet the thermodynamic challenges of life at the redox limit.


Surgical efficacy and survival prediction of patients with unspecified malignant bone tumors.
The surgical efficacy and prognostic outcomes of patients with unspecific malignant bone tumors (UMBTs) remain unclear. The study is to address: 1) What are the clinicopathological features and prognostic determinants for patients with UMBTs? 2) Can a nomogram be developed for clinicians to predict the short and long-term outcomes for individuals with UMBTs? 3) Does surgery improve outcomes for UMBT patients who received radiotherapy or chemotherapy after balancing the confounding bias? 400 UMBT patients were filtrated from the Surveillance, Epidemiology, and End Results database to assess the clinicopathological features, treatments, and factors affecting prognosis. The optimal cutoff values of continuous variables were identified by the x-tile software. Kaplan-Meier method and multivariate Cox proportional hazard modeling were performed to evaluate the independent prognostic factors. Nomogram was further developed by using R software with rms package. The surgical efficacy was further assessed for patients receiving radiotherapy or chemotherapy after performing propensity score matching. The enrolled cohort included 195 (48.8%) female and 205 (51.2%) male patients. The 2- and 5-year cancer-specific survival (CSS) and overall survival (OS) rate were 58.2 ± 3.0%, 46.8 ± 3.2%, and 46.5 ± 2.6%, 34.4 ± 2.5%, respectively. Nomogram was finally developed for CSS and OS according to the identified independent factors: age, tumor extent, primary tumor surgery, tumor size, and pathology grade. For UMBT patients who received radiotherapy or chemotherapy, surgical intervention was associated with better CSS (pr = 0.003, pc = 0.002) and OS (pr = 0.035, pc = 0.002), respectively. Nomogram was developed for individual UMBT patient to predict short and long-term CSS and OS rate, and more external patient cohorts are warranted for validation. Surgery improves outcomes for UMBT patients who received either radiotherapy or chemotherapy.


Teratogenicity of cobalt chloride in Xenopus laevis, assayed by the FETAX procedure.
The teratogenicity of cobalt chloride (CoCl2) was tested by the FETAX (Frog Embryo Teratogenesis Assay: Xenopus) procedure in the South African frog, Xenopus laevis. In five assays, beginning at 5 h post-fertilization, groups of Xenopus embryos were incubated for 96 h in media that contained CoCl2 at concentrations ranging from 1.8 x 10(-6) to 1.8 x 10(-2) mol/L; control groups were incubated in the same medium without added CoCl2. At 101 h post-fertilization, surviving embryos were counted, fixed in formalin, and examined by microscopy to score malformations and measure head-to-tail lengths. In control embryos, survival was greater than or equal to 95% and malformations were less than or equal to 5%. Malformations were found in greater than 99% of embryos exposed to Co2+ levels greater than or equal to 56 mumol/L. Co2+)-exposed embryos showed a concentration-related pattern of malformations, comprising gut malrotation, ocular anomalies, kinked tail, craniofacial dysplasia, cardiac deformities, and dermal blisters. Other concentration-dependent abnormalities, not categorized as malformations, included stunted growth, edema, ventral distention, and hypopigmentation. The median embryolethal concentration (LC50) of CoCl2 was 10.4 (SE +/- 0.4) mmol/L; the median teratogenic concentration (EC50) was 25 (SE +/- 2) mumol/L; the teratogenic index (TI = LC50/EC50) was 416 (SE +/- 13), indicating that CoCl2 is a potent teratogen for Xenopus laevis.


Anti-phospholipase A2 receptor positive membranous nephropathy: investigating the link between electron microscopy stages and clinical outcome.
This retrospective, observational study sought to examine the relationship between Ehrenreich-Churg electron microscopy (EM) stages and long-term outcomes in anti-PLA2R membranous nephropathy (MN). Seventy-one patients with anti-PLA2R MN (median titer 185.7RU/mL) were followed for a median of 46 months, with end-stage kidney disease (ESKD) as the primary endpoint, and response to treatment as a secondary endpoint. Patients were grouped into stages I-II (41 patients) and stages III-IV (30 patients) for analytical purposes. Notably, the III-IV group demonstrated a lower eGFR, lower anti-PLA2R titer, but a higher chronicity score. Kaplan-Meier analysis showed shorter mean kidney survival time in stages III-IV compared to I-II (p 0.03). However, multivariate analysis using Cox regression indicated that Ehrenreich-Churg stages did not significantly influence kidney survival, but lower eGFR at diagnosis and higher histopathological chronicity score did. Remission was achieved by 64% of patients and no relationship between Ehrenreich-Churg stages and treatment response was found. The only identified risk factor for not achieving remission was the severity of hyposerinemia at diagnosis. In conclusion, while EM stages III-IV are associated with more chronic lesions and stages I-II with more active immunologic disease, the histological chronicity score seems to be a stronger predictor of long-term outcomes.


