Structural requirements for the stimulation of neurite outgrowth by two variants of laminin and their inhibition by antibodies.
Laminin derived from the Engelbreth-Holm-Swarm (EHS) tumor and a lamininlike molecule synthesized by RN22 Schwannoma cells both stimulate rapid neurite outgrowth, consistent with a common neurite-promoting site. However, antilaminin antisera can only inhibit the activity of the EHS laminin. The blocking antibodies in such sera are directed against the terminal heparin-binding domain of the laminin long arm (Edgar, D., R. Timpl, and H. Thoenen. 1984. EMBO [Eur. Mol. Biol. Organ.] J. 3: 1463-1468). These epitopes are demonstrated by immunoblotting to be part of the A chain and to be absent in RN22 laminin, showing (through metabolic labeling) that the cells synthesized little if any 440-kD A chain. This indicates that the antibody inhibition was probably due to steric hindrance, a common neurite-promoting site, apparently not being antigenic in native molecules. Antibodies raised against a 25-kD proteolytic fragment derived from the long arm of laminin were then used as probes to identify other potential neurite-promoting structures. Although these antibodies do not cross-react with native laminin, they recognized the B chains of denatured EHS and RN22 molecules on immunoblots. The antibodies also bound to the large proteolytic fragment, derived from the long arm of laminin that contains the neurite-promoting site, thus inhibiting its activity. Taken together, these results point to the localization of normally nonantigenic, defined, B chain sequences within or close to the neurite-promoting site of laminin.


Broad beam attenuation of cobalt-60 gamma rays and 6-, 18-, and 25-MV x rays by lead.
The measurement of photon attenuation by absorbing materials in radiation beams is usually performed using narrow beam geometry. However, radiotherapy treatments rarely simulate narrow beam conditions. The effect of broad beams on the attenuation of cobalt-60 gamma rays and 6-, 18-, and 25-MV x rays by lead is considered both theoretically and experimentally. The theoretical calculations are based on first-scatter considerations and indicate a dependence on treatment geometry (i.e., maximum scattering angle). Measured attenuation coefficients vary by as much as 16%, comparing narrow and broad beam data for typical treatment conditions. Broad beam attenuation coefficients, calculated from the measured zero-area values agree with the measured results to within 2% on average with a maximum deviation of 5%. A very simple empirical procedure is proposed to determine attenuation coefficients for a wide range of field sizes. This agrees with the measured data to within 0.5% on average and 4% at worst. With irregularly shaped absorbers, a sector integration technique is considered in combination with a first-scatter calculation. For a long rectangular field, the agreement between measured and calculated attenuation coefficients is better than 1.5% for all energies. The question of accuracy in attenuation coefficients needed to give an accuracy of 3% in relative transmission is addressed and shows a dependence on absorber thickness. For 75% transmission, the required accuracy in attenuation coefficient is 10%, whereas for 25% transmission, it should be improved to 2%.


Ultrastructural changes in the male germ cells of Bulinus truncatus during spermatogenesis.
The structure of the spermatogonia, spermatocytes, spermatids and Sertoli cells of the hermaphroditic snail Bulinus truncatus was studied by electron microscopy. The spermatogonia are small, with relatively large nuclei. The acrosome develops from a small proacrosomal granule which is probably derived from the Golgi apparatus in the spermatocyte stage. Condensation and elongation of the nuclei were found in the spermatids. The shape and components of the Sertoli cells did not change during the spermatogonium and spermatocyte stages. Before spermiation the Sertoli cells have the morphological features of steroid-producing cells. The study showed that the Sertoli cells are involved in the nutrition and transportation of the spermatogenic cells, in spermiation and in hormone production.


Effect of lowering the glycemic load with canola oil on glycemic control and cardiovascular risk factors: a randomized controlled trial.
Despite their independent cardiovascular disease (CVD) advantages, effects of α-linolenic acid (ALA), monounsaturated fatty acid (MUFA), and low-glycemic-load (GL) diets have not been assessed in combination. We therefore determined the combined effect of ALA, MUFA, and low GL on glycemic control and CVD risk factors in type 2 diabetes. The study was a parallel design, randomized trial wherein each 3-month treatment was conducted in a Canadian academic center between March 2011 and September 2012 and involved 141 participants with type 2 diabetes (HbA1c 6.5%-8.5% [48-69 mmol/mol]) treated with oral antihyperglycemic agents. Participants were provided with dietary advice on either a low-GL diet with ALA and MUFA given as a canola oil-enriched bread supplement (31 g canola oil per 2,000 kcal) (test) or a whole-grain diet with a whole-wheat bread supplement (control). The primary outcome was HbA1c change. Secondary outcomes included calculated Framingham CVD risk score and reactive hyperemia index (RHI) ratio. Seventy-nine percent of the test group and 90% of the control group completed the trial. The test diet reduction in HbA1c units of -0.47% (-5.15 mmol/mol) (95% CI -0.54% to -0.40% [-5.92 to -4.38 mmol/mol]) was greater than that for the control diet (-0.31% [-3.44 mmol/mol] [95% CI -0.38% to -0.25% (-4.17 to -2.71 mmol/mol)], P = 0.002), with the greatest benefit observed in those with higher systolic blood pressure (SBP). Greater reductions were seen in CVD risk score for the test diet, whereas the RHI ratio increased for the control diet. A canola oil-enriched low-GL diet improved glycemic control in type 2 diabetes, particularly in participants with raised SBP, whereas whole grains improved vascular reactivity.


One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial.
Traditional blood glucose-lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in beta-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp-derived measures of beta-cell function, glycemic control, and body weight. Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). beta-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09-2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: -0.8 +/- 0.1 and -0.7 +/- 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference -4.6 kg, P < 0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.


Activation of human platelets by the membrane-expressed A1 domain of von Willebrand factor.
Platelet activation and microthrombus formation are invariable features of xenograft rejection and the vascular injury observed when porcine organs are transplanted into primates. This pathological process could be mediated, at least in part, by aberrant interactions of von Willebrand Factor (vWF) associated with the donor vasculature with host platelets. Unlike human vWF, native porcine vWF (pvWF) interacts with human GPIb independently of shear stress or nonphysiological stimuli, eg, ristocetin. We therefore contrasted the potential of isolated human and porcine vWF-A1-domains to interact with human platelets in vitro. Both human and porcine vWF-A1-domains expressed as glycosyl phosphatidylinositol-linked FLAG fusion proteins on COS-7 cells induced GPIb-dependent aggregation and intracellular Ca++ uptake of platelets, independent of both the remainder of the vWF protein and additional modifying factors. Porcine A1-domains were more potent than human homologues, and in addition ristocetin could boost platelet aggregation only with the human A1-domain. Putative conformational changes in the porcine A1-domain could result in the heightened, ristocetin-independent interactions observed with human platelets and may be of importance for xenograft survival.


The influence of Lasius neoniger (Hymenoptera: Formicidae) on population growth and biomass of Aphis glycines (Hemiptera: Aphididae) in soybeans.
In the United States, the soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), are often tended by the aphid-tending ant, Lasius neoniger Emery (Hymenoptera: Formicidae). In this study, we examined the effects of tending by ants on the density and biomass of soybean aphids on soybeans in Kentucky. We performed cage studies that limited access by ants and/or natural enemies. We used a split-plot design with natural enemy access as the main plot and ant attendance as the sub plot. We found that natural enemy access negatively affected aphid population density in the presence of tending ants, seen as a three- to four-fold increase in aphid density when natural enemies were excluded. In addition, we found that ant tending positively affected aphid biomass, both when natural enemies were given access to aphids or when natural enemies were excluded, seen by a two-fold increase in aphid biomass when ants tended aphids, both in the presence or absence of natural enemies. Biomass accumulation is seen as an important measurement for assessing aphid performance, and we argue that aphid-tending by ants can have an influence on natural field populations of soybean aphids. Agronomic practices that affect ant abundance in soybeans may influence the performance and hence pest outbreaks for this economically important pest.


