Concept of the local and common mucosal immune response.
The available information concerning the origin of IgA-producing plasma cells and the spectrum of IgA-associated antibodies found in external secretions provide arguments that support two pathways of stimulation for a secretory humoral immune response. In addition to an explicitly local immune response induced by a topical antigen application, a second mechanism of induction operating through the sensitization of GALT, and possibly BALT, emerges. The latter pathway of stimulation leads to the appearance of specific IgA-associated antibodies in secretions of mammary, salivary, and lacrymal glands (and perhaps other sites), all of which suggests the existence of a common mucosal secretory system. Not yet explained are the mechanisms involved in the homing to secretory glands of cells sensitized in the remote lymphoid tissues (GALT and BALT), the differentiation patterns of these cells, and the regulation of selective IgA expression.


Double burden of malnutrition among adolescents in rural West Bengal, India.
The aims of this study were to investigate the prevalence of underweight, stunting, and overweight among adolescents in rural West Bengal, India, and identify factors contributing to these forms of malnutrition. This was a cross-sectional study conducted within the Birbhum Health and Demographic Surveillance System in West Bengal, India. Participants were male and female adolescents 10 to 19 y of age (N = 5521). Body mass index (BMI) was calculated using measured heights and weights and z-scores based on the 2007 World Health Organization growth standards. Information on demographic characteristics, diet, and health behaviors was collected through face-to-face interviews using a standardized questionnaire. Modified Poisson regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between each risk factor and outcome. The proportion of underweight was 26.6% overall: 31.1% among boys, and 21.1% among girls. The proportion of stunting was 25% overall: 23.3% among boys and 26.9% among girls. Of the participants, 4.6% were overweight or obese: 4.1% boys and 5.2% girls. Compared with boys, girls had a reduced likelihood of being underweight (adjusted PR, 0.67; 95% CI, 0.59-0.75). Multivariate models also showed that socioeconomic status was strongly associated with all nutritional outcomes. Not having a toilet facility in one's household and poor hand hygiene were also associated with a greater likelihood of stunting. The present results suggested that adolescents in Birbhum, India are substantially affected by the double burden of malnutrition. Nutritional interventions should incorporate efforts to reduce socioeconomic inequality.


Prostate cancer recurring as small-cell carcinoma with a BRCA2 somatic mutation.
Small-cell carcinoma of the prostate has a poor prognosis, and treatment options for the refractory disease are unclear. A 68-year-old man with prostate cancer was referred to our hospital. He was treated with combined androgen blockade (bicalutamide and degarelix acetate). The disease progressed to castration-resistant prostate cancer, but with additional treatment, prostate-specific antigen levels remained below 0.02 ng/mL. However, computed tomography revealed enlarged right inguinal lymph nodes; moreover, his neuron-specific enolase levels were elevated. Histopathologic analysis of a biopsied lymph node confirmed small-cell carcinoma. After administering cytotoxic chemotherapy (etoposide plus cisplatin and amrubicin), the patient temporarily improved before relapsing. After genetic testing of the biopsy specimen revealed a BRCA2 deletion, we administered the oral PARP-2 inhibitor olaparib, which has achieved partial remission for 8 months. PARP-2 inhibition may improve the survival of patients with BRCA2-positive small-cell carcinoma of the prostate.


Joint analysis of case-parents trio and unrelated case-control designs in large scale association studies.
We present a new method for testing association when data from both case-parents trios and unrelated controls are available. Our method combines test statistics for case-parents trio and unrelated case-control studies by adjusting for the correlation that arises when the same set of cases is used for both tests. We further consider several analytical approaches for two-stage studies on a large number of markers, including methods based on the joint analysis. The performance of the proposed approaches is examined by analyzing the simulated data provided by the Genetic Analysis Workshop 15.


Derivatization of polyacrylamide gels with pallidin, a lectin of the cellular slime mold polysphondylium pallidum.
A procedure for covalent immobilization of (glyco) proteins in polyacrylamide gels is described. Pallidin, a cytosolic and membrane protein of Polysphondylium pallidum with the properties of a lectin, was derivatized into polyacrylamide gels. Activity of the derivatized gels was assessed in a cell adhesion assay, using rabbit erythrocytes. Immobilization resulted in stabilization of the binding activity in comparison with the agglutination activity of the soluble protein.


Vitallium radial head prosthesis for acute and chronic elbow fractures and fracture-dislocations involving the radial head.
This retrospective study aims to evaluate the radiographic, functional, and patient-derived outcomes of 16 patients who each received a Vitallium radial head prosthesis for unreconstructable acute fractures of the radial head, as well as previously treated fractures of the radial head associated with residual instability, pain, and stiffness. Follow-up averaged 33 months. A trend toward greater disability and poorer motion was noted in the delayed treatment group compared with the acute replacement group. Overall, the results were excellent in 5 patients, good in 10, and poor in 1, as determined by the Mayo Elbow Performance Score. All elbows were stable at follow-up, and no patient reported wrist pain. Four required further operative treatment of their elbow injuries. Metallic radial head arthroplasty yields satisfactory results in acute unreconstructable radial head fractures or as a salvage procedure for previously treated radial head fractures.


Conformational preferences of sequential fragments of the hinge region of human IgA1 immunoglobulin molecule: II.
The mean solution conformation of tetrapeptide fragments of the hinge region of human IgA1 molecule was investigated by CD and 13C-NMR methods. Distinct conformational differences for the partial sequences were found. Tetrapeptides with the Thr-Pro-Ser-Pro sequence were found to show a clear preference for the beta-turn conformation. Conformational equilibria of these peptides are only slightly affected by acetylation or pH changes. In the case of Pro-Thr-Pro-Ser tetrapeptides conformational equilibria are dominated by unordered forms.


[Genetic studies of Photobacterium mandapamensis. II. The classification of mutants with an altered luminescence intensity according to their sensitivity to exogenous aldehyde].
The collection of 157 dark and dim Photobacterium mandapamensis strains was divided into four groups using the addition of 0.2 ml of 0.15% myristis aldehyde to cell suspension. The luminescence did not change in the presence of the aldehyde in 76 mutants, it decreased in 30 mutants, it was 2--8-fold increased in 35 mutants, and it was increased more than 10-fold in 16 mutant strains. 19 strains of those having luminescence in the presence of the aldehyde have mutations in genes controlling the biosynthesis of the aldehyde factor. Among them mutants are chosen which can be used as indicators for the aldehyde presence in the medium.


Fibrosarcoma of the neck in an adult female.
This paper is a case report of a 53-year-old housewife with fibrosarcoma of the neck. On 27 August 1986, she was admitted to our hospital with discomfort on the right side of her throat and difficulty in swallowing. She had no history of radiation therapy to the neck. The tumor was below the right submandibular gland and was movable. No enlarged lymph nodes were palpated in the neck. The mean CT number of the tumor was 59.5 H.U. The tumor was almost circular and its surface was smooth. Upon operating, the tumor was observed to be connected to the greater cornu of the hyoid bone and the superior cornu of the thyroid cartilage. The tumor measured 50 x 42 x 35 mm and was well circumscribed but not encapsulated. The cut surfaces were generally fleshy, glistening and grayish-white. The tumor was composed of small amounts of collagen and reticulin, producing fairly uniform spindle cells arranged in interlacing bundles, forming a herring bone pattern. The tumor cell showed rather little atypism, but did show obvious mitotic activity. Thus, the tumor was diagnosed as well-differentiated fibrosarcoma. When the patient was last seen, in April 1989, there was no evidence of recurrence.


Comparison of cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer.
The study objective was to compare cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer. Between 2010 and 2015, 457 patients with clinical stage IA (8th edition) non-small cell lung cancer undergoing wedge resection or segmentectomy were identified at 3 institutions. Propensity scores were calculated on the basis of the extent of resection (wedge resection or segmentectomy) and included adjustment for confounding variables, such as age, sex, smoking status, pulmonary functions, laterality, tumor size, maximum standardized uptake value on 18F-fluorodeoxyglucose positron emission tomography, presence of ground-glass opacity on high-resolution computed tomography, histology, and visceral pleural invasion for multivariable analysis and matching. The primary end point was cumulative incidence of recurrence. In all cohorts, postoperative recurrence occurred in 36 of 195 patients (18.5%) undergoing wedge resection and 14 of 262 patients (5.3%) undergoing segmentectomy. Cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 5.3%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 19.1%; P < .001). In propensity score-adjusted multivariable analysis, segmentectomy was identified as an independent favorable prognostic factor for cumulative incidence of recurrence (hazard ratio, 0.47; 95% confidence interval, 0.24-0.90; P = .022). In propensity score matching of 163 pairs, cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 6.6%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 13.2%; P = .041). Cancer control was better in segmentectomy than in wedge resection. Segmentectomy is the preferred oncologic procedure as sublobar resection to treat clinical stage IA non-small cell lung cancer.


A novel regulatory facet for hypertriglyceridemia: The role of microRNAs in the regulation of triglyceride-rich lipoprotein biosynthesis.
Atherosclerotic cardiovascular disease (ASCVD) is one of the major leading global causes of death. Genetic and epidemiological studies strongly support the causal association between triacylglycerol-rich lipoproteins (TAGRL) and atherogenesis, even in statin-treated patients. Recent genetic evidence has clarified that variants in several key genes implicated in TAGRL metabolism are strongly linked to the increased ASCVD risk. There are several triacylglycerol-lowering agents; however, new therapeutic options are in development, among which are miRNA-based therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs (18-25 nucleotides) that negatively modulate gene expression through translational repression or degradation of target mRNAs, thereby reducing the levels of functional genes. MiRNAs play a crucial role in the development of hypertriglyceridemia as several miRNAs are dysregulated in both synthesis and clearance of TAGRL particles. MiRNA-based therapies in ASCVD have not yet been applied in human trials but are attractive. This review provides a concise overview of current interventions for hypertriglyceridemia and the development of novel miRNA and siRNA-based drugs. We summarize the miRNAs involved in the regulation of key genes in the TAGRLs synthesis pathway, which has gained attention as a novel target for therapeutic applications in CVD.