Peripapillary Retinal Nerve Fiber Layer Vascular Microcirculation in Eyes With Glaucoma and Single-Hemifield Visual Field Loss.
Understanding the differences in vascular microcirculation of the peripapillary retinal nerve fiber layer (RNFL) between the hemispheres in eyes with glaucoma with single-hemifield visual field (VF) defects may provide insight into the pathophysiology of glaucoma. To investigate the changes in the microcirculation of the peripapillary RNFL of eyes with glaucoma by using optical microangiography. Eyes with glaucoma and single-hemifield VF defect and normal eyes underwent scanning using an optical microangiography system covering a 6.7 × 6.7-mm2 area centered at the optic nerve head. The RNFL microcirculation was measured within an annulus region centered at the optic nerve head divided into superior and inferior hemispheres. Blood flux index (the mean flow signal intensity in the vessels) and vessel area density (the percentage of the detected vessels in the annulus) were measured. Differences in microcirculation between the hemispheres in eyes with glaucoma and normal eyes and correlations among blood flow metrics, VF thresholds, and clinical optical coherence tomography structural measurements were assessed. Twenty-one eyes from 21 patients with glaucoma (7 men and 14 women; mean [SD] age, 63.7 [9.9] years) and 20 eyes from 20 healthy control individuals (9 men and 11 women; mean [SD] age, 68.3 [10.7] years) were studied. In eyes with glaucoma, the abnormal hemisphere showed a thinner RNFL (mean [SE] difference, 23.5 [4.5] μm; 95% CI, 15.1-32.0 µm; P < .001), lower RNFL blood flux index (mean [SE] difference, 0.04 [0.01]; 95% CI, 0.02-0.05; P < .001), and less vessel area density (mean [SE] difference, 0.08% [0.02%]; 95% CI, 0.05%-0.10%; P < .001) than did the normal hemisphere. Compared with normal eyes, reduced RNFL microcirculation was found in the normal hemisphere of eyes with glaucoma, measured by mean [SE] differences in blood flux index (0.06 [0.01]; 95% CI, 0.04-0.09; P < .001) and vessel area density (0.04% [0.02%]; 95% CI, 0.02%-0.08%; P = .003) but not in RNFL thickness (3.4 [4.7] μm; 95% CI, -6.2 to 12.9 µm; P = .48). Strong correlations were found between the blood flux index and VF mean deviation (Spearman ρ = 0.44; P = .045) and RNFL thickness (Spearman ρ = 0.65; P = .001) in the normal hemisphere of the eye with glaucoma. Reduced RNFL microcirculation was detected in the normal hemisphere of eyes with glaucoma, with strong correspondence with VF loss and RNFL thinning. Although the results suggest that vascular dysfunction precedes structural changes seen in glaucoma, longitudinal studies would be needed to confirm this finding.


HLA-DQA1 genotyping by bi-directional sequencing of PCR-amplified DNA spanning exon 2.
We describe a simple, reliable technique for HLA-DQA1 genotyping based on direct DNA sequencing of PCR amplified fragments from genomic DNA. The alleles of DQA1 can be divided into two subsets, with one subset demonstrating a 3 base deletion in exon 2 relative to the other. Typing heterozygous individuals who possess one allele from each sub-group can be difficult using a direct sequencing approach, since the two overlapping DNA sequences move out of phase by 3 nucleotides once the point of deletion is reached. The complete sequence is obtained by performing two separate sequencing reactions with fluorescent dye primers, coming from either end of the template. This allows all heterozygous positions in exon 2 to be unambiguously assigned.


Sporadic, classic-type renal angiomyolipoma with renal vein and inferior vena cava extension: an incidental case.
Renal angiomyolipomas (AMLs) were first described in the early 1900s by Gravitz, but it was not until 1951 that they were named renal AML. These kidney tumours are rare, occurring in 0.13%-0.44% of the population. These mesenchymal tumours are composed of smooth muscle-like, adipocyte-like and epithelioid cells. Depending on the predominant cell population, it can be further subclassified into classic, epithelioid and AML with epithelial cyst. A 32-year-old woman presented with mild, intermittent, epigastric and right upper quadrant abdominal pain. Abdominal ultrasound revealed an incidental lesion within the inferior vena cava (IVC). A CT scan showed a lesion within the left renal vein extending into the IVC with 40% narrowing and a fat-containing mass in the lower pole of the left kidney of 15 mm suggesting an AML. Thrombectomy was performed. The specimen resulted positive for classic variant renal AML. Initial diagnosis is centred on imagining studies, based in fatty tissue concentration. The AML expresses melanocytic markers. This helps differentiate from renal cell carcinoma. Although AML is considered a benign condition, there is evidence of malignant transformation. Active surveillance is recommended for lesions <4 cm. Nephron sparing surgery is the procedure of choice. Nephrectomy is recommended if there is a high probability of malignancy. Mammalian target of rapamycin (mTOR) inhibitors have been proposed to be an alternative treatment.


Amelioration of insulin lipoatrophy by dexamethasone injection.
Widespread subcutaneous lipoatrophy occurred in a 47-year-old woman after subcutaneous injections of isophane insulin suspension for five months. Subsequent systemic treatment with a dexamethasone (0.08 mg/day) insulin mixture injected subcutaneously into the depressed areas resulted in an impressive return of subcutaneous tissue after eight months of continuous therapy.