The effect of propolis supplementation on cardiovascular risk factors in women with rheumatoid arthritis: A double-blind, placebo, controlled randomized clinical trial.
Propolis has gained popularity in recent years because of its beneficial properties, which make it a possible preventative and therapeutic agent as well as a valuable food and cosmetic ingredient. The objective of this study was to evaluate the effects of propolis supplementation on cardiovascular risk factors in women with rheumatoid arthritis. This randomized, double-blind, placebo-controlled clinical trial was performed among 48 patients diagnosed with rheumatoid arthritis. Subjects were randomly assigned to placebo and intervention groups, supplemented with 1000 mg/day of propolis for 12 weeks. Cardiovascular risk factors including, high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein (MCP-1), Nitric oxide, blood pressure, and lipid profile were assessed pre-and post-intervention. The atherogenic index of plasma value, as well as total cholesterol/high-density lipoprotein cholesterol (HDL-C), triglyceride/HDL-C, and non-HDL-C/HDL-C ratios, were significantly reduced in the intervention group, compared with the placebo group post-intervention (p < 0.05). Moreover, there was a significant reduction in the serum level of hs-CRP in the intervention group when compared with the placebo group (p = 0.001). Furthermore, propolis supplementation could marginally reduce MCP-1 (p = 0.051). These data indicate that propolis supplementation may be a promising treatment strategy for cardiovascular complications among rheumatoid arthritis patients.


Gastric mucosa during treatment with lansoprazole: Helicobacter pylori is a risk factor for argyrophil cell hyperplasia.
The mechanisms causing progression of fundic gastritis and changes in argyrophil cell morphology in patients undergoing long-term treatment with proton pump inhibitors are unknown. The hypothesis of this study was that Helicobacter pylori is a risk factor for both gastritis and argyrophil cell hyperplasia. Forty-two patients with peptic disorders resistant to H2-blockers were treated with 30-90 mg lansoprazole daily for up to 5 years. Serum gastrin levels, antral gastrin cells, fundic argyrophil cells, parameters of gastritis, and H. pylori infection were evaluated regularly. In nonantrectomized patients, serum gastrin levels increased from a median of 76 pg/mL to 163 pg/mL within 3 months. Antral gastrin cell density increased from 175 to 267 cells/mm2 (P < 0.001), and fundic argyrophil cell density increased from 83 to 149 cells/mm2 (P < 0.001). Chronic inflammation, activity, and atrophy of the oxyntic mucosa worsened exclusively in patients with H. pylori infection. Linear and/or micronodular argyrophil cell hyperplasia was diagnosed in 2.6% of patients before lansoprazole and in 29.2% after 5 years treatment. These changes were significantly related to serum gastrin levels, H. pylori infection, chronic inflammation, and atrophy of the oxyntic mucosa. H. pylori represents an important factor for the progression of fundic gastritis and the development of argyrophil cell hyperplasia during long-term treatment with lansoprazole.


Injury toll following the 1997 Maccabiah Games bridge collapse: implications of major disasters for sports medicine teams.
A major disaster was encountered at the 1997 Maccabiah Games in Israel. As the Australian team was about to enter the main stadium for the opening ceremony, a pedestrian bridge they were crossing collapsed, killing 4 athletes and injuring many others. The aim of this paper is to establish the rates, types and anatomical locations of musculoskeletal injuries incurred by members of the Australian Maccabiah Games team, with particular reference to the impact of the bridge collapse. In total, the 410 members of the team (360 athletes and coaches and 50 team officials) reported 166 injuries from their participation in sport and 30 musculoskeletal injuries associated with the collapse of the bridge. The most common sports-related injuries were sprains and strains to the hip/thigh, lumbar spine and ankle/foot regions, while the bridge collapse resulted in, most commonly, sprains and contusions to the hip/thigh, knee, lower leg and ankle/foot regions. In addition, team members incurred many medical and psychological conditions. This paper makes several recommendations for sports medicine staff based on the experience of this significant sport disaster.


The interval between onset and admission predicts disease progression in COVID-19 patients.
The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19). A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively. Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients. The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems.


The ADMA/DDAH pathway is a critical regulator of endothelial cell motility.
Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide production associated with abnormal blood vessel growth and repair, however, the mechanism of action of ADMA is not well understood. We studied the role of exogenous and endogenous ADMA in the regulation of cell motility and actin cytoskeleton in porcine pulmonary endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMECs) from knockout mice that lack one of the enzyme metabolising ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI) as well as endothelial cells overexpressing DDAH in vitro. We show that ADMA induced stress fibre and focal adhesion formation and inhibited cell motility in primary pulmonary endothelial cells. The effects of ADMA depended on the activity of RhoA and Rho kinase and were reversed by overexpression of DDAH, nitric oxide donors and protein kinase G activator, 8-bromo-cGMP. ADMA also inhibited the activities of Rac1 and Cdc42 in cells but these changes had a minor effect on cell motility. Endogenous ADMA increased RhoA activity and inhibited cell motility in PMECs from DDAHI knockout mice and inhibited angiogenesis in vitro. These results are the first demonstration that metabolism of cardiovascular risk factor ADMA regulates endothelial cell motility, an important factor in angiogenesis and vascular repair.


Bus use and older people: a literature review applying the Person-Environment-Occupation model in macro practice.
The same reasons that prompt older people to give up driving can also result in difficulties with accessing public transport. Difficulties using public transport can limit older people's participation in society, thereby impacting negatively on their health. Focusing on public buses, this review explicates the link between bus usability and the health of older people and frames existing evidence on bus usability issues. The Person-Environment-Occupation (PEO) model offers a framework by which bus usability can be assessed. A combination of person-centred, environmental, and occupation-related factors, including bus design, service provision and performance, information, and the attitudes of staff and the community, impact on older people's ability to catch buses. More systematic research needs to take place in order to develop a comprehensive understanding of bus usability. Occupational therapy has a key role to play in conceptualizing, implementing, and evaluating improvements in bus usability for older people.


Proteomic analysis of metabolic pathways supports chloroplast-mitochondria cross-talk in a Cu-limited diatom.
Diatoms are one of the most successful phytoplankton groups in our oceans, being responsible for over 20% of the Earth's photosynthetic productivity. Their chimeric genomes have genes derived from red algae, green algae, bacteria, and heterotrophs, resulting in multiple isoenzymes targeted to different cellular compartments with the potential for differential regulation under nutrient limitation. The resulting interactions between metabolic pathways are not yet fully understood. We previously showed how acclimation to Cu limitation enhanced susceptibility to overreduction of the photosynthetic electron transport chain and its reorganization to favor photoprotection over light harvesting in the oceanic diatom Thalassiosira oceanica (Hippmann et al., 2017, 10.1371/journal.pone.0181753). In order to gain a better understanding of the overall metabolic changes that help alleviate the stress of Cu limitation, we have further analyzed the comprehensive proteomic datasets generated in that study to identify differentially expressed proteins involved in carbon, nitrogen, and oxidative stress-related metabolic pathways. Metabolic pathway analysis showed integrated responses to Cu limitation. The upregulation of ferredoxin (Fdx) was correlated with upregulation of plastidial Fdx-dependent isoenzymes involved in nitrogen assimilation as well as enzymes involved in glutathione synthesis, thus suggesting an integration of nitrogen uptake and metabolism with photosynthesis and oxidative stress resistance. The differential expression of glycolytic isoenzymes located in the chloroplast and mitochondria may enable them to channel both excess electrons and/or ATP between these compartments. An additional support for chloroplast-mitochondrial cross-talk is the increased expression of chloroplast and mitochondrial proteins involved in the proposed malate shunt under Cu limitation.