The Müller-Lyer illusion in the teleost fish Xenotoca eiseni.
In the Müller-Lyer illusion, human subjects usually see a line with two inducers at its ends facing outwards as longer than an identical line with inducers at its ends facing inwards. We investigate the tendency for fish to perceive, in suitable conditions, line length according to the Müller-Lyer illusion. Redtail splitfins (Xenotoca eiseni, family Goodeidae) were trained to discriminate between two lines of different length. After reaching the learning criterion, the fish performed test trials, in which they faced two lines (black or red) of identical length, differing only in the context in terms of arrangement of the inducers, which were positioned at the ends of the line, either inward, outward, or perpendicular. Fish chose the stimulus that appear to humans as either longer or shorter, in accordance with the prediction of the Müller-Lyer illusion, consistently with the condition of the training. These results show that redtail splitfins tend to be subject to this particular illusion. The results of the study are discussed with reference to similar studies concerning the same illusion as recently observed in fish. Contrasting results are presented. The significance of the results in light of their possible evolutionary implications is also discussed.


Rosiglitazone improves muscle insulin sensitivity, irrespective of increased triglyceride content, in ob/ob mice.
The present study was performed to examine the effects of rosiglitazone treatment on tissue-specific insulin sensitivity. Therefore, we used obese, insulin-resistant ob/ob mice and measured the effects of rosiglitazone treatment on insulin sensitivity and simultaneously tissue-specific uptake of glucose and free fatty acids (FFA) under hyperinsulinemic euglycemic clamp conditions. Rosiglitazone treatment resulted in significantly higher body weight and decreased plasma levels of glucose, insulin, and triglyceride (TG). Glucose tolerance, as well as insulin sensitivity, was improved upon rosiglitazone treatment, as assessed by glucose tolerance and insulin sensitivity tests. Hyperinsulinemic euglycemic clamps showed increased glucose infusion rates with increased whole body insulin sensitivity. Rosiglitazone treatment resulted in increased glucose uptake by cardiac and skeletal muscle under hyperinsulinemic euglycemic clamp conditions, while no differences were observed in FA uptake. Measurement of TG content showed that rosiglitazone treatment resulted in decreased TG content of cardiac muscle, but increased TG content of skeletal muscle. We conclude that rosiglitazone treatment leads to strong improvement of insulin sensitivity, irrespective of increased muscle TG content, in ob/ob mice.


Effect of probiotic supplementation on plasma metabolite profile after Roux-Y gastric bypass: a prospective, randomized, double-blind, placebo-controlled clinical trial.
There is evidence that metabolic profile changes after Roux-Y gastric bypass (RYGB), especially due to modifications in the gastrointestinal tract. In addition, previous studies have suggested that probiotics can modify the microbiome and produce metabolites important for metabolic health maintenance. In this sense, the aim of this study was to verify the influence of probiotic supplementation on the plasma metabolite profile after RYGB. This was a randomized, double-blind, placebo-controlled clinical trial conducted with 31 patients subjected to RYGB surgery, randomized in probiotic group that was supplemented with a probiotic supplement (FloraVantage®) for 3 months after surgery or a placebo group. Plasma metabonomics was performed using nuclear magnetic resonance (NMR) at the preoperative period (T0) and at 45-50 days (T1) and 90-95 days (T2) during the postoperative period/intervention. Reductions in trimethylamine-N-oxide (TMAO) and alanine were observed in both groups, however this reduction was greater in the probiotic group (TMAO 13.82%, p = 0.01 and alanine 14.03%, p = 0.03) at T2. Additionally, β-hydroxybutyrate (BHB) levels increased 10.77% in the probiotic group (p = 0.03) compared to the placebo group at T2. Supplementation with Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 was able to associate with significant differences in relevant plasma metabolites associated with improved metabolic health.


The Genomics of Hairy Cell Leukaemia and Splenic Diffuse Red Pulp Lymphoma.
Classical hairy cell leukaemia (HCLc), its variant form (HCLv), and splenic diffuse red pulp lymphoma (SDRPL) constitute a subset of relatively indolent B cell tumours, with low incidence rates of high-grade transformations, which primarily involve the spleen and bone marrow and are usually associated with circulating tumour cells characterised by villous or irregular cytoplasmic borders. The primary aim of this review is to summarise their cytogenetic, genomic, immunogenetic, and epigenetic features, with a particular focus on the clonal BRAFV600E mutation, present in most cases currently diagnosed with HCLc. We then reflect on their cell of origin and pathogenesis as well as present the clinical implications of improved biological understanding, extending from diagnosis to prognosis assessment and therapy response.


Ontogeny of polyamines in relation to nucleic acids in brain and spinal cord of the developing human fetus.
The polyamines, spermine and spermidine, and the diamine, putrescine, were estimated in relation to the distribution of RNA and DNA in cerebral cortex, cerebellum and spinal cord of the human CNS during prenatal development. Polyamines were found to be maximally located in the spinal cord, minimum being in cerebellum. Relation between polyamines and nucleic acids was region specific.


SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.


Embryonic induction: is the Nieuwkoop centre a useful concept?
Regionalisation of the amphibian embryo is classically thought to involve induction by the Spemann organiser, itself induced by the Nieuwkoop centre. This model has now been extended to teleosts, with the identification of a gene that appears to define the zebrafish equivalent of the Nieuwkoop centre.


Discovery of the possible mechanisms in kouyanqing granule for treatment of oral ulcers based on network pharmacology.
Oral ulcer diseases are complex inflammatory diseases caused by multi-factors, which severely impact patient quality of life. Kouyanqing Granule (KYQG) has been used to treat inflammatory diseases of the mouth and throat, including recurrent aphthous stomatitis (RAS), traumatic ulcers, oral leukoplakia and so on. However, the underlying molecular mechanisms of KYQG in treating these diseases are still unclear. We aimed to explore the possible mechanisms in KYQG for the treatment of oral ulcers. An innovative network pharmacology method was established by incorporating targets searching and fishing, network analysis, and silico validation to discover the pharmacological mechanisms of action of KYQG for the treatment of oral ulcers. Then, we verified the reliability of this method by an animal experiment. Our data indicated that a total of 47 key targets were screened, which mainly involved in three function modules including the inhibition of inflammation, the regulation of immunological response, and the suppression of oxidative stress. The implementation of these functions relies on the complex multi-pathways network, especially TNF signaling pathway and HIF-1 signaling pathway. The results of the experimental verification indicated that KYQG significantly inhibited the serum levels of cyclooxygenase-2 (COX2), matrix metalloproteinase 9 (MMP9) and tumor necrosis factor-alpha (TNF-α) in rats with oral ulcer. KYQG exhibited the therapeutic effects on oral ulcers probably by inhibiting inflammation, regulating immunological response, and suppressing oxidative stress through a complex multi-pathways network. Particularly, TNF signaling pathway and HIF-1 signaling pathway may play crucial roles in the protection of KYQG against oral ulcers. This work not only offers a method for understanding the functional mechanisms of KYQG for treating oral ulcer diseases from a multi-scale perspective but also may provide an efficient way for research and development of complex composition formula.


Next-generation sequencing analysis of semen microbiome taxonomy in men with nonobstructive azoospermia vs. fertile controls: a pilot study.
To study how the semen microbiome profile in men with nonobstructive azoospermia (NOA) differs from that of fertile controls (FCs). Using quantitative polymerase chain reaction and 16S ribosomal RNA, we sequenced semen samples from men with NOA (follicle-stimulating hormone >10 IU/mL, testis volume <10 mL) and FCs and performed a comprehensive taxonomic microbiome analysis. All patients were identified during evaluation at the outpatient male andrology clinic at the University of Miami. In total, 33 adult men, including 14 diagnosed with NOA and 19 with proven paternity undergoing vasectomy, were enrolled. Bacterial species in the semen microbiome were identified. Alpha-diversity was similar between the groups, suggesting similar diversity within samples, whereas beta-diversity was different, suggesting differences in taxa between samples. In the NOA men, the phyla Proteobacteria and Firmicutes were underrepresented, and Actinobacteriota were overrepresented compared with FC men. At the genus level, Enterococcus was the most common amplicon sequence variant in both groups, whereas 5 genera differed significantly between the groups, including Escherichia and Shigella, Sneathia, and Raoutella. Our study showed significant differences in the seminal microbiome between men with NOA and fertile men. These results suggest a loss of functional symbiosis may be associated with NOA. Further research into the characterization and clinical utility of the semen microbiome and its causal role in male infertility is necessary.


Excess premature (3-month) mortality in advanced pancreatic cancer could be related to fatal vascular thromboembolic events. A hypothesis based on a systematic review of phase III chemotherapy studies in advanced pancreatic cancer.
An at least 3-month expected survival is a common inclusion criterion in cancer treatment trials, including advanced pancreatic cancer phase III studies. Published survival curves for advanced pancreatic cancer however seem to reflect a substantial survival shortfall. We wanted to assess the strength of this observation and search for an explanation by reviewing the literature. A Medline and EMBASE search was done for chemotherapy or chemotherapy based phase III studies in advanced pancreatic cancer published since 1997. Similar search was done at the American Society's of Clinical Oncology web site for abstracts presented since 2000. Three months mortality was based on the survival curves presented. Fourteen papers and five abstracts met our criteria and are included in our review. Six thousand two hundred and twelve patients participated in these trials and 1,447 (23.3%) died in the first 3-month period. Figures were worse in patients with metastases and poorer performance status. Assuming that most deaths during treatment happened during the first 3-months, cause of death was reported in only 40 cases (2.8%). Progressive cancer was reported as cause of death in 21 of these cases. Less frequent causes of death were reported to be infections, 'complications of cancer', thromboembolic events and renal failure. Overall treatment-related deaths represent a very small percentage of the deaths happening during the 3-month period, and are unlikely to be under-reported given the Good Clinical Practice oversight of these trials. Progressive cancer is likely to be an important cause of early mortality but given the very select nature of the trial-related population this cannot explain the phenomenon of 3-month early death burden of 23.3%. Our hypothesis, supported by multiple autopsy series, is that early death burden in advanced pancreatic cancer trial patients is likely to be due to under-reported vascular thromboembolic events. Thromboprophylaxis needs to be addressed in future trials.