IL-13 is a central mediator of chemical-induced airway hyperreactivity in mice.
While the importance of the Th2 cytokine IL-13 as a central mediator of airway hyperreactivity (AHR) has been described in allergic protein-induced asthma, this has never been investigated in chemical-induced asthma. We examined the importance of IL-13 in a mouse model of chemical-induced AHR, using toluene-2,4-diisocyanate (TDI). In a first set-up, wild type (WT) and IL-13 knockout (KO) C57Bl/6 mice were dermally treated on days 1 and 8 with 1% TDI or vehicle (acetone/olive oil) on both ears. On day 15, mice received an intranasal instillation with 0.1% TDI or vehicle. In a second set-up, WT mice sensitized with 1% TDI or vehicle, received i.v. either anti-IL-13 or control antibody prior to the intranasal challenge. TDI-sensitized and TDI-challenged WT mice showed AHR to methacholine, in contrast to TDI-sensitized and TDI-challenged IL-13 KO mice, which also showed lower levels of total serum IgE. TDI-sensitized and TDI-challenged IL-13 KO mice had lower numbers of T-cells in the auricular lymph nodes. TDI-treated WT mice, receiving anti-IL-13, showed no AHR, in contrast to those receiving control antibody, despite increased levels of IgE. Anti-IL-13 treatment in TDI-treated WT mice resulted in lower levels of serum IL-13, but did not induce changes in T- and B-cell numbers, and in the cytokine production profile. We conclude that IL-13 plays a critical role in the effector phase of chemical-induced, immune-mediated AHR. This implicates that anti-IL-13 treatment could have a beneficial effect in patients with this asthma phenotype.


Benign chest wall lipoblastoma: report of a case.
This report deals with a 22-month-old boy who had a benign lipoblastoma on the chest wall. The tumor was located intrathoracically and was well-encapsulated. It was yellowish in color with a shiny cut surface and consisted of multiple lobules. Histologically, peripheral immature lipoblasts with fat vacuoles of various size and central mature fat cells containing a single, large fat vacuole are characteristic of this tumor. No local recurrence has been found during the 17 months since total excision.


Small changes of dietary (n-6) and (n-3)/fatty acid content ration alter phosphatidylethanolamine and phosphatidylcholine fatty acid composition during development of neuronal and glial cells in rats.
It has been suggested that the fat composition of infant formula should provide arachidonic acid [20:4(n-6)] and docosahexaenoic acid [22:6(n-3)] or increased alpha-linolenic acid [18:3(n-3)] to optimize the (n-3) and (n-6) fatty acid content of brain during infant development. This experiment examined the effects of feeding increased levels of 18:3(n-3), 20:4(n-6) and 22:6(n-3) on brain development in neonatal rats. Diets varying in (n-6) and (n-3) fatty acid content with or without 20:4(n-6) or 22:6(n-3), at levels proposed for infant formula, were fed to nursing dams from parturition and subsequently to weaned pups until 6 wk of age. Neuronal and glial cells were isolated from the frontal region, cerebellum and hippocampus of the brain. Fatty acid analyses of ethanolamine- and choline-phosphoglycerides indicated that small changes in the dietary (n-6)/(n-3) ratio significantly altered neuronal and glial membrane fatty acid composition. Brain regions and cell types varied in amount and rate of 20:4(n-6) and 22:6(n-3) accretion. Fatty acid composition of individual phosphoglycerides was distinct and exhibited changes with age. Inclusion of both 20:4(n-6) and 22:6(n-3) in the diet resulted in alteration of brain fatty acid composition reflecting the fatty acid composition of the diet. If analogous developmental changes occur in human brain, then these results imply that addition of 20:4(n-6) and 22:6(n-3) or a reduced 18:2(n-6):18:3(n-3) ratio in infant formula may result in fatty acid profiles of neuronal and glial cells in formula-fed infants similar to those observed in breast-fed infants.


Membrane lipids and the endoplasmic reticulum unfolded protein response: An interesting relationship.
The unfolded protein response of the endoplasmic reticulum (UPR(ER)) is a conserved signaling circuit that ensures ER protein homeostasis (proteostasis). In the UPR(ER) of higher eukaryotes, multiple sensors cooperatively perceive proteostatic disturbances in the ER lumen and induce downstream adaptive changes. Besides direct proteotoxic insults, altered lipid profiles can also lead to UPR(ER) activation, evidently because abnormal lipid composition impairs protein folding. However, 2 recent studies propose an alternative mechanism of UPR(ER) sensor activation. In one report, UPR(ER) activation occurred in cells expressing UPR(ER) sensors lacking the very domains that sense unfolded proteins; the other study found that Caenorhabditis elegans worms displayed UPR(ER) activation without apparent proteostatic imbalance in the ER lumen. Collectively, these studies suggest that lipid disequilibrium-activated UPR(ER) is not strictly accompanied by compromised ER proteostasis and hint at a lipid membrane-monitoring role of the UPR(ER). These discoveries raise several important questions: does the UPR(ER) monitor and maintain homeostasis of the ER membrane and/or its lipids? In turn, does the UPR(ER) initiate downstream regulatory events that specifically alleviate lipid or proteostatic imbalance? And what is the physiological significance of proteostasis-independent UPR(ER) activation? In this commentary, we will discuss these issues and highlight the utility of C. elegans as an in vivo model to study lipid disequilibrium-induced UPR(ER) and related pathways.