Drug deprescription-withdrawal risk, prevention, and treatment.
In most cases, a sudden interruption of most medications has no major consequences. There are well-recognized therapies that, when withheld, can either lead to the reappearance of the symptoms they were controlling or to signs or symptoms of withdrawal. In this article, we present a table including medications that when interrupted can produce withdrawal syndromes, the signs and symptoms of the withdrawal syndrome, the time to onset and resolution of the syndrome, information regarding alternative delivery options for the drug/s when the oral route is not possible, as well as prevention and therapy.


Pauli algebraic analysis of polarized light modulation.
The modification of the polarization and spectral structure of light by electro-optic modulation with longitudinal effect in crystals of class 42 m is analyzed in the frame of a Pauli algebraic and Poincaré geometric approach. The results are generalized, in a vectorial Pauli algebraic form, for any birefringent time-varying device.


Analysis of marker enzymes in the K562 erythroleukaemia cell line: no coordinate expression of red cell enzymes on induction of haemoglobin synthesis.
Six sublines of the K562 erythroleukaemic cell line were examined by starch gel electrophoresis for the red cell enzymes carbonic anhydrase, CA I and II, pyruvate kinase, PK1 (R), and lactic dehydrogenase, LDH (B), both uninduced and following induction of haemoglobin synthesis with sodium butyrate or haemin. Neither CA or PK1 (R) enzymes were present constitutively found to be inducible characteristics; the LDH isoenzyme pattern showed equal expression of A and B subunits and did not change to the red cell form (B greater than A) on induction. Subline heterogeneity was also examined by analysis of a further 11 polymorphic enzymes, and cell line contamination was found not to account for the previously reported variations in inducibility by sodium butyrate.


[National guidelines of diagnosis and treatment of the non-Hodgkin lymphoma].
Non-Hodgkin lymphoma comprises a heterogeneous group of haematological malignancies, classified according to their clinic, anatomic-pathological features and, lately, to their molecular biomarkers. Despite the therapeutic advances, nearly half of the patients will die because of this disease. The new diagnostic tools have been the cornerstone to design recent therapy targets, which must be included in the current treatment guidelines of this sort of neoplasms by means of clinical trials and evidence-based medicine. In the face of poor diagnoses devices in most of the Mexican hospitals, we recommend the present diagnose stratification, and treatment guidelines for non-Hodgkin lymphoma, based on evidence. They include the latest and most innovative therapeutic approaches, as well as specific recommendations for hospitals with limited framework and therapy resources.


The basic DNA-binding protein of Bombyx mori nuclear polyhedrosis virus: the existence of an additional arginine repeat.
The basic DNA-binding protein of the Bombyx mori nuclear polyhedrosis virus (BmNPV) was purified by HPLC and a sequence of 45 amino acids from the N-terminus was determined. There were no detectable modifications such as N-terminal blockage, glycosylation, or phosphorylation. The amino acid sequence showed high homology to the predicted amino acid sequences of the basic proteins of Autographa californica NPV (AcNPV) and Orgyia pseudotsugata NPV (OpNPV) (90 and 76%, respectively), however, the BmNPV basic protein possessed an additional sequence of 10 amino acids. A DNA fragment encoding the basic protein was identified in a BmNPV DNA library by screening for possible DNA sequences coding for the basic protein's amino acid sequence. The nucleotide sequence of the basic protein of BmNPV was more similar to that of AcNPV (97%) than to that of OpNPV (62%). Homology plot analysis of the nucleotide sequence indicates that the BmNPV basic protein internal repeat evolved very recently.


Downregulation of SIRT4 Expression Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma.
SIRT4, a mitochondria-localized sirtuin, represses glutamine metabolism by inhibiting glutamate dehydrogenase (GDH). The current study aimed to evaluate the clinical and biological significance of SIRT4 in esophageal squamous cell carcinoma (ESCC). The study comprised 172 patients with surgically resected ESCC in two independent cohorts. SIRT4 mRNA expression was analyzed in Cohort 1 (n = 79) and SIRT4 protein expression in Cohort 2 (n = 93). The association of SIRT4 expression with clinicopathological parameters and prognosis was assessed. Furthermore, the biological role of SIRT4 in ESCC cell lines was examined. SIRT4 expression was not correlated with any clinicopathological parameters in both cohorts. In Cohort 1, low-SIRT4-expression cases had poorer overall survival than high-SIRT4-expression cases (p = 0.016). In Cohort 2, SIRT4-negative cases had poorer overall survival and disease-free survival than SIRT4-positive cases (p = 0.011 and 0.0026). Multivariate analysis revealed that SIRT4 expression was an independent prognostic factor for overall survival (HR = 2.06, p = 0.038). The rate of distant recurrence was significantly higher in SIRT4-negative cases than in SIRT4-positive cases (39.4 vs. 7.4%; p = 0.0023). In vitro, SIRT4 knockdown significantly increased GDH activity and promoted cell proliferation and migration. SIRT4 is a potential prognostic biomarker in ESCC.


New treatments for stroke.
Stroke is the third leading cause of death and the leading cause of adult disability in the United States. With an annual incidence of over 500,000, stroke has enormous social and economic consequences. Ischemic stroke comprises over 80% of all strokes, with strokes caused by intracerbral hemorrhage and subarachnoid hemorrhage making up the rest. Recent advances in the understanding of stroke risk factors and the mechanisms of nervous system damage in acute stroke, especially ischemic stroke, have led to new therapies for both prevention and treatment. Anticoagulation with warfarin can prevent cardioembolic stroke resulting from atrial fibrillation. Carotid endarterectomy can prevent stroke caused by internal carotid artery stenosis. Tissue plasminogen activator, a clot-dissolving medication, has recently been proven effective in acute ischemic stroke if administered within three hours of onset. Despite these advances, stroke remains common, and most acute stroke unfortunately remains untreatable. Current and future approaches emphasize educating the public and healthcare professionals regarding stroke warning signs and the need for emergent care. Active clinical research is exploring even newer treatments based on the scientific basis of stroke neurobiology.


Profile and risk factors for congenital heart defects: A study in a tertiary care hospital.
Congenital heart defects (CHDs) are an important cause of mortality and morbidity in children representing a major global health burden. It is thus important to determine their prevalence and spectrum and identify risk factors associated with the development of heart defects. A case-control study was carried out in the Department of Pediatrics and Center of Cardiology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India, from February 2014 to August 2015. All patients referred with complaints or clinical examination suggestive of CHDs were further evaluated with echocardiography. On Echocardiography, patients having CHDs were included as cases and those having a normal echocardiographic study were included as controls. Healthy controls were also included. 400 cases and 400 controls were thus identified; preterms having patent ductus arteriosus and patent foramen ovale and those with acquired heart defects were excluded. Risk factors among cases and controls were further studied. Acyanotic heart defects were 290 (72.50%) of the total heart defects, whereas the contribution of cyanotic heart defects was 110 (27.50%). Out of all CHDs, ventricular septal defect was the most common lesion with contribution of 152 (38%) cases, whereas among the cyanotic heart defects, Tetralogy of Fallot was the most common lesion (18% of total cases). Out of the total 400 cases, 261 were males (65.25%). On univariate analysis, paternal age (odds ratio, OR, 2.01), bad obstetric history (OR, 2.65), antenatal febrile illness (OR, 4.12), and advanced maternal age (OR, 3.28) were found to increase the risk of CHD whereas intake of multivitamin (OR, 3.02) was found to be protective. The risk factors were further analyzed with multivariate logistic regression analysis and all the above factors were found to be significantly associated. We noted that the profile of CHD in our population was similar to the published literature although many were missed during infancy and detected later in life. Several antenatal factors were found to be associated with the incidence of congenital heart disease emphasizing the need to prioritize antenatal care and counseling to pregnant mothers along with good maternal nutrition and folic acid supplementation.