Prognostic utility of a novel risk prediction model of 1-year mortality in patients surviving to discharge after surgery for congenital or acquired heart disease.
We sought to develop a novel risk prediction model of 1-year mortality after congenital heart surgery that accounts for clinical, anatomic, echocardiographic, and socioeconomic factors. This was a single-center, retrospective review of consecutive index operations for congenital or acquired heart disease, from January 2011 to January 2021, among patients with known survival status at 1 year after discharge from the index hospitalization. The primary outcome was postdischarge mortality at 1 year. Variables of interest included age, prematurity, noncardiac anomalies or syndromes, the Childhood Opportunity Index, primary procedure, major adverse postoperative complications, and the Residual Lesion Score. Logistic regression was used to develop a weighted risk score for the primary outcome. Internal validation using a bootstrap-resampling approach was performed. Of 10,412 consecutive operations for congenital or acquired heart disease, 8808 (84.6%) cases met entry criteria, including survival to discharge. There were 190 (2.2%) deaths at 1 year postdischarge. A weighted risk score was formulated on the basis of the variables in the final risk prediction model, which included all aforementioned risk factors of interest. This model had a C-statistic of 0.82 (95% confidence interval, 0.80-0.85). The median risk score was 6 (interquartile range, 4-8) points. Patients were categorized as low (score 0-5), medium (score 6-10), high (score 11-15), or very high (score 16-20) risk. The expected probability of mortality was 0.4% ± 0.2%, 2.0% ± 1.1%, 10.1% ± 5.0%, and 36.6% ± 9.6% for low-risk, medium-risk, high-risk, and very high-risk patients, respectively. A risk prediction model of 1-year mortality may guide prognostication and follow-up of patients after discharge after surgery for congenital or acquired heart disease.


Spatial-temporal analysis of dengue deaths: identifying social vulnerabilities.
Currently, dengue fever, chikungunya fever, and zika virus represent serious public health issues in Brazil, despite efforts to control the vector, the Aedes aegypti mosquito. This was a descriptive and ecological study of dengue deaths occurring from 2002 to 2013 in São Luis, Maranhão, Brazil. Geoprocessing software was used to draw maps, linking the geo-referenced deaths with urban/social data at census tract level. There were 74 deaths, concentrated in areas of social vulnerability. The use of geo-technology tools pointed to a concentration of dengue deaths in specific intra-urban areas.


Numerical investigation of airflow in an idealized human extra-thoracic airway: a comparison study.
Large eddy simulation (LES) technique is employed to numerically investigate the airflow through an idealized human extra-thoracic airway under different breathing conditions, 10, 30, and 120 l/min. The computational results are compared with single and cross hot-wire measurements, and with time-averaged flow field computed by standard [Formula: see text] and [Formula: see text]-SST Reynolds-averaged Navier-Stokes (RANS) models and the Lattice Boltzmann method (LBM). The LES results are also compared to root-mean-square (RMS) flow field computed by the Reynolds stress model (RSM) and LBM. LES generally gives better prediction of the time-averaged flow field than RANS models and LBM. LES also provides better estimation of the RMS flow field than both the RSM and the LBM.


HIV-associated talaromycosis: Does timing of antiretroviral therapy matter?
No current academic data is available with respect to the optimal timing to initiate antiretroviral therapy (ART) in HIV-positive patients with talaromycosis. Our study aimed to evaluate the optimal timing of ART initiation for patients presenting with AIDS-related talaromycosis. In this prospective, randomized, open-label multicenter trial, 228 patients from 15 hospitals in China were randomly assigned to an early ART group (initiation of ART within 2 weeks after randomization) and a deferred ART group (initiation of ART 2 weeks after randomization). The primary endpoint was all-cause mortality during the 48 weeks after randomization. We observed a significant difference in mortality between the early ART group and the deferred ART group (2.2% vs. 8.9%, 95%CI: -0.15 to 14.05, p = 0.049). The composite outcome of AIDS-defining events or death in the early ART group was found to be lower than that in the deferred ART group (3.3% vs. 14.9%; 95%CI: 2.93 to 19.23, p = 0.008). The prognosis of HIV-infected patients with talaromycosis in the early ART group was more favorable than that of patients in the deferred ART group. These results demonstrate that early ART initiation should be considered in HIV-infected patients with talaromycosis .


Genetic analyses using GGE model and a mixed linear model approach, and stability analyses using AMMI bi-plot for late-maturity alpha-amylase activity in bread wheat genotypes.
Low falling number and discounting grain when it is downgraded in class are the consequences of excessive late-maturity α-amylase activity (LMAA) in bread wheat (Triticum aestivum L.). Grain expressing high LMAA produces poorer quality bread products. To effectively breed for low LMAA, it is necessary to understand what genes control it and how they are expressed, particularly when genotypes are grown in different environments. In this study, an International Collection (IC) of 18 spring wheat genotypes and another set of 15 spring wheat cultivars adapted to South Dakota (SD), USA were assessed to characterize the genetic component of LMAA over 5 and 13 environments, respectively. The data were analysed using a GGE model with a mixed linear model approach and stability analysis was presented using an AMMI bi-plot on R software. All estimated variance components and their proportions to the total phenotypic variance were highly significant for both sets of genotypes, which were validated by the AMMI model analysis. Broad-sense heritability for LMAA was higher in SD adapted cultivars (53%) compared to that in IC (49%). Significant genetic effects and stability analyses showed some genotypes, e.g. 'Lancer', 'Chester' and 'LoSprout' from IC, and 'Alsen', 'Traverse' and 'Forefront' from SD cultivars could be used as parents to develop new cultivars expressing low levels of LMAA. Stability analysis using an AMMI bi-plot revealed that 'Chester', 'Lancer' and 'Advance' were the most stable across environments, while in contrast, 'Kinsman', 'Lerma52' and 'Traverse' exhibited the lowest stability for LMAA across environments.


[Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia].
Sixty-two patients with generalized anxiety disorder (GAD) and neurasthenia were studied. The effect of selank (30 patients) was compared to that of medazepam (32 patients). Patient's state was assessed with psychometric scales (Hamilton, Zung, CGI). Enkephalin activity in the blood serum was measured as well. The anxiolytic effects of both drugs were similar but selank had also antiasthenic and psychostimulant effects. The clinical-biological study revealed that patients with GAD and neurasthenia had the decreased level of tau(1/2) leu-enkephalin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with selank mostly in patients with GAD.


A scale for the estimation of sleep problems in clinical research.
Problems in sleeping are widely prevalent in modern society and are often one of the presenting complaints of patients consulting physicians. In addition, there is scattered epidemiologic evidence and considerable clinical support that disturbed or inadequate sleep may be a risk factor for clinical emergence of cardiovascular disease and for total mortality. The role of sleep problems both as a precursor and as a sequela of disease states could be better delineated in large groups by the availability of a brief, reliable and standardized scale for sleep disturbance. Such a scale could also be used to evaluate the impact of different therapies upon sleep problems. This paper presents data from two study populations responding to three and four item self-report scales. From 9 to 12% of air traffic controllers reported various sleep problems to have occurred on half or more of the days during the prior month, whereas 12-22% of patients 6 months after cardiac surgery reported such frequent sleep problems. Utilizing data from the 6 and 12 month follow-ups, test-retest reliability of the three-item scale in cardiac surgery patients was found to be 0.59. Internal consistency coefficients for the three and four-item scales were 0.63 and 0.79 respectively.


Pattern recognition control of multifunction myoelectric prostheses by patients with congenital transradial limb defects: a preliminary study.
Electromyography (EMG) pattern recognition offers the potential for improved control of multifunction myoelectric prostheses. However, it is unclear whether this technology can be successfully used by congenital amputees. The purpose of this investigation was to assess the ability of congenital transradial amputees to control a virtual multifunction prosthesis using EMG pattern recognition and compare their performance to that of acquired amputees from a previous study. Preliminary cross-sectional study. Four congenital transradial amputees trained and tested a linear discriminant analysis (LDA) classifier with four wrist movements, five hand movements, and a no-movement class. Subjects then tested the classifier in real time using a virtual arm. Performance metrics for the residual limb were poorer than those with the intact limb (classification accuracy: 52.1% ± 15.0% vs. 93.2% ± 15.8%; motion-completion rate: 49.0%± 23.0% vs. 84.0% ± 9.4%; motion-completion time: 2.05 ± 0.75 s vs. 1.13 ± 0.05 s, respectively). On average, performance with the residual limb by congenital amputees was reduced compared to that reported for acquired transradial amputees. However, one subject performed similarly to acquired amputees. Pattern recognition control may be a viable option for some congenital amputees. Further study is warranted to determine success factors.


Experimental evidence of harmful effects of Crithidia mellificae and Lotmaria passim on honey bees.
The trypanosomatids Crithidia mellificae and Lotmaria passim are very prevalent in honey bee colonies and potentially contribute to colony losses that currently represent a serious threat to honey bees. However, potential pathogenicity of these trypanosomatids remains unclear and since studies of infection are scarce, there is little information about the virulence of their different morphotypes. Hence, we first cultured C. mellificae and L. passim (ATCC reference strains) in six different culture media to analyse their growth rates and to obtain potentially infective morphotypes. Both C. mellificae and L. passim grew in five of the media tested, with the exception of M199. These trypanosomatids multiplied fastest in BHI medium, in which they reached a stationary phase after around 96 h of growth. Honey bees inoculated with either Crithidia or Lotmaria died faster than control bees and their mortality was highest when they were inoculated with 96 h cultured L. passim. Histological and Electron Microscopy analyses revealed flagellated morphotypes of Crithidia and Lotmaria in the lumen of the ileum, and adherent non-flagellated L. passim morphotypes covering the epithelium, although no lesions were evident. These data indicate that parasitic forms of these trypanosomatids obtained from the early stationary growth phase infect honey bees. Therefore, efficient infection can be achieved to study their intra-host development and to assess the potential pathogenicity of these trypanosomatids.


[Effect of chondroitin sulfate-A attached titanium surface on culture osteoblast].
To investigation the in vitro effect of CS-A attached titanium surface on the culture of osteoblast. We examined the cell proliferation, the ALP activities, and the Calcium contents in the Ostelblast cultured on the Titanium surfaces attached with different concentrations of CS-A Calcium. The CS-A promots the proliferation of osteoblast and increases the calcium content on the titanium disks. The biocompatibility of titanium was improved after CS-A attached titanium surface.