Transfusion treatment at Sestre Milosrdnice University Hospital Center during a twelve-year period.
Transfusion treatment is administered according to clinical and laboratory results, with ongoing patient assessments. Decisions on necessary measures to prevent any adverse and unexpected events and reactions are made on the basis ofhemovigilance and ongoing gathering and analysis of relevant data. Information about transfusion treatment at the Sestre milosrdnice University Hospital Center, Vinogradska site, was retrospectively collected for a period of twelve years (2001-2012). In that period, 14137.25 ± 1693.07 units of all blood products were used, where red blood cells (RBC) accounted for 67.34%, fresh frozen plasma (FFP) for 17.55%, and platelet concentrates (PC) for 14.32%. During the study period, the consumption of RBC was even, of FFP decreased by 45% and of PC increased by 58%. RBC transfusions were received by 10.43% of hospitalized patients, 1.46% of them during surgical procedures. Transfusions of all blood products were received by 14.63% of patients. We found 247 adverse reactions to all blood products. Febrile nonhemolytic and allergic reactions were quite equally represented, 49.5% each. As for other reactions (1%), one transfusion associated circulatory overload and one transfusion related acute lung injury were recorded. There were no fatal post-transfusion reactions.


Barriers to Engaging Communities in a Dengue Vector Control Program: An Implementation Research in an Urban Area in Hanoi City, Vietnam.
The dengue situation in the urban setting of Hanoi city, Vietnam, is emerging, focusing on inner districts. Previous studies showed that a dengue vector control program in Hanoi was not effective because of the lack of adequate engagement of the local government authorities, health sector, and community. This implementation research aimed to explore barriers to implementing community engagement in a dengue vector control program in an urban district of Hanoi city. Ten in-depth interviews and 14 focus group discussions were conducted at Lang Thuong, Khuong Thuong, Tho Quan, and Kim Lien wards in Dong Da district, Hanoi city. Data collection was implemented from April to June 2017. All discussions were recorded and transcribed verbatim. Data were analyzed using the content analysis approach. Secondary data from the dengue vector control program reports were used to support the qualitative evidence. We found that the barriers to implementing effective community engagement were as follows: 1) lack of interest and an attitude of dependency on action from the health sector of local people's committee, 2) lack of enthusiasm of mass organizations and community leaders, 3) overburdened workloads and lack of communication skills from health sector, 4) low awareness and readiness from community, 5) lack of detailed policy guidelines and low enforcement of related policy, and 6) limited budget. Recommended actions should be made to improve the community engagement in the current resource-limited context of Vietnam by both top-down and bottom-up approaches.


Dual effects of capsaicin on responses of the rabbit ear artery to field stimulation.
1. The effects of capsaicin (Cap) on contractions of ring segments of rabbit ear artery induced by field stimulation were studied. 2. At low concentrations (0.3-3 microM) Cap caused transient enhancement and at higher concentrations (above 3 microM) inhibition of stimulation-induced contractions, without affecting noradrenaline (NA)-induced contractions. 3. In the continuous presence of high concentrations of Cap, rebound facilitation was observed after inhibition, and at this stage, Cap elicited less inhibition of the response. 4. Repeated application of Cap at 60 min intervals irreversibly desensitized the artery to the inhibitory effect of Cap. 5. Functional removal of the endothelium enhanced the facilitatory effect of low concentrations of Cap and attenuated its inhibitory effect. 6. Pretreatment with indomethacin abolished the facilitatory effect of Cap and enhanced its inhibitory effect, indicating that prostaglandins are involved in the action of Cap. The effect of indomethacin was more marked in preparations from which the endothelium had been removed. 7. Desensitization to substance P (SP) or substance K (SK), did not affect either the inhibitory or the facilitatory effect of Cap. 8. These results suggest that the dual effects of Cap on stimulation-induced contractions of rabbit ear artery may arise from the release of multiple mediators that act prejunctionally to modulate NA release. The stimulant effect seems to be mediated by prostanoids, while the inhibitory effect seems to be caused by a substance(s) that is not SP or SK. The possibility that the mediator is calcitonin gene-related peptide requires further study.


Possible role of lens collagen in cataractogenesis.
The solubility characteristics of collagen in human cataractous eye lenses were studied in relation to age. Post-operative cataractous lenses were collected form eye camps in Phulbani district of Orissa. These were preserved in 70% alcohol and immediately transferred to the laboratory. Various fractions in the collagen obtained from lens capsule of each lens sample were estimated. The salt-soluble and the acid-soluble collagens showed positive correlation with age. The insoluble and total capsular collagen increased with increasing age. The solubility percentage of collagen in salt and acid solutions decreased significantly with increasing age. The possible role of lens collagen in the development of cataract with increasing age is discussed in the background of cross-link theory of aging.


Trends in the Prevalence of Blindness and Correlation With Health Status in Korean Adults: A 10-Year Nationwide Population-Based Study.
Contemporary data on vision impairment form an important basis for public health policies. However, most data on the clinical epidemiology of blindness are limited by small sample sizes and focused not on systemic conditions but ophthalmic diseases only. In this study, we examined the ten-year trends of blindness prevalence and its correlation with systemic health status in Korean adults. This study investigated 10,000,000 participants randomly extracted from the entire Korean population (aged ≥ 20 years) who underwent a National Health Insurance Service health checkup between 2009 and 2018. Participants with blindness, defined as visual acuity in the better-seeing eye of ≤ 20/200, were identified. The prevalence of blindness was assessed, and the systemic health status was compared between participants with blindness and without blindness. The mean prevalence of blindness was 0.473% (47,115 blindness cases) and tended to decrease over ten years (0.586% in 2009 and 0.348% in 2018; P < 0.001). The following factors were significantly associated with blindness: female sex, underweight (body mass index < 18.5), high serum creatinine (> 1.5 mg/dL), and bilateral hearing loss. In addition, except for those aged 30-39 and 40-49 years, high fasting glucose (≥ 126 mg/dL) and low hemoglobin (male: < 12 g/dL, female: < 10 g/dL) were significantly correlated with prevalent blindness. Our ten-year Korean nationwide population-based study suggested a gradual decrease in the prevalence of blindness and its association with specific systemic health status. These conditions might be the cause or consequence of blindness and can be used as a reference for the prevention and/or rehabilitation of blindness to establish public health policies.