The impacts of China's dual carbon policy on green innovation: Evidence from Chinese heavy-polluting enterprises.
Encouraging enterprises to engage in green innovation is a potent strategy for reducing carbon emissions from production. As one of the largest carbon emitters, China has launched a series of policies to achieve carbon peaking and neutrality collectively referred to as China's dual carbon policy. However, existing research on the impact of China's dual carbon policy on green innovation by heavy-polluting enterprises is insufficient. To fill this gap, this study constructed a theoretical model to draw hypotheses about the impact of the dual carbon policy on enterprises' green innovation and verified this impact using a difference-in-differences model to conduct a quasi-natural experiment based on data from 2010 to 2022 from Chinese A-share-listed enterprises. The results indicate that the dual carbon policy had a significantly positive influence on green innovation in heavy-polluting enterprises. Moreover, environmental tax mediated this effect, while enterprises' total costs and subsidies positively moderated it. Additionally, the impact exhibited variations based on several key factors, including green patent type, carbon emissions, enterprise ownership structure, and Environmental, Social, and Governance ratings. This study supplements related research on the effects of environmental policy on green innovation and provides both theoretical and empirical support for adapting subsequent environmental policies.


Electrocardiographic changes in tetanus: a serial study.
Serial electrocardiograms (ECGs) were recorded in 20 consecutive male patients admitted to the Infectious Diseases Hospital, Calcutta with generalised tetanus. Age of patients varied from 5 to 40 years (mean age 20.4 years). Ten patients died. ECGs were recorded daily for the first week after admission and later every 2nd or 3rd day. Altogether, 167 ECGs were analysed. Sinus tachycardia was present in 17 (85%) patients, prolonged QT interval in 12 (60%) patients, non-specific ST-T abnormalities in 12 (60%) patients and P wave changes in 10 (50%) patients. Other abnormalities recorded, included short PR interval, supraventricular tachycardia, intraventricular conduction delay, sinus bradycardia, 1 degree A-V block, abnormal axis deviation, right ventricular hypertrophy and sino-atrial Wenckebach phenomenon, although all of the findings cannot clearly be attributed to tetanus. Spatial QRS-T angle was calculated in 18 of these patients to determine any possible change in this parameter of prognostic significance. Two out of 9 who survived had abnormally wide (greater than or equal to 55 degrees) spatial QRS-T angle on admission; the angle narrowed with recovery. In the non-survivor group, 4 patients had abnormally wide QRS-T angles on admission; further widening was noted in patients on whom follow-up tracings were available. The difference in spatial QRS-T angle between the survivor and the non-survivor groups was statistically significant (p less than 0.05). Spatial QRS-T angle changes have not been reported in tetanus before. Although non-specific, serial study in individual cases would be useful in assessing prognosis.


Differential effect of cyclosporin A on the expression of T and B lymphocyte activation antigens.
We have used a monoclonal antibody (Mab) to the interleukin 2 (IL 2) receptor as well as a Mab to the transferrin receptor to analyze the effects of cyclosporin A (CsA) on the induction and expression of these activation antigens on mitogen-stimulated murine T and B lymphocytes. The same concentration (0.25 microgram/ml) of CsA that produced optimal inhibition of the T cell proliferative response to concanavalin A (Con A) was also very effective at inhibiting IL 2 production and the induction of IL 2 responsiveness, as well as the expression of the IL 2 and transferrin receptors when measured 72 hr after mitogen activation. Surprisingly, CsA only minimally inhibited expression of these receptors 24 hr after the addition of mitogen; however, T cell blasts recovered from these cultures failed to respond to IL 2 even though IL 2 receptor expression was only modestly decreased. These results suggest that inhibition of the maturation of receptor expression is secondary to an early effect of CsA in blocking the induction of IL 2 responsiveness or to an arrest in the sequence of events required for maturation of T cells that bear high densities of these receptors. In contrast to the results observed with T lymphocytes, CsA had no effect on the B cell proliferative response to lipopolysaccharide (LPS) or on the induction of the IL 2 and transferrin receptors on activated B lymphocytes.


Parasite age-intensity relationships in red-spotted newts: does immune memory influence salamander disease dynamics?
Acquired immune memory in vertebrates influences transmission and persistence of infections, with consequences for parasite dynamics at both the individual and population levels. The potential impact of acquired immunity is of particular interest for salamanders, whose acquired immune systems are thought to be less effective than those of frogs and other tetrapods. One way to examine the importance of acquired immunity to parasite dynamics at the population level is by examining the relationship between host age and parasite infection intensity. Acquired immunity reduces infection rates in older animals, causing decreased parasite intensity in older age classes and leading to curvilinear age-intensity relationships for persistent parasites and convex age-intensity relationships for transient parasites. We used age-intensity relationships to look for the signature of acquired immunity for 12 parasite taxa of red-spotted newts (Notophthalmus viridescens), using data from a 2-year parasitological survey of six newt populations. We estimated ages from snout-vent length (SVL) based on the relationship between SVL and skeletochronologically-derived ages in a subset of newts. We found evidence of acquired immunity to two parasite taxa, bacterial pathogens and the protist Amphibiocystidium viridescens, whose convex age-intensity relationships could not be easily explained by alternative mechanisms. Our results suggest that the acquired immune response of newts is sufficient to influence the dynamics of at least some parasites.


Erectile dysfunction in type 2 diabetic men: relationship to exercise fitness and cardiovascular risk factors in the Look AHEAD trial.
Determinants of erectile dysfunction in diabetic men have not been adequately investigated as potential mediators of change. To determine the prevalence and correlates of erectile dysfunction (ED) in overweight men with type 2 diabetes in the multicenter, Look AHEAD trial (Action for Health in Diabetes). International Index of Erectile Function (IIEF), self-reported use of phosphodiesterase type 5 inhibitors, laboratory measures of adiposity, cardiometabolic parameters, and exercise fitness. Male participants aged 45-75 in the Look AHEAD trial in a committed relationship were recruited for an ongoing study of sexual function and diabetes. Eligible participants completed the IIEF questionnaire and provided updated information on use of medical treatments for sexual dysfunction. Baseline sexual function results for participants in the male ancillary study are reported here; intervention data and results for female participants are presented elsewhere. A total of 373 eligible male participants completed all sexual function questionnaires, of whom 263 (68.7%) were sexually active at the time of the study. Almost half (49.8%) of the men reported mild or moderate degrees of ED, and 24.8% had complete ED. Among sexually active participants, 42.6% had sought medical help for their problem, and 39.7% reported use of ED medications. ED was significantly associated with age (odds ratio [OR] = 1.05; confidence interval [CI]: 1.01-1.10) baseline HbA(1c) (OR = 1.31; CI: 1.05-1.63), hypertension history (OR = 2.41; CI: 1.34-4.36), and metabolic syndrome (OR = 3.05, CI: 1.31-7.11). Of note, cardiorespiratory fitness was found to be protective of ED in a multivariable analysis (OR = 0.61; P < 0.001). ED is prevalent in this sample of obese, type 2 diabetic men in the Look AHEAD study. Cardiovascular risk factors were highly associated with ED in this population, and cardiorespiratory fitness was protective in this analysis.