Effect of Post-Cesarean Delivery Oral Cephalexin and Metronidazole on Surgical Site Infection Among Obese Women: A Randomized Clinical Trial.
The rate of obesity among US women has been increasing, and obesity is associated with increased risk of surgical site infection (SSI) following cesarean delivery. The optimal perioperative antibiotic prophylactic regimen in this high-risk population undergoing cesarean delivery is unknown. To determine rates of SSI among obese women who receive prophylactic oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery. Randomized, double-blind clinical trial comparing oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery for the prevention of SSI in obese women (prepregnancy BMI ≥30) who had received standard intravenous preoperative cephalosporin prophylaxis. Randomization was stratified by intact vs rupture of membranes prior to delivery. The study was conducted at the University of Cincinnati Medical Center, Cincinnati, Ohio, an academic and urban setting, between October 2010 and December 2015, with final follow-up through February 2016. Participants were randomly assigned to receive oral cephalexin, 500 mg, and metronidazole, 500 mg (n = 202 participants), vs identical-appearing placebo (n = 201 participants) every 8 hours for a total of 48 hours following cesarean delivery. The primary outcome was SSI, defined as any superficial incisional, deep incisional, or organ/space infections within 30 days after cesarean delivery. Among 403 randomized participants who were included (mean age, 28 [SD, 6] years; mean BMI, 39.7 [SD, 7.8]), 382 (94.6%) completed the trial. The overall rate of SSI was 10.9% (95% CI, 7.9%-14.0%). Surgical site infection was diagnosed in 13 women (6.4%) in the cephalexin-metronidazole group vs 31 women (15.4%) in the placebo group (difference, 9.0% [95% CI, 2.9%-15.0%]; relative risk, 0.41 [95% CI, 0.22-0.77]; P = .01). There were no serious adverse events, including allergic reaction, reported in either the antibiotic group or the placebo group. Among obese women undergoing cesarean delivery who received the standard preoperative cephalosporin prophylaxis, a postoperative 48-hour course of oral cephalexin and metronidazole, compared with placebo, reduced the rate of SSI within 30 days after delivery. For prevention of SSI among obese women after cesarean delivery, prophylactic oral cephalexin and metronidazole may be warranted. clinicaltrials.gov Identifier: NCT01194115.


Kinetics, mechanism, and application of sodium persulfate activated by sodium hydroxide for removing 1,2-dichloroethane from groundwater.
1,2-Dichloroethane (1,2-DCA) is a common compound found in groundwater contaminated with organics. This compound is difficult to remove from groundwater and has the potential to inflict significant harm on human health and the environment. This study used sodium persulfate (Na2S2O8) activated by sodium hydroxide (NaOH) to remove 1,2-DCA from aqueous solutions. Density functional theory was employed to calculate the potential energy surface of the reactants, intermediates, transient states, and products to thoroughly analyze the degradation pathways. The computations were performed in combination with in situ remediation of a 1,2-DCA plume from a point source to verify the industrial applicability of the technology. The results showed the 1,2-DCA removal efficiency was impacted considerably by the Na2S2O8 dosage and the dosing sequence of Na2S2O8 and NaOH, with the mean removal ratio reaching 96.24%. A free radical reaction was the main pathway of 1,2-DCA degradation; superoxide radical (O2•-) existed stably and played a key role in the reaction, and the main transformation proceeded via a vinyl chloride intermediate. The maximum removal of 1,2-DCA reached 91.79% in the in situ remediation. The developed technology exhibits important advantages in enabling flexible control over chemical dosages, long durations of effective activity, and rapid full-cycle remediation.


AQP3-mediated activation of the AMPK/SIRT1 signaling pathway curtails gallstone formation in mice by inhibiting inflammatory injury of gallbladder mucosal epithelial cells.
Inflammatory injury of gallbladder mucosal epithelial cells affects the development of cholelithiasis, and aquaporin 3 (AQP3) is an important regulator of inflammatory response. This study reports a mechanistic insight into AQP3 regulating gallstone formation in cholelithiasis based on high-throughput sequencing. A mouse model of cholelithiasis was induced using a high-fat diet, and the gallbladder tissues were harvested for high-throughput sequencing to obtain differentially expressed genes. Primary mouse gallbladder mucosal epithelial cells were isolated and induced with Lipopolysaccharides (LPS) to mimic an in vitro inflammatory injury environment. Cell biological phenotypes were detected by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay, flow cytometry, Cell Counting Kit-8 (CCK-8) assay, and Trypan blue staining. In addition, enzyme linked immunosorbent assay (ELISA) determined the production of inflammatory factors in mouse gallbladder mucosa. Whole-transcriptome sequencing data analysis identified 489 up-regulated and 1007 down-regulated mRNAs. Bioinformatics analysis revealed that AQP3 was significantly down-regulated in mice with cholelithiasis. AQP3 might also confer an important role in LPS-induced gallbladder mucosal injury. Overexpression of AQP3 activated the AMPK (adenosine monophosphate-activated protein kinase) / SIRT1 (sirtuin-1) signaling pathway to reduce LPS-induced inflammatory injury of the gallbladder mucosa epithelium, thereby ameliorating gallbladder damage and repressing gallstone formation in mice. Data from our study highlight the inhibitory role of AQP3 in gallbladder damage and gallstone formation in mice by reducing inflammatory injury of gallbladder mucosal epithelial cells, which is achieved through activation of the AMPK/SIRT1 signaling pathway.


Kidney-secreted erythropoietin lowers lipidemia via activating JAK2-STAT5 signaling in adipose tissue.
Dyslipidemia is commonly observed in various kidney diseases, renal specific secreted erythropoietin (EPO) may participate in this process. However, how this process is regulated remains elusive. Dyslipidemia was evaluated in chronic kidney disease and ischemia kidney injury animal model. Primary cultured adipocytes were harvested to investigate the lipid metabolic effect of EPO. Lipidemia was evaluated in EPO treated animals. Blood samples from cardiac surgery-induced kidney injury patient were collected to assess correlationship between EPO and lipidemia. We found a decrease in secreted EPO and hypertriglyceridemia in chronic kidney disease (CKD) mice. In contrast, in renal ischemia animal model, increased EPO triggered by hypoxia signaling activation, was accompanied by decreased triglyceride (TG) in serum. Mechanistically, circulating EPO modulated JAK2-STAT5 signaling, which in turn enhanced lipid catabolism in peripheral adipose tissue and contributed to dysregulated lipidemia. Delivering of recombinant EPO into both wild type and CKD mice suppressed TG in serum by accelerating lipid catabolism in adipose tissue. In a cohort of patients diagnosed with acute kidney injury after cardiopulmonary bypass surgery, the decreased TG and cholesterol negatively correlated with increased EPO in serum. This study depicted a new mechanism by which renal secreted EPO controlled lipidemia in kidney diseases including chronic kidney disease. Circulating EPO stimulated lipid catabolism by targeting JAK2-STATA5 signaling in peripheral adipose tissue, providing new therapeutic target for dyslipidemia treatment. This work was supported by grants from the National Natural Science Foundation of China (Nos. 81700640 and 81970608).


Microsuction of blastocoelic fluid before vitrification increased survival and pregnancy of mouse expanded blastocysts, but pretreatment with the cytoskeletal stabilizer did not increase blastocyst survival.
To ascertain effects of thermal change, size of blastocoele, artificial shrinkage, and cytoskeletal stabilizer on survival of blastocysts from vitrification. In vitro and in vivo study. University infertility clinic and academic research laboratory. Female mice of outbred ICR strain, aged 6 to 8 weeks. In experiment 1, various stages of mouse blastocysts were vitrified by using conventional straws or closed pulled straws (CPS). In experiment 2, microsuction was performed of blastocoelic fluid for blastocysts and expanded blastocysts before vitrification. In experiment 3, cytochalasin B (CCB) was used to treat embryos during vitrification. In experiment 4, vitrified expanded blastocysts were transferred to pseudopregnant mice. Survival and pregnancy. The survival rates of early blastocysts were high and not different between the conventional straws and the CPS. The survival rates decreased for blastocysts and expanded blastocysts in both of the two methods. But the use of CPS achieved higher survival rates for blastocysts (83% vs. 70%) and expanded blastocysts (60% vs. 39%) than did the conventional straws. Microsuction before vitrification increased the survival rates for blastocysts (92% vs. 80%) and expanded blastocysts (89% vs. 59%). Survival of vitrified embryos was not distinct between CCB treatment and non-CCB treatment. The percentage of live young from vitrified expanded blastocysts using microsuction was greater than that from vitrified expanded blastocysts without microsuction (34% vs. 9%). The size of the blastocoeles influenced survival of blastocysts from vitrification. A rapid thermal change of CPS and effective reduction of blastocoelic fluid by microsuction may facilitate vitrification and reduce ice crystal damage for blastocysts and expanded blastocysts. The microfilament inhibitor of CCB treatment did not increase their survival rates.


Effects of Replacing a Central Glycine Residue in GLP-1 on Receptor Affinity and Signaling Profile.
Agonists of the glucagon-like peptide-1 receptor (GLP-1R) are used to treat diabetes and obesity. Cryo-EM structures indicate that GLP-1 is completely α-helical when bound to the GLP-1R. The mature form of this hormone, GLP-1(7-36), contains a glycine residue near the center (Gly22). Since glycine has the second-lowest α-helix propensity among the proteinogenic α-amino acid residues, and Gly22 does not appear to make direct contact with the receptor, we were motivated to explore the impact on agonist activity of altering the α-helix propensity at this position. We examined GLP-1 analogues in which Gly22 was replaced with L-Ala, D-Ala, or β-amino acid residues with varying helix propensities. The results suggest that the receptor is reasonably tolerant of variations in helix propensity, and that the functional receptor-agonist complex may comprise a conformational spectrum rather than a single fixed structure.