Bis-methionyl coordination in the crystal structure of the heme-binding domain of the streptococcal cell surface protein Shp.
Surface proteins Shr, Shp, and the ATP-binding cassette (ABC) transporter HtsABC are believed to make up the machinery for heme uptake in Streptococcus pyogenes. Shp transfers its heme to HtsA, the lipoprotein component of HtsABC, providing the only experimentally demonstrated example of direct heme transfer from a surface protein to an ABC transporter in Gram-positive bacteria. To understand the structural basis of heme transfer in this system, the heme-binding domain of Shp (Shp(180)) was crystallized, and its structure determined to a resolution of 2.1 A. Shp(180) exhibits an immunoglobulin-like beta-sandwich fold that has been recently found in other pathogenic bacterial cell surface heme-binding proteins, suggesting that the mechanisms of heme acquisition are conserved. Shp shows minimal amino acid sequence identity to these heme-binding proteins and the structure of Shp(180) reveals a unique heme-iron coordination with the axial ligands being two methionine residues from the same Shp molecule. A negative electrostatic surface of protein structure surrounding the heme pocket may serve as a docking interface for heme transfer from the more basic outer cell wall heme receptor protein Shr. The crystal structure of Shp(180) reveals two exogenous, weakly bound hemins, which form a large interface between the two Shp(180) molecules in the asymmetric unit. These "extra" hemins form a stacked pair with a structure similar to that observed previously for free hemin dimers in aqueous solution. The propionates of the protein-bound heme coordinate to the iron atoms of the exogenous hemin dimer, contributing to the stability of the protein interface. Gel filtration and analytical ultracentrifugation studies indicate that both full-length Shp and Shp(180) are monomeric in dilute aqueous solution.


[Cell mediated immunity against tubular basement membranes in children with glomerular disease (author's transl)].
Applying a rosette assay we examined peripheral lymphocytes for their sensitivity against enzymatically solubilized tubular basement membranes (TBM). 20 healthy children and 34 children with glomerular diseases were tested. 2 patients from the panel of acute glomerulonephritis and 5 patients with chronic glomerulonephritis showed reactivity against this structure. Children with idiopathic nephrotic syndrome as well as patients with Alport's syndrome revealed no cell mediated immunity against TBM. On grounds of these findings we suggest that tubular involvement in glomerular diseases is not only secondary injury by affection of the glomerular appartus, but may be regarded as a target of the cell mediated immunity.


Childhood cognitive performance and risk of mortality: a prospective cohort study of gifted individuals.
Recent research suggests that childhood cognitive performance is associated with various health outcomes, but the nature of the relation is not well understood. It is unclear whether the association occurs across the continuum of cognitive performance, and if it is independent of socioeconomic status. Prospective data from the Terman Life Cycle Study were used to evaluate the hypothesis of a monotonic relation between childhood intelligence quotient (IQ) and adult mortality and to determine whether there exists a threshold beyond which the protective effects of IQ are no longer evident. A total of 897 individuals of school age who scored 135 or higher on the Stanford-Binet IQ test were recruited in 1922. Cox proportional hazards regression was used to estimate survival over a 64-year period. A 15-point advantage in childhood IQ was significantly associated with a decreased risk of mortality (hazard ratio = 0.68, 95% confidence interval: 0.49, 0.93) for IQ scores up to 163; beyond that, the risk of death plateaued. Results were similar when the sample was limited to those participants whose fathers had nonmanual occupations. Childhood IQ, even at the upper end of the distribution, is a significant predictor of mortality, independent of childhood social position.


Perspectives for improved and more accurate classification of thyroid epithelial tumors.
Histologic examination of thyroid nodules is the current standard to distinguish benign from malignant thyroid epithelial tumors and to classify histologic subtypes. This review analyzes the problems in histological differential diagnosis as well as contradictions between histology and molecular data and describes possibilities to combine histology with molecular data in an effort to more accurately classify thyroid epithelial tumors. Published literature, addressing the current recommendations for thyroid tumor classification, as well as literature on the application of histology and molecular studies on the etiology of thyroid tumors is analyzed. The current histologic criteria to classify thyroid tumors, especially follicular-patterned tumors, are hampered by considerable interobserver variability. The detection of somatic mutations via genotyping and the definition of potentially informative gene expression signatures by microarray analyses, which can distinguish cancer subtypes as well as low- and high-risk cohorts, have recently demonstrated significant diagnostic potential. Moreover, in a routine diagnostic setting, micro-RNA profiling appears most promising due to their relative stability and the high accuracy of their expression profiles. It is very likely that molecular definitions of thyroid tumors mentioned in the current World Health Organization classification will be further developed, leading to future progress in defining thyroid tumor types by an integrated histologic and molecular approach. These integrated classifications need to be evaluated for their specific impact on thyroid tumor diagnosis and prognosis.