Evaluation of effluent toxicity as an indicator of aquatic life condition in effluent-dominated streams: a pilot study.
The types and quality of data needed to determine relationships between chronic whole effluent toxicity (WET) test results and in-stream biological condition were evaluated using information collected over a 1.5-y period from 6 different sites across the United States. A data-quality-objectives approach was used that included several proposed measurement quality objectives (MQOs) that specified desired precision, bias, and sensitivity of methods used. The 6 facilities used in this study (4 eastern and 2 western United States) all had design effluent concentrations >60% of the stream flow. In addition to at least quarterly chronic Ceriodaphnia dubia, Pimephales promelas (fathead minnow), and Selenastrum capricornutum (green algae) WET tests, other tests were conducted to address MQOs, including splits, duplicates, and blind positive and negative controls. Macroinvertebrate, fish, and periphyton bioassessments were conducted at multiple locations upstream and downstream of each facility. The test acceptance criteria of the US Environmental Protection Agency (USEPA) were met for most WET tests; however, this study demonstrated the need to incorporate other MQOs (minimum and maximum percent significant difference and performance on blind samples) to ensure accurate interpretation of effluent toxicity. More false positives, higher toxicity, and more "failed" (noncompliant) tests were observed using no-observed-effect concentration (NOEC) as compared to the IC25 endpoint (concentration causing > or =25% decrease in organism response compared to controls). Algae tests often indicated the most effluent toxicity in this study; however, this test was most susceptible to false positives and high interlaboratory variability. Overall, WET test results exhibited few relationships with bioassessment results even when accounting for actual effluent dilution. In general, neither frequency of WET noncompliance nor magnitude of toxicity in tests were significantly related to differences in biological condition upstream and downstream of a discharge. Periphyton assessments were most able to discriminate small changes downstream of the effluent, followed by macroinvertebrates and fish. Although sampling methods were robust, more replicate samples collected upstream and downstream of each facility were needed to increase detection power. In general, macroinvertebrate and periphyton assessments together appeared to be sufficient to address project objectives.


Cine cone beam CT reconstruction using low-rank matrix factorization: algorithm and a proof-of-principle study.
Respiration-correlated CBCT, commonly called 4DCBCT, provides respiratory phase-resolved CBCT images. A typical 4DCBCT represents averaged patient images over one breathing cycle and the fourth dimension is actually breathing phase instead of time. In many clinical applications, it is desirable to obtain true 4DCBCT with the fourth dimension being time, i.e., each constituent CBCT image corresponds to an instantaneous projection. Theoretically it is impossible to reconstruct a CBCT image from a single projection. However, if all the constituent CBCT images of a 4DCBCT scan share a lot of redundant information, it might be possible to make a good reconstruction of these images by exploring their sparsity and coherence/redundancy. Though these CBCT images are not completely time resolved, they can exploit both local and global temporal coherence of the patient anatomy automatically and contain much more temporal variation information of the patient geometry than the conventional 4DCBCT. We propose in this work a computational model and algorithms for the reconstruction of this type of semi-time-resolved CBCT, called cine-CBCT, based on low rank approximation that can utilize the underlying temporal coherence both locally and globally, such as slow variation, periodicity or repetition, in those cine-CBCT images.


Acoustic responses after total destruction of the cochlear receptor: brainstem and auditory cortex.
Acoustically evoked neural activity has been recorded from the brainstem and auditory cortex of guinea pigs after complete destruction of the organ of Corti by the aminoglycosidic antibiotic amikacin. These responses to sound differ in important respects from the evoked potentials normally recorded from the auditory pathways. At the brainstem level they resemble the potentials reported by others after stimulation of the vestibular nerve.


Properties of the ribosome-inactivating proteins gelonin, Momordica charantia inhibitor, and dianthins.
The amino acid and sugar compositions of four ribosome-inactivating proteins (gelonin, Momordica charantia inhibitor, dianthin 30 and dianthin 32) were determined. The proteins are all basic glycoproteins (pI greater than 8) containing mannose (more abundant in gelonin), glucose, xylose, fucose (absent from gelonin) and glucosamine. The ribosome-inactivating properties of the proteins examined are not modified by pretreatment with N-ethylmaleimide. Precipitating and inactivating antibodies can be raised against ribosome-inactivating proteins; a weak cross-reaction was observed only between dianthin 30 and dianthin 32.


Medicinal products for geriatric patients in Germany : Current status of regulatory requirements and clinical reality.
Geriatric patients are the main users of medicinal products, although this patient group is most commonly excluded from clinical trials. Several guidelines from the International Conference on Harmonisation (ICH) and the European Medicines Agency (EMA) have tried to ensure the development and the safe use of medicines for geriatric patients. This article aims to evaluate geriatric information provided by the summary of product characteristics (SmPC) to prescribers using relevant medicinal products in Germany for patients older than 65 years. Based on the annually published drug prescription report (Arzneiverordnungsreport), medication which was prescribed mainly (above 80%) or at a high defined daily dose (DDD [doses per day] > 400) to patients older than 65 years in 2016 was reviewed regarding relevant geriatric information. The average compliance for the investigated drugs regarding geriatric information according to EMA guidelines is 27%. At least older patients are mentioned in the SmPC most frequently (68%). Information about doses or dose adjustments for patients with certain stages of frailty was not provided by the pharmaceutical companies. Current information in the SmPC for a safe and effective use of medicines for older patients is insufficient and does not conform to EMA guidelines. Compared to drug authorization in pediatrics where the industry is obliged to submit a special pediatric investigation plan (PIP) to cover the needs of this certain patient group, a mandatory geriatric investigation plan (GIP) similar to the PIP would be an appropriate measure to provide safe and effective medicines for older patients.


Phase transition in the cuprates from a magnetic-field-free stiffness meter viewpoint.
A method to measure the superconducting (SC) stiffness tensor [Formula: see text], without subjecting the sample to external magnetic field, is applied to La1.875Sr0.125CuO4. The method is based on the London equation [Formula: see text], where J is the current density and A is the vector potential which is applied in the SC state. Using rotor free A and measuring J via the magnetic moment of superconducting rings, [Formula: see text] at T → Tc is extracted. The technique is sensitive to very small stiffnesses (penetration depths on the order of a few millimeters). The method is applied to two different rings: one with the current running only in the CuO2 planes, and another where the current must cross planes. We find different transition temperatures for the two rings, namely, there is a temperature range with two-dimensional stiffness. Additional low energy muon spin rotation measurements on the same sample determine the stiffness anisotropy at T < Tc.


Spontaneous formation of stably-attached and 3D-organized hepatocyte aggregates on oxygen-permeable polydimethylsiloxane membranes having 3D microstructures.
In order to enhance the viability and the differentiated functions of primary hepatocytes in cultures, it appears important to have them organized within a three-dimensional (3D) structure which promotes extensive cell-cell contacts, but also to be adequately supplied with oxygen. Here, we report a simple methodology satisfying these two fundamental but sometimes conflicting issues: primary rat hepatocytes were cultured on polydimethylsiloxane (PDMS) membranes with 3D-pillared microstructures with various dimensions, so that the cells could organize themselves around the pillars into various kinds of 3D multicellular aggregates, while being continuously supplied with oxygen by diffusion through the PDMS membrane. As expected, under such conditions, hepatocyte cultures exhibited higher albumin secretion and urea synthesis rates. It appeared then that as the spacing decreased between the pillars, the cells were more stably organized into smaller spherical aggregates and displayed the highest albumin secretion rates. Such a simple design is likely to be included in a new drug/chemical screening system in a practical microplate format, but also appears applicable to microfluidic devices.


Extravascular CBG-like sites in rat kidney and mineralocorticoid receptor specificity.
To determine the intrarenal distribution of extravascular corticosteroid-binding globulin- (CBG) like sites, we measured the specific binding of [3H]corticosterone to supernatants prepared from papilla-inner medulla, outer medulla, and cortex from adrenalectomized rats. Renal papilla-inner medulla of exhaustively perfused kidneys contained 8-20 times higher concentrations of such sites than cortex or outer medulla. The ontogeny and steroid specificities of such sites were identical to those of plasma CBG; their molar concentration in the inner medulla-papilla was 4 times that of plasma CBG, consistent with local accumulation of CBG. Cytosols from all three zones bound [3H]aldosterone in the presence of RU-26988, a highly specific synthetic glucocorticoid, with high affinity (Kd 4 degrees C, 0.3-0.4 X 10(-9) M) and limited capacity (papilla-inner medulla, 23-34; outer medulla, 15-16; cortex, 12-17 fmol/mg). In papilla-inner medulla the apparent specificity of such [3H]aldosterone binding sites was aldosterone greater than corticosterone greater than dexamethasone, in contrast to aldosterone = corticosterone greater than dexamethasone in outer medulla and cortex. We propose that extravascular CBG confers mineralocorticoid specificity on the papilla-inner medulla [3H]aldosterone binding sites. In addition, given the higher levels of extravascular than intravascular CBG and the recurrent vascular architecture of the renal medulla-papilla, a countercurrent exchange model is proposed for renewable sequestration of corticosterone in the region.