[Randomised clinical trial to evaluate the efficacy of a multi-factorial intervention to reduce hospitalisation and improve the quality of life of patients with heart failure].
To evaluate the efficacy of a multi-disciplinary non-pharmacological intervention to reduce cardiovascular mortality and hospital re-admissions due to heart failure. Randomised, open, controlled, parallel, multi-centre prospective clinical trial. Sardenya Primary Care Centre (PCC), les Corts PCC, "El Remei" PCC (Vic Sud), Vall d'Hebron Hospital, Hospital Clínic, Vic Hospital, Hospital Dos de Maig. 300 patients diagnosed with heart failure. Monthly home visits with intercalated phone calls from very well trained nursing staff to provide education on the illness and treatments, optimise therapy compliance, and inform on self-monitoring and management (especially early detection and treatment of decompensation). Combined variable of mortality for cardiovascular reasons and re-hospitalisation due to heart failure (via Casualty and/or Admissions) at 1 year. Health-related quality of life. Open study, as it is impossible to mask the intervention. The home intervention is not too complex and is easily performed by well-trained health professionals. Its use could be generalised, if a clinically relevant degree of efficacy was shown.


Rugose small colony variant and its hyper-biofilm in Pseudomonas aeruginosa: Adaption, evolution, and biotechnological potential.
One of the hallmarks of the environmental bacterium Pseudomonas aeruginosa is its excellent ecological flexibility, which can thrive in diverse ecological niches. In different ecosystems, P. aeruginosa may use different strategies to survive, such as forming biofilms in crude oil environment, converting to mucoid phenotype in the cystic fibrosis (CF) lung, or becoming persisters when treated with antibiotics. Rugose small colony variants (RSCVs) are the adaptive mutants of P. aeruginosa, which can be frequently isolated from chronic infections. During the past years, there has been a renewed interest in using P. aeruginosa as a model organism to investigate the RSCVs formation, persistence and pathogenesis, as RSCVs represent a hyper-biofilm formation, high adaptability, high-tolerance sub-population in biofilms. This review will briefly summarize recent advances regarding the phenotypic, genetic and host interaction associated with RSCVs, with an emphasis on P. aeruginosa. Meanwhile, some non-pathogenic bacteria such as Pseudomonas fluorescence, Pseudomonas putida and Bacillus subtilis will be also included. Remarkable emphasis is given on intrinsic functions of such hyper-biofilm formation characteristic as well as its potential applications in several biocatalytic transformations including wastewater treatment, microbial fermentation, and plastic degradation. Hopefully, this review will attract the interest of researchers in various fields and shape future research focused not only on evolutionary biology but also on biotechnological applications related to RSCVs.


Cutaneous diseases preceding diagnoses of lymphoreticular malignancies.
Dermatology visits during a 5-year period before the diagnosis of lymphoreticular malignancy in 258 subjects were reviewed and compared with visits made by 258 randomly selected, age- and sex-matched control subjects in the same period. Six of the 96 patients with leukemia and none of their matched controls (p less than 0.05) had cutaneous malignancies 20 to 60 months before the diagnosis of leukemia. There was no increase in cutaneous malignancies preceding lymphoma. A common factor predisposing to both cutaneous malignancy and leukemia, such as a defect in immunosurveillance, is suggested.


A prospective cohort study of trends in self-poisoning, Newcastle, Australia, 1987-2012: plus ça change, plus c'est la même chose.
To examine inhospital mortality and morbidity associated with self-poisoning with different drug classes over an extended period. A prospective cohort study over 26 years (1987-2012) with limited follow-up of patients presenting consecutively to a primary and tertiary referral toxicology centre covering Newcastle, Lake Macquarie and Port Stephens, Australia. Hospital length of stay, types of drugs ingested, intensive care unit (ICU) admission, requirement for ventilation, inhospital deaths and rates of antidepressant drug use in Australia. Over the study period, there were 17 266 admissions of patients poisoned by 34 342 substances (16 723 drugs available only on prescription). The median length of stay was 16 hours, 12.2% of patients (2101/17 266) were admitted to an ICU, 7.4% (1281/17 266) were ventilated and 78 (0.45%) died in hospital. Patient demographics, social and psychiatric factors remained stable over the 26-year period, but case fatality decreased (from 0.77% [15/1955] to 0.17% [7/4060]) as did ICU admissions (19.2% [376/1955] to 6.9% [280/4060]), ventilation (13.7% [268/1955] to 4.8% [193/4060]) and LOS. The most frequently ingested substances were alcohol, benzodiazepines, paracetamol, antidepressants and antipsychotics. There was a substantial fall in some highly toxic drugs (tricyclic antidepressants, barbiturates, conventional antipsychotics and theophylline), but increases in less toxic selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors and paracetamol. A greater than sixfold increase in community antidepressant use was accompanied by only minor changes in overall and antidepressant self-poisoning rates. Over two decades, there were decreases in poisonings by many highly toxic drugs which were associated with substantial reductions in morbidity and inhospital deaths. Despite massive increases in the number of antidepressant prescriptions, neither rates of self-harm nor the proportion of antidepressant poisonings increased markedly.


The influence of demographics and comorbidity on persistence with anti-seizure medication.
To examine the rate of persistence with anti-seizure medications (ASMs) in a cohort of patients with epilepsy, and to investigate the impact of a range of clinical and demographic factors on persistence METHODS: Patients receiving ASMs for epilepsy were identified from linked, routinely collected data within the NHS Greater Glasgow and Clyde health board area between January 2011 and August 2019. Persistence with individual ASMs at 365-days after initiation was assessed using a 90-day allowable gap between individual prescriptions. Univariate logistic regression was used to estimate the association between 1-year persistence with ASM and demographic characteristics, comorbidities, and medication characteristics. In total, 6,449 patients with epilepsy were identified - 1,631 were new users of ASMs at baseline and 4,818 had been prescribed at least one ASM prior to baseline. Persistence with individual ASMs ranged 11.8% to 78.6%. Persistence was significantly lower in younger patients and patients who had previously been non-persistent to ASMs. Persistence was higher amongst those with cardiac comorbidities, previous stroke, or higher overall comorbidity, as well as those prescribed newer ASMs. Persistence varied widely. Demographic factors, previous non-persistence and overall number of comorbidities were more important determinants of persistence to anti-seizure medications than specific individual comorbidities. Interventions to improve persistence should be targeted at younger patients from more deprived backgrounds and those who have previously been non-persistent with ASMs.


Normal epithelial cells modulating HLA class I surface molecules are susceptible to lysis mediated by CD3(+) and CD3(-) "nonspecific" killer cells.
Natural killer (NK) cells and NK-like T cells have been described as efficiently lysing neoplastic cells derived from hematopoietic tumors. By modulating the expression of HLA class I surface molecules on normal epithelial cells, we also observed that nonneoplastic cells can efficiently be lysed by "nonspecific" effectors. Clonal analysis clearly demonstrates that the presence of HLA-specific inhibitory NK receptors, such as CD94, CD158a, and CD158b, described on NK cells, is responsible for the inhibitory signal. Thus, NK cells, as well as NK-like T cells, in the absence of HLA surface molecules on normal target cells, efficiently lyse epithelial cells.


Metabolism of prostaglandin E1 and of glutathione conjugate of prostaglandin A1 (GSH-prostaglandin A1) by prostaglandin 9-ketoreductase from rabbit kidney.
Rabbit kidney prostaglandin 9-ketoreductase was found to metabolize the glutathione conjugate of prostaglandin A1 (GSH-prostaglandin A1). Apparent Km (GSH-prostaglandin A1) 13 microM and apparent Km (prostaglandin E1) 200 microM. The cytosolic preparation was subjected to gelfiltration and isoelectric focusing, which revealed that metabolism of prostaglandin E1 and GSH-prostaglandin A1 occurs by means of the same fractions. Furthermore, prostaglandin E1 and GSH-prostaglandin A1 are competitive inhibitors of the enzyme, when GSH-prostaglandin A1 and prostaglandin E1 are tested as substrates, respectively. It si concluded, that GSH-prostaglandin A1 is a much better substrate for prostaglandin 9-ketoreductase from rabbit kidney than is prostaglandin E1.


Src kinase contributes to the metastatic spread of carcinoma cells.
The involvement of Src kinase during carcinoma metastasis has been explored by using the NBT-II rat carcinoma cell line, which can be induced to scatter in vitro through Src activity. Here we show that Src activity was not required for growth of tumors derived from NBT-II cells injected into nude mice. In contrast, the presence of micrometastases was strictly dependent on Src, since the percentage of mice bearing metastases was dramatically reduced by the expression of a dominant-negative mutant of Src (SrcK-) or of Csk, the natural inhibitor of Src. Furthermore, metastatic cells originating from NBT-II cells displayed a Src activity higher than the parental cells, confirming that Src gives a selective advantage during the metastatic process. Finally, anatomopathological analysis of the primary tumors arising from NBT-II cells expressing Csk or SrcK- constructs revealed a highly differentiated epithelial phenotype contrasting with the poor differentiation of tumors derived from parental cells. The differentiated phenotype correlated with the presence of desmosomes at the cell periphery and the absence of vimentin intermediate filaments. Altogether, these data demonstrate that Src activity correlates with the loss of epithelial differentiation concomitantly with the increase of the metastatic potential of carcinoma cells.


Interrelationships between indices of longitudinal movement of the common carotid artery wall and the conventional measures of subclinical arteriosclerosis.
Our objective was to study the interrelationships between longitudinal movement of the wall of the common carotid artery and the conventional measures of arteriosclerosis in a large and well-characterized study population. Successful longitudinal movement analyses were performed on 292 subjects. The peak-to-peak and retrograde amplitudes of the longitudinal movement were directly correlated with carotid artery distensibility (r = 0·21, P<0·001 and r = 0·23, P<0·001, respectively) and inversely correlated with pulse wave velocity (r = -0·14, P<0·05 and r = -0·17, P<0·01, respectively). All longitudinal motion parameters were independent of brachial flow-mediated dilatation and intima-media thickness. Our findings indicate that arterial stiffening modulates longitudinal movement and, therefore, measurement of longitudinal movement can be of value in the assessment of vascular health.