Hydrogen Peroxide Induced Toxicity Is Reversed by the Macrocyclic IRAP-Inhibitor HA08 in Primary Hippocampal Cell Cultures.
Angiotensin IV (Ang IV), a metabolite of Angiotensin II, is a bioactive hexapeptide that inhibits the insulin-regulated aminopeptidase (IRAP). This transmembrane zinc metallopeptidase with many biological functions has in recent years emerged as a new pharmacological target. IRAP is expressed in a variety of tissues and can be found in high density in the hippocampus and neocortex, brain regions associated with cognition. Ang IV is known to improve memory tasks in experimental animals. One of the most potent IRAP inhibitors known today is the macrocyclic compound HA08 that is significantly more stable than the endogenous Ang IV. HA08 combines structural elements from Ang IV and the physiological substrates oxytocin and vasopressin, and binds to the catalytic site of IRAP. In the present study we evaluate whether HA08 can restore cell viability in rat primary cells submitted to hydrogen peroxide damage. After damaging the cells with hydrogen peroxide and subsequently treating them with HA08, the conceivable restoring effects of the IRAP inhibitor were assessed. The cellular viability was determined by measuring mitochondrial activity and lactate dehydrogenase (LDH) release. The mitochondrial activity was significantly higher in primary hippocampal cells, whereas the amount of LDH was unaffected. We conclude that the cell viability can be restored in this cell type by blocking IRAP with the potent macrocyclic inhibitor HA08, although the mechanism by which HA08 exerts its effects remains unclear.


A review of endodontic medicaments.
Endodontic intracanal medicaments are often used when root canal therapy cannot be completed in a single visit. Properties of the more commonly used medicaments are outlined, their effectiveness is examined, and recommendations for use are made, based on evidence in the literature reviewed here.


Mimicry in misophonia: A large-scale survey of prevalence and relationship with trigger sounds.
Misophonia is often referred to as a disorder that is characterized by excessive negative emotional responses, including anger and anxiety, to "trigger sounds" which are typically day-to-day sounds, such as those generated from people eating, chewing, and breathing. Misophonia (literally "hatred of sounds") has commonly been understood within an auditory processing framework where sounds cause distress due to aberrant processing in the auditory and emotional systems of the brain. However, a recent proposal suggests that it is the perceived action (e.g., mouth movement in eating/chewing sounds as triggers) of the trigger person, and not the sounds per se, that drives the distress in misophonia. Since observation or listening to sounds of actions of others are known to prompt mimicry in perceivers, we hypothesized that mimicking the action of the trigger person may be prevalent in misophonia. Apart from a few case studies and anecdotal information, a relation between mimicking and misophonia has not been systematically evaluated. In this work, we addressed this limitation by collecting data on misophonia symptoms and mimicry behavior using online questionnaires from 676 participants. Analysis of these data shows that (i) more than 45% of individuals with misophonia reported mimicry, indicating its wide prevalence, (ii) the tendency to mimic varies in direct proportion to misophonia severity, (iii) compared to other human and environmental sounds, trigger sounds of eating and chewing are more likely to trigger mimicking, and (iv) the act of mimicking provides some degree of relief from distress to people with misophonia. This study shows prevalence of mimicry and its relation to misophonia severity and trigger types. The theoretical framework of misophonia needs to incorporate the phenomenon of mimicry and its effect on management of misophonia distress.


Neuroprotective effects of electro acupuncture on hypoxic-ischemic encephalopathy in newborn rats Ass.
Hypoxic-ischemic encephalopathy (HIE) is a common and potentially devastating condition in the neonate, associated with high mortality and morbidity. Effective treatment options are limited and therefore alternative therapies such as acupuncture are increasingly used. Previous studies have shown that electro acupuncture promoted proliferation of neural progenitor cell and increased expression of neurotrophic factor in HIE. However, effects of electro acupuncture on downstream signaling pathways have been rarely researched. So, in the present study, we aimed to evaluate the neuroprotective effects of electro acupuncture on HIE and to further investigate the role of GDNF family receptor member RET and its key downstream PI3-K/Akt pathway in the process. A rat HIE model was constructed by the left common carotid artery (LCCA) ligation method in combination with hypoxic treatment. Considering that Baihui (GV20), Dazhui (GV14), Quchi (LI11) and Yongquan (KI1) are commonly used in clinics for stroke treatment and are easy to locate, we chose the above four acupoints as the combination for electro acupuncture treatment which was performed once a day for different time periods. Hematoxylin-eosin (HE) staining and transmission electron microscopy results showed that electro acupuncture could ameliorate neurologic damage and alleviate the degenerative changes of ultra structure of cortical neurons in rats subjected to HIE. And the longer acupuncture treatment lasted, the better its therapeutic effect would be. This was accompanied by gradually increased expression of GDNF family receptor RET at the mRNA level and its downstream signaling Akt at the protein level in the ischemic cortex. These findings suggest that electro acupuncture shows neuroprotective effects in HIE, which at least in part is attributed to activation of PI3-K/Akt signaling pathway.