Effects of phosphate limitation on soluble microbial products and microbial community structure in semi-continuous Synechocystis-based photobioreactors.
All bacteria release organic compounds called soluble microbial products (SMP) as a part of their normal metabolism. In photobioreactor (PBR) settings, SMP produced by cyanobacteria represent a major pool of carbon and electrons available to heterotrophic bacteria. Thus, SMP in PBRs are a major driver for the growth of heterotrophic bacteria, and understanding the distribution of SMP in PBRs is an important step toward proper management of PBR microbial communities. Here, we analyzed the SMP and microbial communities in two Synechocystis sp. PCC6803-based PBRs. The first PBR (PBRP0) became phosphate limited after several days of operation, while the second PBR (PBRP+) did not have phosphate limitation. Heterotrophic bacteria were detected in both PBRs, but PBRP0 had a much higher proportion of heterotrophic bacteria than PBRP+. Furthermore, PBRP+ had greater biomass production and lower SMP production per unit biomass than PBRP0. Carbohydrates that were most likely derived from hydrolysis of extracellular polymeric substances (EPS) dominated the SMP in PBRP0, while products resulting from cell lysis or decay dominated the SMP in PBRP+. Together, our data support that maintaining phosphate availability in Synechocystis-based PBRs is important for managing SMP and, thus, the heterotrophic community.


The cytoplasmic tail of the influenza C virus glycoprotein HEF negatively affects transport to the cell surface.
The surface glycoprotein, HEF, of influenza C virus (C/Johannesburg/1/66) has been shown to undergo a post-translation conformational change that is evident in a dramatic change of electrophoretic mobility. If the corresponding gene is expressed in the absence of other viral proteins, this folding process does not occur at all or only very inefficiently. A chimaeric protein, HEF-HA(Tail), in which the short cytoplasmic tail (Arg-Thr-Lys) of HEF was replaced by the cytoplasmic tail of the haemagglutinin of an influenza A virus (fowl plague virus) was constructed. In contrast to the wild-type protein, the chimaeric protein was detected on the cell surface. No further improvement of the surface expression was observed when both the transmembrane domain and the cytoplasmic tail were replaced by the corresponding domains of either the influenza A haemagglutinin or gp40, an endogenous protein of MDCK cells. For the HEF-HA(Tail) construct this study shows that a substantial amount of the protein is converted to the 100 kDa mature form that is observed in virus-infected cells. The HEF-HA expressed on the cell surface reacted positively in esterase and haemadsorption assays, indicating that it was present in a biologically active form. The results show that the short cytoplasmic tail of HEF has a negative effect on the folding and surface transport of this protein. How this effect may be prevented during a virus infection is discussed.


[Contemporary approach to the treatment of complicated diabetic angiopathy of the lower extremities].
The experience of treatment of 278 patients with diabetes mellitus, complicated by the lower extremities diabetic angiopathy, was summarized. The authors had proposed the complex of treatment, including combined application of the high- and low-energy laser irradiation and catheterization of the shin arteries branches and the anterior abdominal wall superficial arteries for an adequate introduction of medicinal agents towards the affection focus. Application of the method proposed had promoted the results of treatment improvement, had permitted to proceed with economical amputation of extremity and to escape the reoperations performance.


The nucleotide recognized by the Escherichia coli A restriction and modification enzyme.
The nucleotide recognition sequence for the restriction-modification enzyme of Escherichia coli A (EcoA) has been determined to be GAG-7N-GTCA. This sequence is fairly similar, but distinctly different from the two other type I restriction enzyme recognition sites known for E. coli B and E. coli K12, respectively. N6-adenosine methylation has been observed at nucleotide positions 2 and 12 within that sequence after modification by EcoA. As a reference point for mapping the single EcoA site in lambda, the position of lambda point mutation Oam29 has been determined also.


Ubiquitin and Parkinson's disease through the looking glass of genetics.
Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.


Mineral fibre content of lung in mesothelial tumours: preliminary report.
A survey was made, through pathologists, of all 274 fatal cases of primary malignant mesothelioma in North America in 1972. For each case, a control with pulmonary metastases from a primary tumour other than lung cancer was matched for sex and age. Relatives and friends of both cases and controls were interviewed; and specimens of lung tissue were obtained for 100 case-control pairs and analysed 'blind' by electron microscopy and X-ray energy dispersion analysis. This report describes the preliminary results of the analyses of asbestos fibres in the first 37 case-control pairs: chrysotile fibres were far more prevalent than amphiboles, but equal quantities were found in cases and controls. There was, however, a clear excess of amosite fibres in male cases as compared with controls.


Practice patterns of bupropion co-prescription with antipsychotic medications.
Objective: Bupropion is one of the few medications with an FDA indication for smoking cessation. This is of particular significance due to the high co-morbidity of tobacco use disorder in patients with schizophrenia spectrum and other psychotic disorders. We sought to determine whether historical suggestions of bupropion's pro-dopaminergic activity lead prescribers to withhold bupropion in populations receiving antipsychotic medications. Methods: The prevalence in clinical practice of the combination of bupropion and 10 antipsychotic formulations was determined by a computer review of the Genoa Healthcare database for all prescribers at 10 participating community mental health centers. Actual prevalence was compared with expected prevalence using the test of proportions. A Bonferroni correction for multiple comparisons was included. Results: Clozapine, p = 0.0004, and the microsphere formulation of risperidone, p = 0.0045, were prescribed with bupropion significantly less often that chance. None of the other eight antipsychotic formulations were prescribed significantly differently than chance. Conclusions: The co-prescription of bupropion and antipsychotic medication may be affected by historical misconceptions regarding bupropion's purportedly pro-dopamine properties. Viable options for the treatment of tobacco use disorder should not be discounted prematurely in patients with schizophrenia spectrum and other psychotic disorders. We suggest further study on the safety and efficacy of the combination of bupropion and antipsychotic medication is needed.


Gait mechanics in those with/without medial compartment knee osteoarthritis 5 years after anterior cruciate ligament reconstruction.
The objective of the study was to evaluate differences in gait mechanics 5 years after unilateral anterior cruciate ligament reconstruction surgery, for non-osteoarthritic (n = 24) versus osteoarthritic (n = 9) subjects. For the involved knee, the osteoarthritic group demonstrated significantly lower peak knee flexion angles (non-osteoarthritic = 24.3 ± 4.6°, osteoarthritic = 19.1 ± 2.9°, p = 0.01) and peak knee flexion moments (non-osteoarthritic = 5.3 ± 1.2% Body Weight × Height, osteoarthritic = 4.4 ± 1.2% Body Weight × Height, p = 0.05). Differences in peak knee adduction moment approached significance, with a higher magnitude for the osteoarthritic group (non-osteoarthritic = 2.4 ± 0.8% Body Weight × Height, osteoarthritic = 2.9 ± 0.5% Body Weight × Height, p = 0.09). Peak medial compartment joint load was evaluated using electromyography-informed neuromusculoskeletal modeling. Peak medial compartment joint load in the involved knee for the two groups was not different (non-osteoarthritic = 2.4 ± 0.4 Body Weight, osteoarthritic = 2.3 ± 0.6 Body Weight). The results suggest that subjects with dissimilar peak knee moments can have similar peak medial compartment joint load magnitudes. There was no evidence of inter-limb asymmetry for either group. Given the presence of inter-group differences (non-osteoarthritic vs. osteoarthritic) for the involved knee, but an absence of inter-limb asymmetry in either group, it may be necessary to evaluate how symmetry is achieved, over time, and to differentiate between good versus bad inter-limb symmetry, when evaluating knee gait parameters. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:625-633, 2017.