Survival of Trypanosoma cruzi metacyclic trypomastigotes within Coxiella burnetii vacuoles: differentiation and replication within an acidic milieu.
Coxiella burnetii, the etiological agent of Q fever, is an obligate intracellular bacterium that resides within acidified vacuoles with secondary lysosomal characteristics. Infective stages of Trypanosoma cruzi, the causative agent of Chagas' disease, actively invade a wide variety of cells, a process followed by lysosomal recruitment. Recently, we have investigated and characterized early events that occur in Vero cells persistently colonized with C. burnetii when doubly infected with T. cruzi trypomastigote forms. Kinetic studies of trypomastigote transfer indicated that parasitophorous vacuoles (PV) of metacyclic trypomastigotes are rapidly and efficiently fused to C. burnetii vacuoles. Based on these observations we have investigated the behavior of metacyclic trypomastigotes within C. burnetii vacuoles beyond 12 h of co-infection inside Vero cells. Using indirect immunofluorescence with MAb against different developmental stages, it was possible to follow the T. cruzi differentiation process within C. burnetii vacuoles after up to 96 h post-invasion. We observed that metacyclic trypomastigotes began to differentiate after 12 h of infection, and 24 h later amastigotes were the prevailing forms within C. burnetii vacuoles. T. cruzi amastigote replication within C. burnetii vacuoles was confirmed using video and time-lapse confocal microscopy and around 36 h of co-infection, cytokinesis took about 70 min to occur. After 72 h, we observed that amastigote forms seemed to escape from C. burnetii vacuoles. Labeling of amastigotes within C. burnetii vacuoles using a polyclonal antibody to C9 complement protein suggested that TcTOX (T. cruzi hemolysin) could play a role in parasite escape from C. burnetii. We concluded that T. cruzi has an outstanding adaptation capability and can survive within a hostile milieu such as C. burnetii vacuoles.


Evaluation of the national nursing model and four nursing documentation systems in Finland--lessons learned and directions for the future.
To evaluate the feasibility of the national nursing model and usability of four widely used nursing documentation systems and to study their usefulness in multi-professional collaboration and information exchange. Qualitative usability study methods were used, including the use of scenario walkthroughs, contextual inquiries, thematic interviews and inspection-based expert reviews in the users' clinical contexts. The nursing process model was shown to be feasible in nursing practice but the national nursing classification was considered too detailed, multi-layered and difficult to use and understand. The four evaluated nursing documentation systems had many usability problems which resulted in them being difficult to use and produced extra documentation workload. Generally, electronic nursing documentation improves patients' and health professionals' legal protection and makes nursing care more transparent; however, the documentation systems did not provide good support for multi-professional care and information exchange. Nursing models should comply better with nursing practices and support nurses in patient care and interventions. An essential improvement in practice would be the use of specific templates that are easy to apply in specific situations with homogeneous patient groups. Collaborative care aspects and better utilization of information require that the nursing model is designed to support not just documentation but also information utilization.


Persistent organochlorines in raccoon dogs (Nyctereutes procyonoides) from Japan: Hepatic sequestration of oxychlordane.
The present study determined the accumulation features of persistent organochlorines (OCs) such as polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), and chlordane compounds (CHLs) in wild raccoon dogs (RDs; Nyctereutes procyonoides) collected from Kanagawa prefecture in Japan during 2001. In livers of RDs, CHLs were remarkably dominant (20 times higher than PCBs) followed by PCBs>DDTs>HCHs>HCB, whereas the chemicals in muscles were in the order of CHLs>PCBs>HCHs>DDTs>HCB. The accumulation pattern of OCs in RDs was different from those in Japanese humans and avian species reported previously, which generally accumulate higher levels of DDTs and PCBs than CHLs. This result indicates that RDs have been exposed to relatively high levels of CHLs and have high metabolic and elimination capacity for DDTs. In fact, CHL levels in RDs were higher than those in humans and some avian species, while DDT levels in RDs were much lower than other animals. In particular, extremely high accumulation levels of oxychlordane, which is a metabolite from chlordanes and nonachlors, were observed in RD livers. The higher toxic potency of oxychlordane than parent compounds may suggest that RDs are at high risk by this metabolite. On lipid weight basis, PCBs, HCHs and HCB levels were almost similar in livers and muscles, suggesting that the tissue distribution of these compounds principally followed the lipid-dependent accumulation. However, accumulation levels of oxychlordane and p,p'-DDD in livers were significantly higher than those in muscles, and concentration ratios of liver to muscle (L/M ratios) of these compounds were greater than 1.0 in all the specimens. This phenomenon was similar to PCDD/DF congener accumulation patterns observed previously in RDs. When relationships between hepatic TEQs and L/M ratios were examined for oxychlordane and p,p'-DDD, L/M ratios for these compounds significantly increased with hepatic TEQ levels, suggesting their hepatic sequestration in TEQs-dependent manner.


Adaptive differentiation of body size in speciating mole rats.
We report the body weight of 1,653 subterranean mole rats comprising 12 populations and 4 chromosomal species (2n=52, 54, 58 and 60) of the Spalax ehrenbergi superspecies in Israel. The sample was collected from 1970 to 1985 and includes all captured animals with a minimal age of 10 months. The results indicated the following. (a) Body weight of males was significantly higher than that of females. (b) There is a southward latitudinal gradient in body size. Northern animals living in cooler and more productive mesic environments are larger than southern animals living in warmer and less productive xeric environments. (c) The interspecific differences for each sex are statistically significant. (d) Body size is negatively correlated with temperature variables, and positively correlated with plant cover (reflecting productivity or food resources) and rainy days. (e) The best predictors of body size, explaining up to 87% of the variation in size included various combinations of temperature variables and plant cover.We conclude that in both adaptation and speciation natural selection is a major agent of differentiation of body size in accordance with multiple factors, primarily temperature and food resources operating on the energetics balance.


Immobilization of Lipase in Cu-BTC MOF with Enhanced Catalytic Performance for Resolution of N-hydroxymethyl Vince Lactam.
Metal-organic frameworks (MOFs) can be used as the immobilization carriers to protect the physicochemical properties of enzymes and improve their catalytic performance. Herein, we report an in situ co-precipitation method to immobilize lipase from Candida sp. 99-125 in Cu-BTC MOF (BTC = 1, 3, 5-benzene tricarboxylic acid, H3BTC). Characterizations of the immobilized lipase (lipase@Cu-BTC) have confirmed the entrapment of lipase molecules in Cu-BTC MOF. The immobilized lipase has been successfully applied for resolving N-hydroxymethyl vince lactam (N-HMVL) and its catalytic activity is five times that of native enzyme. More importantly, we found that Cu-BTC MOF can afford powerful protection for enzyme in nearly dry organic solvent and endow the immobilized lipase with excellent reusability and storage stability. Our present study may widen the application of immobilized enzyme with MOF as the immobilized carrier.


Impact of lymphovascular invasion on otherwise low-risk papillary thyroid carcinomas: a retrospective and observational study.
Presence of venous vascular invasion is a criterion of intermediate risk of recurrence in papillary thyroid carcinoma (PTC). However, the presence and type of vascular invasion (lymphatic or venous) is often underreported and its impact on PTCs without other risk features remains unknown. The aim of this study was to evaluate the impact of both lymphatic and venous invasion on the risk of recurrence/persistence on otherwise low-risk PTCs. Retrospective study including patients with otherwise low-risk PTCs but with vascular invasion, diagnosed between 2013 and 2019. The persistence/recurrence during the follow-up was evaluated. Pathology was reviewed to confirm the presence of lymphovascular invasion and determine the type of invasion. A total of 141 patients were included. Lymphovascular invasion was confirmed in 20.6%. After surgery, 48.9% (N = 69) of the patients received radioactive iodine (RAI). The median follow-up time was 4 [3-6] years. Overall, 6 (4.2%) patients experienced persistent/recurrent disease in the neck, including 3 with lymphovascular invasion, confirmed as "only lymphatic". Overall, patients with tumors harboring lymphovascular invasion had sensibly more persistent/recurrence disease compared with those without lymphovascular invasion (10.3% vs 2.7%, p = 0.1), especially in the subgroup of patients not treated with RAI (20% vs 1.6%, p = 0.049) [OR 15.25, 95% CI 1.24-187.85, p = 0.033]. Lymphovascular invasion, including lymphatic invasion only, is associated with a sensibly higher risk of persistent/recurrent disease in otherwise low-risk PTCs, namely in patients not treated with RAI. Lymphatic invasion could have a role in risk-stratification systems for decision making.


The next wave in metabolome analysis.
The metabolome of a cell represents the amplification and integration of signals from other functional genomic levels, such as the transcriptome and the proteome. Although this makes metabolomics a useful tool for the high-throughput analysis of phenotypes, the lack of a direct connection to the genome makes it difficult to interpret metabolomic data. Nevertheless, functional genomics has produced examples of the use of metabolomics to elucidate the phenotypes of otherwise silent mutations. Despite several successes, we believe that future metabolomic studies must focus on the accurate measurement of the concentrations of unambiguously identified metabolites. The research community must develop databases of metabolite concentrations in cells that are grown in several well-defined conditions if metabolomic data are to be integrated meaningfully with data from the other levels of functional-genomic analysis and to make a significant contribution to systems biology.


Isolation and biological characterization of mouse LM fibroblast variants resistant to the cytotoxicity of polyriboinosinic polyribocytidylic acid after interferon treatment.
Mouse LM fibroblasts growing continuously in the absence of serum have an increased sensitivity to the cytotoxicity of poly(rI) X poly(rC) after interferon (IFN) exposure. This has allowed the isolation by an enrichment procedure of several independent and stable variant clones (IFN + I X C)R which are resistant to such a treatment. One of the resistant variants has been more extensively characterized as far as IFN action and IFN production are concerned. It behaves identically to the wild-type parent except for the spontaneous release of low amounts of IFN. The target of the mutation probably resides in a late step in the development of the cytotoxic response as revealed by microinjection techniques. The (IFN + I X C)R variants characterized here thus appear different from mutants in the IFN system isolated so far.