Examining cognitive-behavioral therapy change mechanisms for decreasing depression, weight, and insulin resistance in adolescent girls at risk for type 2 diabetes.
Depression in adolescence is linked to risk for type 2 diabetes (T2D). In this secondary data analysis of a randomized controlled trial comparing cognitive-behavioral therapy (CBT) to a control program to ameliorate insulin resistance via reducing depression symptoms, we examine which CBT change mechanisms (e.g., behavioral activation, cognitive restructuring) contributed to decreased depression and subsequent improvements in body mass index (BMI), percent body fat, and insulin resistance. Girls 12-17y with overweight/obesity and family history of T2D were randomized to six-week group CBT (n = 61) or health education (HealthEd; n = 58). At baseline and post-treatment, adolescents completed questionnaires assessing activities, thoughts, and depression symptoms. At baseline, post-treatment, and one-year, BMI was calculated and insulin outcomes were derived from two-hour oral glucose tolerance testing. At baseline and one-year, percent body fat was assessed with dual-energy x-ray absorptiometry. Indirect effects of CBT components were tested on one-year changes in BMI, percent body fat, and insulin indices through decreases in depression symptoms during treatment. Intervention was tested as a moderator. In CBT, but not HealthEd, there was an indirect effect of increased physical activity during treatment on decreased one-year BMI via reductions in depression symptoms during treatment. Also, there were conditional indirect effects in CBT of increased pleasantness of physical and social activity during treatment on decreased one-year BMI via decreased depression symptoms during treatment. Behavioral activation may be a useful intervention to decrease depression and reduce excess weight gain in the targeted prevention of T2D in at-risk adolescent girls. NCT01425905, clinicaltrials.gov.


An enhanced targeted identification strategy for the selective identification of flavonoid O-glycosides from Carthamus tinctorius by integrating offline two-dimensional liquid chromatography/linear ion-trap-Orbitrap mass spectrometry, high-resolution diagnostic product ions/neutral loss filtering and liquid chromatography-solid phase extraction-nuclear magnetic resonance.
Targeted identification of potentially bioactive molecules from herbal medicines is often stymied by the insufficient chromatographic separation, ubiquitous matrix interference, and pervasive isomerism. An enhanced targeted identification strategy is presented and validated by the selective identification of flavonoid O-glycosides (FOGs) from Carthamus tinctorius. It consists of four steps: (i) enhanced separation and detection by offline two-dimensional liquid chromatography/LTQ-Orbitrap MS (offline 2D-LC/LTQ-Orbitrap MS) using collision-induced dissociation (CID) and high-energy C-trap dissociation (HCD); (ii) improved identification of the major aglycones by acid hydrolysis and LC-SPE-NMR; (iii) simplified spectral elucidation by high-resolution diagnostic product ions/neutral loss filtering; and (iv) more convincing structural identification by matching an in-house library. An offline 2D-LC system configuring an Acchrom XAmide column and a BEH Shield RP-18 UPLC® column enabled much better separation of the easily co-eluting components. Combined use of CID and HCD could produce complementary fragmentation information. The intensity ratios of the aglycone ion species ([Y0-H]-/Y0- and [Y0-2H]-/Y0-) in the HCD-MS2 spectra were found diagnostic for discriminating the aglycone subtypes and characterizing the glycosylation patterns. Five aglycone structures (kaempferol, 6-hydroxykaempferol, 6-methoxykaempferol, carthamidin, and isocarthamidin) were identified based on the 1H-NMR data recorded by LC-SPE-NMR. Of the 107 characterized flavonoids, 80 FOGs were first reported from C. tinctorius. Unknown aglycones, pentose, and novel acyl substituents were discovered. A new compound thereof was isolated and fully identified, which could partially validate the MS-oriented identification. This integral strategy can improve the potency, efficiency, and accuracy in the detection of new compounds from medicinal herbs and other natural sources.


Udder health in the periparturient period.
The periparturient period is associated with rapid differentiation of secretory parenchyma, intense mammary growth, copious synthesis and secretion, and marked accumulation of colostrum and milk. Udder health during this time is an important factor associated with the production of maximum quantities of high quality milk. Intramammary infections that occur during the dry period can adversely affect udder health, resulting in decreased milk production, altered milk composition, and impaired mammary function. Bovine mammary glands are markedly susceptible to new infections during the periparturient period, especially prior to parturition. Many infections that occur at this time are associated with clinical mastitis during early lactation. Methods of controlling mastitis in the dry period have focused primarily on the use of antibiotics. However, antibiotic therapy at drying off does not appear to prevent new infections in the periparturient period. This is most likely due to lack of persistence of antibiotics. Furthermore, antibiotics used currently are less effective against environmental pathogens, in particular coliform bacteria, which can cause a high proportion of intramammary infections during the periparturient period. Methods of controlling bovine mastitis during the periparturient period is an important area that requires additional research. Procedures need to be developed that are effective against a variety of bacteria, including environmental mastitis pathogens, if additional control is to be achieved.