Congenital dislocation of the hip associated with central core disease.
Central core disease is a congenital, non-progessive myopathy with proximal muscle weakness most prevalent about the pelvic girdle. Including out two patients there have been seven recorded cases of congenital hip dislocation associated with central core disease in children. Initial and recurrent contractures about the hip and knee should suggest the possibility of central core disease. However, the definitive diagnosis can only be made by muscle biopsy.


Evaluation of the Microring YT system for identifying clinical yeast isolates.
The Microring YT is a commercial system for identifying clinical yeast isolates. The system uses a series of discs impregnated with inhibitory agents mounted on a ring. The pattern of growth and inhibition produced provides a six digit code which can be compared with a table provided by the manufacturer. The performance of this system was compared with the API 32C in the identification of 606 yeast isolates (355 clinical and 251 environmental strains). The Microring YT system was in 72.6% agreement with the API 32C system. The sensitivity of identification of different species varied from 38% to 100%. The API 32C system has a more extensive database than the Microring YT and is thus more reliable for use, but it is considerably more expensive. It is concluded that although the Microring YT is cheap, easy, and convenient to use, it is inadequate for many common Candida species.


Structural basis for the recognition in an idiotype-anti-idiotype antibody complex related to celiac disease.
Anti-idiotype antibodies have potential therapeutic applications in many fields, including autoimmune diseases. Herein we report the isolation and characterization of AIM2, an anti-idiotype antibody elicited in a mouse model upon expression of the celiac disease-specific autoantibody MB2.8 (directed against the main disease autoantigen type 2 transglutaminase, TG2). To characterize the interaction between the two antibodies, a 3D model of the MB2.8-AIM2 complex has been obtained by molecular docking. Analysis and selection of the different obtained docking solutions was based on the conservation within them of the inter-residue contacts. The selected model is very well representative of the different solutions found and its stability is confirmed by molecular dynamics simulations. Furthermore, the binding mode it adopts is very similar to that observed in most of the experimental structures available for idiotype-anti-idiotype antibody complexes. In the obtained model, AIM2 is directed against the MB2.8 CDR region, especially on its variable light chain. This makes the concurrent formation of the MB2.8-AIM2 complex and of the MB2.8-TG2 complex incompatible, thus explaining the experimentally observed inhibitory effect on the MB2.8 binding to TG2.


Cardiovascular responses to intrathecal administration of L- and D-baclofen in the rat.
D- and L-baclofen were given intrathecally at the T2 spinal level in the anaesthetized rat. D-Baclofen, in doses of 7, 35 and 70 nmol produced graded increases in arterial pressure but heart rate remained unaffected. Responses appeared within 30 s, peaked at 2 min and decayed over the next 5 min. Injection i.v. of 70 nmol of D-baclofen failed to alter arterial pressure or heart rate. In contrast, intrathecal administration of L-baclofen decreased both arterial pressure and heart rate. The amplitude and time course of the effects depended on the dose used; 700 nmol of L-baclofen had stronger and longer effects than those induced by 70 nmol, while 7 nmol had no effect. (I.v. injection of 70 nmol of L-baclofen had similar effects to intrathecal administration but with different time course and amplitude.) When given at the T9 level at doses of 70 nmol, D- and L-baclofen had effects similar to those observed at the second thoracic level. Effects of intrathecal administration of D- and L-baclofen at T2 were prevented by pretreatment with either hexamethonium (10 mg/kg i.v.) or lidocaine (25 microliters of a 1% solution, intrathecally). The results suggest that D- and L-baclofen-sensitive receptors in the spinal cord are involved in regulating sympathetic output in pathways to the vessels and/or to the heart. In addition, our results suggest that D- or L-baclofen may not act via classical GABAB receptors or that two types of GABAB receptor exist in spinal sympathetic pathways.


Coconut oil protects cortical neurons from amyloid beta toxicity by enhancing signaling of cell survival pathways.
Alzheimer's disease is a progressive neurodegenerative disease that has links with other conditions that can often be modified by dietary and life-style interventions. In particular, coconut oil has received attention as having potentially having benefits in lessening the cognitive deficits associated with Alzheimer's disease. In a recent report, we showed that neuron survival in cultures co-treated with coconut oil and Aβ was rescued compared to cultures exposed only to Aβ. Here we investigated treatment with Aβ for 1, 6 or 24 h followed by addition of coconut oil for a further 24 h, or treatment with coconut oil for 24 h followed by Aβ exposure for various periods. Neuronal survival and several cellular parameters (cleaved caspase 3, synaptophysin labeling and ROS) were assessed. In addition, the influence of these treatments on relevant signaling pathways was investigated with Western blotting. In terms of the treatment timing, our data indicated that coconut oil rescues cells pre-exposed to Aβ for 1 or 6 h, but is less effective when the pre-exposure has been 24 h. However, pretreatment with coconut oil prior to Aβ exposure showed the best outcomes. Treatment with octanoic or lauric acid also provided protection against Aβ, but was not as effective as the complete oil. The coconut oil treatment reduced the number of cells with cleaved caspase and ROS labeling, as well as rescuing the loss of synaptophysin labeling observed with Aβ treatment. Treatment with coconut oil, as well as octanoic, decanoic and lauric acids, resulted in a modest increase in ketone bodies compared to controls. The biochemical data suggest that Akt and ERK activation may contribute to the survival promoting influence of coconut oil. This was supported by observations that a PI3-Kinase inhibitor blocked the rescue effect of CoOil on Aβ amyloid toxicity. Further studies into the mechanisms of action of coconut oil and its constituent medium chain fatty acids are warranted.


Altered Expression of Two Small Secreted Proteins (ssp4 and ssp6) Affects the Degradation of a Natural Lignocellulosic Substrate by Pleurotus ostreatus.
Pleurotus ostreatus is a white-rot fungus that can degrade lignin in a preferential manner using a variety of extracellular enzymes, including manganese and versatile peroxidases (encoded by the vp1-3 and mnp1-6 genes, respectively). This fungus also secretes a family of structurally related small secreted proteins (SSPs) encoded by the ssp1-6 genes. Using RNA sequencing (RNA-seq), we determined that ssp4 and ssp6 are the predominant members of this gene family that were expressed by P. ostreatus during the first three weeks of growth on wheat straw. Downregulation of ssp4 in a strain harboring an ssp RNAi construct (KDssp1) was then confirmed, which, along with an increase in ssp6 transcript levels, coincided with reduced lignin degradation and the downregulation of vp2 and mnp1. In contrast, we observed an increase in the expression of genes related to pectin and side-chain hemicellulose degradation, which was accompanied by an increase in extracellular pectin-degrading capacity. Genome-wide comparisons between the KDssp1 and the wild-type strains demonstrated that ssp silencing conferred accumulated changes in gene expression at the advanced cultivation stages in an adaptive rather than an inductive mode of transcriptional response. Based on co-expression networking, crucial gene modules were identified and linked to the ssp knockdown genotype at different cultivation times. Based on these data, as well as previous studies, we propose that P. ostreatus SSPs have potential roles in modulating the lignocellulolytic and pectinolytic systems, as well as a variety of fundamental biological processes related to fungal growth and development.