The relationship between pre-registration house officers and their consultants.
Previous studies have drawn attention to the importance of the trainee/trainer relationship in determining job satisfaction and motivation to learn. To study the relationship between pre-registration house officers and their consultants through exploring an interpersonal exchange and the emotional context in which the exchange took place. To consider any association between the type of relationship implied and the trainee's attitude to their career. Postal questionnaire covering a wide range of issues. This study focused on an open question about a significant or interesting exchange, followed by supplementary questions exploring the emotional context of the exchange. 336 hospitals throughout the United Kingdom. A cohort of doctors were followed from the time of their application to medical school, and studied towards the end of their pre-registration year (n=2456). The response rate to the questionnaire was 58.4%. Responses were categorised as Support and supervision; Unreasonable behaviour; Consultant fallibility; Fair criticism and No exchange. Over half the responses described an interaction that made them feel positive. Trainees particularly appreciated positive feedback, clinical support, teaching, career advice, patronage, or social interaction. The importance of formal appraisal or review sessions in providing the setting for a positive exchange was confirmed. Positive interactions were associated with a positive view of medicine as a career. A minority described an interaction that was negative, involving unreasonable demands, criticism (whether perceived as fair or unfair), humiliation, or sexism. These were associated with a more negative view of medicine as a career, and of themselves as doctors.


Prostaglandins and gastrointestinal function.
Much work has been done and much remains to be done in defining the role of the prostaglandins in the physiology and pathophysiology of the gastrointestinal tract. The following statements summarize the current knowledge of the prostaglandins in human gastrointestinal function: 1. Prostaglandins of the E type have been isolated from human gastrointestinal tissue. They are naturally occurring 20 carbon hydroxy fatty acids synthesized and degraded in the same intestinal tissue by a 15-prostaglandin dehydrogenase. 2. Prostaglandins E2 and PGF2alpha have opposing, dose-related effects on the lower esophageal sphincter and lower two thirds of the esophagus. Sphincter pressure is decreased and esophageal contractions are inhibited by PGE2, whereas sphincter pressure is increased and esophageal contractions are induced by PGF2alpha. 3. Basal and stimulated gastric acid secretion is inhibited by PGE and its methyl analogues, but not by PGF, in a dose-related, nonselective manner. Oral administration of PGE methyl analogues may be an effective mode of therapy in peptic ulcer disease. 4. The prostaglandins reduce absorption and induce secretion of electrolytes and water in the jejunum and ileum but not in the colon. This secretory effect has been implicated in certain pathologic conditions. 5. The prostaglandins appear to be vasodilators of the hepatic circulation. Prostaglandin E contracts the gall bladder, relaxes the sphincter of Oddi and inhibits isosmotic fluid transport. 6. Pancreatic secretion and insulin release are inhibited by the prostaglandins in vivo and secretion is stimulated in vitro. The actual role of the prostaglandins in insulin release is not known.


Testicular development and the formation of spermatic granulomas of the epididymis after obstruction of the vas deferens in immature rats.
Aims were to determine the effects of obstruction of the vas deferens prior to sexual maturation on testicular growth and the formation of spermatic granulomas. The vas deferens was ligated and divided bilaterally in 10-day-old Lewis rats. Testis weight and volume did not differ significantly between obstructed rats and sham controls at the majority of the intervals studied, including the end of the experiment at 128 days, although some temporary changes were observed. Testes of obstructed animals showed normal histological differentiation. Nearly all obstructed animals developed spermatic granulomas of the epididymis once they matured. When obstructed prior to sexual maturation, the testes are affected only transiently, but significant epididymal alterations occur. Spermatic granulomas are located predominantly in the epididymis rather than the vas deferens.


Survival of extremely premature babies in a geographically defined population: prospective cohort study of 1994-9 compared with 2000-5.
To assess changes in survival for infants born before 26 completed weeks of gestation. Prospective cohort study in a geographically defined population. Former Trent health region of the United Kingdom. All infants born at 22+0 to 25+6 weeks' gestation to mothers living in the region. Terminations were excluded but all other births of babies alive at the onset of labour or the delivery process were included. Outcome for all infants was categorised as stillbirth, death without admission to neonatal intensive care, death before discharge from neonatal intensive care, and survival to discharge home in two time periods: 1994-9 and 2000-5 inclusive. The proportion of infants dying in delivery rooms was similar in the two periods, but a significant improvement was seen in the number of infants surviving to discharge (P<0.001). Of 497 infants admitted to neonatal intensive care in 2000-5, 236 (47%) survived to discharge compared with 174/490 (36%) in 1994. These changes were attributable to substantial improvements in the survival of infants born at 24 and 25 weeks. During the 12 years of the study none of the 150 infants born at 22 weeks' gestation survived. Of the infants born at 23 weeks who were admitted to intensive care, there was no significant improvement in survival to discharge in 2000-5 (12/65 (18%) in 2000-5 v 15/81 (19%) in 1994-9). Survival of infants born at 24 and 25 weeks of gestation has significantly increased. Although over half the cohort of infants born at 23 weeks was admitted to neonatal intensive care, there was no improvement in survival at this gestation. Care for infants born at 22 weeks remained unsuccessful.


The dark respiration of Anacystis nidulans. Production of HCN from histidine and oxidation of basic amino acids.
The basic amino acids, L-arginine, L-lysine, LO-irnithine, and to a lesser extent L-histidine, strongly stimulate the O2 uptake of cell suspensions of the blue-green alga or cyanobacterium anacystis nidulans. In the case of L-histidine, the extra O2 consumption is associated with the formation in vivo of small amounts of HCN, particularly in an atmosphere of O2. The enzyme responsible for both the stimulated O2 uptake with the basic amino acids and the formation of HCN from histidine has been isolated and identified as an L-amino acid oxidase specific for the basic amino acids. The purification (15 000-fold) of this enzyme is described. The isolated enzyme is inhibited by o-phenanthroline, which has a similar inhibitory effect on the O2 uptake of cell suspensions with (and without) added amino acids. The basic amino acid oxidase, which is not inhibited by HCN, can be regarded as an 'alternate' oxidase in A. nidulans. An oxidase sensitive to HCN is apparently also operative. At high concentrations of lysine or arginine added HCN can almost double the initial rate of O2 consumption of cell suspensions. This can be attributed to the inhibition of catalase by HCN. At low concentrations of the amino acids, and with more prolonged incubation time, HCN becomes inhibitory. One interpretation could be that the HCN-sensitive terminal oxidase is also involved in the extra O2 uptake elicited by the basic amino acids, but other interpretations are possible. The extra O2 uptake elicited by histidine is almost completely inhibited by HCN, which is consistent with the finding that histidine is a relatively poor substrate for the basic amino acid oxidase.


Health behavior modification after electron beam computed tomography and physician consultation.
This study aimed to determine whether participants reported altering health behaviors (physical activity, diet, and alcohol consumption) after seeing results from an electron-beam computed tomography (EBCT) scan for coronary artery calcium and reviewing these results with a physician. Clinicians attempt to motivate patients to control cardiovascular risk factors by adopting healthy behaviors and reducing harmful actions. Asymptomatic patients (N = 510) were evaluated by EBCT for the extent of coronary artery calcium. Information pertaining to demographics, health history, and lifestyle/health behaviors was obtained from each participant at the time of the EBCT scan. Patients were given their numerical calcium score, shown images of their coronary arteries, and counseled by a physician for lifestyle and medical risk modification based on their coronary artery calcium score. Approximately 6 years after the scan, participants completed a follow-up questionnaire related to lifestyle modifications. In multivariable analysis, the presence and extent of coronary artery calcium was significantly associated with beneficial health behavior modifications. Specifically, the greater a patient's coronary artery calcium score, the more likely they were to report increasing exercise (odds ratio = 1.34, P = 0.02), changing diet (odds ratio = 1.40, P < 0.01), and changing alcohol intake (odds ratio = 1.46, P = 0.05). This study suggests that seeing and being counseled on the presence and extent of coronary artery calcium is significantly associated with behavior change.


Emerging roles for protein S-palmitoylation in immunity from chemical proteomics.
The activation of innate and adaptive immune signaling pathways and effector functions often occur at cellular membranes and are regulated by complex mechanisms. Here we review the growing number of proteins which are known to be regulated by S-palmitoylation in immune cells emerging from recent advances in chemical proteomics. These chemical proteomic studies have highlighted the roles of this dynamic lipid modification in regulating the specificity and strength of immune responses in different lymphocyte populations.


Boolean model of anchorage dependence and contact inhibition points to coordinated inhibition but semi-independent induction of proliferation and migration.
Epithelial cells respond to their physical neighborhood with mechano-sensitive behaviors required for development and tissue maintenance. These include anchorage dependence, matrix stiffness-dependent proliferation, contact inhibition of proliferation and migration, and collective migration that balances cell crawling with the maintenance of cell junctions. While required for development and tissue repair, these coordinated responses to the microenvironment also contribute to cancer metastasis. Predictive models of the signaling networks that coordinate these behaviors are critical in controlling cell behavior to halt disease. Here we propose a Boolean regulatory network model that synthesizes mechanosensitive signaling that links anchorage to a matrix of varying stiffness and cell density sensing to contact inhibition, proliferation, migration, and apoptosis. Our model can reproduce anchorage dependence and anoikis, detachment-induced cytokinesis errors, the effect of matrix stiffness on proliferation, and contact inhibition of proliferation and migration by two mechanisms that converge on the YAP transcription factor. In addition, we offer testable predictions related to cell cycle-dependent anoikis sensitivity, the molecular requirements for abolishing contact inhibition, and substrate stiffness dependent expression of the catalytic subunit of PI3K. Moreover, our model predicts heterogeneity in migratory vs. non-migratory phenotypes in sub-confluent monolayers, and co-inhibition but semi-independent induction of proliferation vs. migration as a function of cell density and mitogenic stimulation. Our model serves as a stepping-stone towards modeling mechanosensitive routes to the epithelial to mesenchymal transition, capturing the effects of the mesenchymal state on anoikis resistance, and understanding the balance between migration versus proliferation at each stage of the epithelial to mesenchymal transition.


Sialis primitivus sp. nov. (Megaloptera: Sialidae), a remarkable new alderfly species from China.
A new species of the alderfly, Sialis primitivus sp. nov. from China is described. Remarkably, the general habitus of the new species resembles the New World genera Protosialis van der Weele, 1909 and Ilyobius Enderlein, 1910 as well as the Madagascan endemic genus Haplosialis Navás, 1927 by having similar wing venation. However, the characteristics of mouthparts and genitalia indicate the new species belongs to Sialis and probably represents the basalmost species among all known extant Sialis species.