Mixed cerium-platinum oxides: Electronic structure of [CeO]Ptn (n = 1, 2) and [CeO2]Pt complex anions and neutrals.
The electronic structures of several small Ce-Pt oxide complexes were explored using a combination of anion photoelectron (PE) spectroscopy and density functional theory calculations. Pt and Pt2 both accept electron density from CeO diatomic molecules, in which the cerium atom is in a lower-than-bulk oxidation state (+2 versus bulk +4). Neutral [CeO]Pt and [CeO]Pt2 complexes are therefore ionic, with electronic structures described qualitatively as [CeO(+2)]Pt(-2) and [CeO(+)]Pt2 (-), respectively. The associated anions are described qualitatively as [CeO(+)]Pt(-2) and [CeO(+)]Pt2 (-2), respectively. In both neutrals and anions, the most stable molecular structures determined by calculations feature a distinct CeO moiety, with the positively charged Ce center pointing toward the electron rich Pt or Pt2 moiety. Spectral simulations based on calculated spectroscopic parameters are in fair agreement with the spectra, validating the computationally determined structures. In contrast, when Pt is coupled with CeO2, which has no Ce-localized electrons that can readily be donated to Pt, the anion is described as [CeO2]Pt(-). The molecular structure predicted computationally suggests that it is governed by charge-dipole interactions. The neutral [CeO2]Pt complex lacks charge-dipole stabilizing interactions, and is predicted to be structurally very different from the anion, featuring a single Pt-O-Ce bridge bond. The PE spectra of several of the complexes exhibit evidence of photodissociation with Pt(-) daughter ion formation. The electronic structures of these complexes are related to local interactions in Pt-ceria catalyst-support systems.


Late lesions of experimental contagious caprine pleuropneumonia caused by Mycoplasma capricolum ssp. capripneumoniae.
A clinical, bacteriological, serological and patho-anatomical study was carried out on 12 goats surviving the acute stage of contagious caprine pleuropneumonia (CCPP), experimentally produced with Mycoplasma capricolum ssp. capripneumoniae (M. capripneumoniae), with the major aims of investigating the chronic stage of the disease and elucidating the possibility of a carrier state beyond the acute fulminant phase. The goats were killed 9, 16, 82 or 126 days after the onset of acute clinical signs. On day 9, clinical signs included low grade fever and persistent coughing. Thereafter, only intermittent coughing was recorded. Serum titres of complement-fixing antibodies to M. capripneumoniae were high at the period of fever but dropped thereafter. Post-mortem examination showed acute fibrinous pleuropneumonia on days 9 and 16, and chronic pleuropneumonia on days 82 and 126, including sequester formations in goats killed on day 126. Mycoplasma capripneumoniae was isolated on days 9 and 16 but not on later occasions. The study showed that goats recovered from acute CCPP may have lesions for a long time thereafter but provide no evidence of a carrier state among long-term survivors.


Boosting the Quantum Yield of Oxygen-Doped g-C3N4 via a Metal-Azolate Framework-Enhanced Electron-Donating Strategy for Highly Sensitive Sulfadimethoxine Tracing.
Two of the most persistent challenges for the sensing applications of luminescent carbon nitride-based materials are poor quantum yields and aggregation-induced luminescence quenching in aqueous environments. Herein, a highly emissive oxygen-doped carbon nitride composite (OCNP@M7) was synthesized, with a metal-azolate framework (MAF-7) serving as a luminous booster. Both experimental studies and theoretical calculations suggest that the MAF-enhanced electron-donating effect dramatically promoted the electron density on the π-structure of oxygen-doped carbon nitride. In addition, the structural rigidity of MAF-7 effectively inhibits both aggregation and nonradiative energy dissipation. Consequently, OCNP@M7 exhibits strong and stable blue emission under UV light irradiation and an absolute quantum yield up to 95.2%, which is, as far as we know, the highest value among fluorescent carbon nitride materials in solution ever reported. OCNP@M7 could further function as a high-efficiency fluorescent probe for the sensitive detection of sulfadimethoxine residues in complex environments. It is anticipated that this strategy can be extended to fabricate various carbon nitride-based antibiotic monitoring systems with tailor-made functions.


Staphylococcus hominis septicaemia in patients with cancer.
We report two cases of Staphylococcus hominis septicaemia associated with the use of intravenous catheters. Both patients had advanced malignant disease, but infection was eliminated rapidly with antibiotic treatment administered via the catheters. This report confirms the pathogenicity of Staph. hominis, particularly in immunocompromised patients. We recommend the wider use of an effective scheme for the correct identification of blood culture isolates of coagulase-negative staphylococci.


Effect of additives on gas-phase catalysis with immobilised Thermoanaerobacter species alcohol dehydrogenase (ADH T).
This paper presents a strategy for preparing an efficient immobilised alcohol dehydrogenase preparation for a gas-phase reaction. The effects of additives such as buffers and sucrose on the immobilisation efficiency (residual activity and protein loading) and on the gas-phase reaction efficiency (initial reaction rate and half-life) of Thermoanaerobacter sp. alcohol dehydrogenase were studied. The reduction of acetophenone to 1-phenylethanol under in situ cofactor regeneration using isopropanol as co-substrate was used as a model reaction at fixed reaction conditions (temperature and thermodynamic activities). A strongly enhanced thermostability of the enzyme in the gas-phase reaction was achieved when the enzyme was immobilised with 50 mM phosphate buffer (pH 7) containing sucrose five times the protein amount (on weight/weight basis). This resulted in a remarkable productivity of 200 g L(-1) day(-1) even at non-optimised reaction conditions. The interaction of additives with the enzyme and water affects the immobilisation and gas-phase efficiencies of the enzyme. However, it was not possible to predict the effect of additives on the gas-phase reaction efficiency even after knowing their effect on the immobilisation efficiency.