Differential response of lymphocytes to free and sepharose-linked anti-immunoglobulin during different phases of the cell cycle.
During proliferation induced by anti-immunoglobulins, B lymphocytes undergo cell volume increases prior to onset of DNA synthesis. Although both Sepharose-linked and free anti-immunoglobulin evoked essentially identical increases in cell volume, the Sepharose-linked antibody induced a significantly greater DNA synthesis than free antibody as judged from [3H]thymidine incorporation studies using mass cell culture technique, as well as by using autoradiographic analysis of individual cells. These findings are considered in terms of possible differences in triggering cell volume increases and DNA synthesis by free and linked anti-immunoglobulin and/or the possible existence of B cell subpopulations responding differentially to free and to linked antibody.


Effect of Punica granatum fruit peel on glucose-6-phosphate dehydrogenase and malate dehydrogenase in amphistome Gastrothylax indicus.
Increasing anthelmintic resistance and the impact of conventional anthelmintics on the environment, it is important to look for alternative strategies against helminth parasite in sheep. Important lipogenic enzymes like glucose-6-phosphate dehydrogenase (G-6-PDH) and malate dehydrogenase (MDH) show subcellular distribution pattern. Activity of G-6-PDH was largely restricted to cytosolic fraction while MDH was found in both cytosolic and mitochondrial fraction in Gastrothylax indicus. Following in vitro treatment with ethanolic and aqueous extracts of Punica granatum fruit peel and commercial anthelmintic, albendazole G-6-PDH activity was decreased by 19-32 %, whereas MDH was suppressed by 24-41 %, compared to the respective control. Albendazole was quite effective when compared with negative control and both the extracts. The results indicate that phytochemicals of plant may act as potential vermifuge or vermicide.


Changes in the receptor-G protein-adenylyl cyclase system in heart failure from various types of heart muscle disease.
The abnormalities of the receptor-G protein-adenylyl cyclase (RCG) system in failing human myocardium as the result of 1) idiopathic dilated cardiomyopathy (IDC), 2) ischemic dilated cardiomyopathy (ISCDC), and 3) primary pulmonary hypertension (PPH) were investigated. Depending on the etiology of heart failure, abnormalities of the RCG system result from a reduced number of beta 1 receptors, uncoupling of beta 1 or beta 2 receptors, alteration of G protein function, or decreased catalytic subunit activity of adenylyl cyclase. Compared to IDC, beta 1 receptor down-regulation is less pronounced in ISCDC, and slightly more pronounced in PPH. Preliminary data suggest that beta 1 receptor down-regulation results from alteration in steady-state receptor mRNA levels. Increased functional activity of Gi protein, which seems to result from posttranslational modification, is observed in IDC and ISCDC. Altered Gi protein function may be the basis for beta-receptor uncoupling in IDC and ISCDC, whereas in PPH, this phenomenon may result from altered adenylyl cyclase function. Catalytic subunit activity of adenylyl cyclase is decreased in order of increasing pulmonary hypertension in right-ventricular preparations from PPH greater than IDC greater than ISCDC. However, catalytic subunit activity is similar in LV preparations from all three groups. The decrease in adenylyl cyclase catalytic subunit activity may be the result of the marked cellular injury produced by pressure overload. In summary, numerous desensitization phenomena occur in the failing human heart that are etiology- or model-dependent. To a certain extent, these changes are teleologically beneficial, as they are able to partially protect the failing heart from potentially toxic adrenergic stimuli.


Binding of brevetoxins and ciguatoxin to the voltage-sensitive sodium channel and conformational analysis of brevetoxin B.
The marine toxins known generically as brevetoxins, as well as their structural relative ciguatoxin, are known as polyether ladder toxins, and bind uniquely to site 5 of the voltage-sensitive sodium channel. Rat brain synaptosome binding data show similarities in binding affinity for brevetoxins having the same structural (ladder) backbone, but different affinities between brevetoxins having different backbones. Ciguatoxin has a different backbone from the brevetoxins, but binds even more strongly to the same site. Could the flexibility of the backbone be related to their relative toxicities? As part of an effort to identify the common pharmacophore for the toxins, Monte Carlo methods were used to generate conformational models of the polyether ladder toxin brevetoxin B (PbTx-2) which shows significant flexibility at the juncture of the two 7-membered rings.


The First Report of the Acrotretoid Brachiopod Hadrotreta from the Tsinghsutung Formation Cambrian (Series 2, Stage 4), Guizhou, South China.
Hadrotreta is a worldwide acrotretoid brachiopod reported from the Cambrian Series 2 to Miaolingian. Here, a number of well-preserved fossils of Hadrotreta, identified as Hadrotreta cf. H. timchristiorum, were found in the Protoryctocephalus arcticus Zone of the Tsinghsutung Formation of Cambrian Series 2, Stage 4 in Jianhe, Guizhou, south China. This is the first report of Hadrotreta in China, which enriches its global palaeogeographical distribution. Hadrotreta is very similar to acrotretoids such as Kostjubella, Vandalotreta, Linnarssonia, and Eohadrotreta. It differs from them with its well-developed ventral boss-like apical process, apical pits, and dorsal median sulcus. In view of the palaeogeography of Hadrotreta, this genus was mainly distributed in low-latitude regions. Hadrotreta was only found in south China and Laurentia during the Cambrian Age 4, then expanded its distribution to other regions such as Siberia, Baltica, the Kazakh Terranes, the Far East, and Gondwana Pange during the Miaolingian Epoch. Hadrotreta seems to have shifted from deeper water to shallow-water environments during the period from the Cambrian Series 2 to the Miaolingian.


A simplified technique for in vivo analysis of sister-chromatid exchanges using 5-bromodeoxyuridine tablets.
A small tablet of 5-bromodeoxyuridine (BrdU), implanted subcutaneously in a mouse, provides sustained release of base analog sufficient to effect substitution of DNA throughout an entire replication period. As illustrated by studies of mouse bone-marrow and spleen cells in the presence or absence of cyclophosphamide, this depot method of BrdU administration greatly simplifies in vivo analysis of sister-chromatid-exchange formation.


Heat transfer during TTFields treatment: Influence of the uncertainty of the electric and thermal parameters on the predicted temperature distribution.
Tumor Treating Fields (TTFields) is a technique currently used in the treatment of glioblastoma. It consists in applying an electric field (EF) with a frequency of 200 kHz using two pairs of transducer arrays placed on the head. Current should be injected at least 18 h/day and induce a minimum EF intensity of 1 V/cm at the tumor bed for the treatment to be effective. To avoid scalp burns, Optune, the device used to apply this technique in patients, monitors the temperature of the transducers and keeps them below 41 °C by reducing the injected current. The goal of this study was to quantify the impact of the uncertainty associated with the electric and thermal parameters on the predicted temperature of the transducers and of each tissue when TTFields were applied. We used a realistic head model, added the two pairs of transducers arrays on the scalp and a virtual lesion, mimicking a glioblastoma tumor in the right hemisphere. Minimum, standard and maximum values for the electric and thermal properties of each tissue were taken from the literature after an extensive review. We used finite element methods (COMSOL Multiphysics) to solve Laplace's equation for the electric potential and Pennes' equation for the temperature distribution. We observed that the electric conductivity of the scalp and skull, as well as scalp's blood perfusion and thermal conductivity were the parameters to which tissue and transducers temperature were most sensitive to. Considering all simulations, scalp's maximum temperature was around 43.5 °C, skull's 42 °C, CSF's 41.2 °C and brain's 39.3 °C. According to the literature, for this temperature range, some physiological changes are predicted only for the brain. The average temperature of the transducers varied between 38.1 °C and 41.6 °C which suggests that modelling TTFields current injection is very sensitive to the parameters chosen. Better knowledge of the physical properties of tissues and materials and how they change with the temperature is needed to improve the accuracy of these predictions. This information would likely decrease the predicted temperature maxima in the brain and thus help ascertaining TTFields safety from a thermal point of view.


A design optimized prime editor with expanded scope and capability in plants.
The ability to manipulate the genome in a programmable manner has illuminated biology and shown promise in plant breeding. Prime editing, a versatile gene-editing approach that directly writes new genetic information into a specified DNA site without requiring double-strand DNA breaks, suffers from low efficiency in plants1-5. In this study, N-terminal reverse transcriptase-Cas9 nickase fusion performed better in rice than the commonly applied C-terminal fusion. In addition, introduction of multiple-nucleotide substitutions in the reverse transcriptase template stimulated prime editing with enhanced efficiency. By using these two methods synergistically, prime editing with an average editing frequency as high as 24.3% at 13 endogenous targets in rice transgenic plants, 6.2% at four targets in maize protoplasts and 12.5% in human cells was achieved, which is two- to threefold higher than the original editor, Prime Editor 3. Therefore, our optimized approach has potential to make more formerly non-editable target sites editable, and expands the scope and capabilities of prime editing in the future.


Zanamivir-resistant influenza viruses with Q136K or Q136R neuraminidase residue mutations can arise during MDCK cell culture creating challenges for antiviral susceptibility monitoring.
Surveillance of circulating influenza strains for antiviral susceptibility is important to ensure patient treatment guidelines remain appropriate. Influenza A(H3N2) and A(H1N1)pdm09 virus isolates containing mutations at the Q136 residue of the neuraminidase (NA) that conferred reduced susceptibility to the NA inhibitor (NAI) zanamivir were detected during antiviral susceptibility monitoring. Interestingly, the mutations were not detectable in the viruses from respective clinical specimens, only in the cultured isolates. We showed that variant viruses containing the Q136K and Q136R NA mutations were preferentially selected in Madin-Darby canine kidney epithelial (MDCK) cells, but were less well supported in MDCK-SIAT1 cells and embryonated eggs. The effect of Q136K, Q136R, Q136H and Q136L substitutions in NA subtypes N1 and N2 on NAI susceptibility and in vitro viral fitness was assessed. This study highlights the challenges that cell culture derived mutations can pose to the NAI susceptibility analysis and interpretation and reaffirms the need to sequence viruses from respective clinical specimens to avoid misdiagnosis. However, we also demonstrate that NA mutations at residue Q136 can confer reduced zanamivir, peramivir or laninamivir susceptibility, and therefore close monitoring of viruses for mutations at this site from patients being treated with these antivirals is important.