Long-term outcomes of sacral nerve stimulation for faecal incontinence.
Sacral nerve stimulation (SNS) has proven short- to medium-term effectiveness for the treatment of faecal incontinence (FI); fewer long-term outcomes have been presented and usually in small series. Here, the long-term effectiveness of SNS was evaluated in a large European cohort of patients with a minimum of 5 years' follow-up. Prospectively registered data from patients with FI who had received SNS for at least 5 years from ten European centres were collated by survey. Daily stool diaries, and Cleveland Clinic and St Mark's incontinence scores were evaluated at baseline, after implantation and at the last follow-up. SNS was considered successful when at least 50 per cent symptom improvement was maintained at last follow-up. A total of 407 patients underwent temporary stimulation, of whom 272 (66·8 per cent) had an impulse generator implanted; 228 (56·0 per cent) were available for long-term follow-up at a median of 84 (i.q.r. 70-113) months. Significant reductions in the number of FI episodes per week (from median 7 to 0·25) and summative symptom scores (median Cleveland Clinic score from 16 to 7, St Mark's score from 19 to 6) were recorded after implantation (all P < 0·001) and maintained in long-term follow-up. In per-protocol analysis, long-term success was maintained in 71·3 per cent of patients and full continence was achieved in 50·0 per cent; respective values based on intention-to-treat analysis were 47·7 and 33·4 per cent. Predictive analyses determined no significant association between pretreatment variables and successful outcomes. Risk of long-term failure correlated with minor symptom score improvement during the temporary test phase. SNS remains an effective treatment for FI in the long term for approximately half of the patients starting therapy.


Mortality and Survival Analysis of Burn Patients Admitted in a Critical Care Burn Unit, Saudi Arabia.
Burn injury is associated with a high mortality risk. Recent epidemiological data on burn injury and mortality rate from Saudi Arabia is lacking. This study aimed to analyze the survival rates and its predictability using the Baux score in patients with burn injury at a tertiary care hospital in Saudi Arabia. This retrospective study included all patients admitted to the burn unit at King Fahd Hospital of the University, Al Khobar, between March 2014 and February 2020. Patients' burn characteristics and calculated revised Baux scores were collected. The age, burn wound size, type of burn, burn extension, and Baux score of the survivors and non-survivors were compared. A total number of 102 patients were included, and their mean age was 24.2 years (range: 9 months to 78 years). The mean affected total body surface area was 26.4%. Ninety patients (88%) suffered from flame/scald burn. The mortality rate was 17.6% (18 patients); all these patients had flame burns. No patient with a revised Baux score ≥110 survived (n = 14; 77% of the total deaths), while there was no mortality at score <36. Inhalational injuries were reported in 18 patients, of which 13 (72%) died. Patients with patent airway and no inhalation injury were 19 times more likely to survive than those with a compromised airway (P < 0.001). In terms of the depth of burn, partial thickness increased the likeliness of survival by 10 times compared with full thickness (P < 0.003). Inhalational injury and burn size were the most prognostic factors of burn injury in this study. As all cases of mortality were from flame burns, regulation on flammable materials and safety measures should be promoted to the public.


Toxoplasma gondii-induced neutrophil extracellular traps are relevant to glycolysis, TLR2, and TLR4 MAPK signaling pathway in goats.
Toxoplasma gondii (T. gondii) exhibits a significantly high prevalence of infection in goats, leading to adverse consequences such as abortion and stillbirth in ewes, thereby posing a substantial challenge to the goat farming industry. Neutrophil extracellular traps (NETs) have been shown to capture T. gondii in goats; however, the precise mechanisms underlying NET release in goats remain poorly understood. Therefore, the aim of our research was to elucidate the involved mechanism. We assessed the cytotoxicity of T. gondii on neutrophils using CCK-8 assay, visualized the structure of T. gondii-induced goat NETs through immunofluorescence, quantified ROS release during T. gondii-induced NET formation using fluorescence microplate analysis, and employed inhibitors targeting TLR 2, TLR4, NADPH oxidase, ERK1/2, and P38 MAPK signaling pathways as well as glycolysis to dissect the mechanisms underlying T. gondii-induced NET release. Within 1 h, T. gondii did not exhibit significant cytotoxicity towards neutrophils in our findings. The formation of typical NET structures induced by T. gondii involved DNA, citrullinated histone 3 (citH3), and neutrophil elastase (NE). Additionally, T. gondii significantly stimulated the release of NETs in goats. The process was accompanied by the production of reactive oxygen species (ROS) mediated through NADPH oxidase, p38, and ERK1/2 signaling pathways. Inhibition of these pathways resulted in a decrease in NET release. Moreover, inhibition of TLR 2, TLR4, and glycolysis also led to a reduction in T. gondii-induced NET release. Overall, our study demonstrates that T. gondii can induce characteristic NET structures and elucidates the involvement of various mechanisms including TLR2/TLR4 signaling pathway activation, NADPH oxidase activity modulation via ROS production regulation through p38 MAPK and ERK1/2 signaling pathways, and glycolysis regulation during the innate immune response against T. gondii infection in goats.


Lack of beneficial effects of granulocyte colony-stimulating factor in patients with subacute myocardial infarction undergoing late revascularization: a double-blind, randomized, placebo-controlled clinical trial.
Early clinical studies have suggested that administration of granulocyte-colony stimulating factor (G-CSF) may improve the clinical condition of patients suffering from myocardial infarction (MI).This prospective, randomized, double-blind, placebo-controlled single-centre trial aims to assess the safety and clinical efficacy of G-CSF administration in patients with subacute MI and impaired LV function undergoing delayed primary percutaneous coronary intervention (PCI). A total of 16 patients (13 men, mean age 51 years) with subacute ST-segment elevation MI and a left ventricular (LV) ejection fraction (EF) of less than 45% at baseline who underwent late revascularization, were included in the study. Patients were randomized in a double-blind fashion to receive either G-CSF (at a dose of 10 microg/kg body weight) or placebo for five consecutive days. End points consisted of assessment of safety parameters as well as changes of global and regional myocardial function from baseline until six months following PCI. G-CSF administration resulted in a significant mobilization of different cell populations (four-fold increase in WBC count and a six-fold increase in CD34+ cells). G-CSF treatment was well tolerated in most patients and no major adverse cardiac events or severe G-CSF-related side effects were identified during hospitalization and at follow-up. No significant differences were observed between the G-CSF and placebo groups regarding global and regional myocardial function parameters. G-CSF administration is safe, but not effective, in improving impaired LV functional parameters in patients with subacute MI who had an impaired baseline EF of less than 45%.


Concurrent jellyfish blooms and tenacibaculosis outbreaks in Northern Norwegian Atlantic salmon (Salmo salar) farms.
Tenacibaculosis is an increasing problem in the Norwegian Atlantic salmon aquaculture industry causing significant economic losses. In September 2015, two separate outbreaks of suspected tenacibaculosis occurred at two Atlantic salmon farms in Finnmark County in Northern Norway. The events resulted in major losses of smolts newly transferred into seawater. Prior to, and during the outbreaks, large numbers of small jellyfish, identified as Dipleurosoma typicum (Boeck) were observed in the vicinity of the farms and inside the net-pens. This study investigates the possible link between the jellyfish, Tenacibaculum spp. and the tenacibaculosis outbreaks. Bacteriology, histology, scanning and transmission electron microscopy, and real-time RT-PCR screening were performed on both fish and jellyfish samples. Based on the findings, Tenacibaculum finnmarkense was found to be the dominant bacteria associated with the tenacibaculosis outbreaks at both sites and that D. typicum is unlikely to be a vector for this fish pathogenic bacterium. However, results do show that the jellyfish caused direct damage to the fish's skin and may have exacerbated the bacterial infection by allowing an entry point for bacteria.


Genomic mRNA profiling reveals compensatory mechanisms for the requirement of the essential splicing factor U2AF.
The large subunit of the U2 auxiliary factor (U2AF) recognizes the polypyrimidine tract (Py-tract) located adjacent to the 3' splice site to facilitate U2 snRNP recruitment. While U2AF is considered essential for pre-mRNA splicing, its requirement for splicing on a genome-wide level has not been analyzed. Using Solexa sequencing, we performed mRNA profiling for splicing in the Schizosaccharomyces pombe U2AF(59) (prp2.1) temperature-sensitive mutant. Surprisingly, our analysis revealed that introns show a range of splicing defects in the mutant strain. While U2AF(59) inactivation (nonpermissive) conditions inhibit splicing of some introns, others are spliced apparently normally. Bioinformatics analysis indicated that U2AF(59)-insensitive introns have stronger 5' splice sites and higher A/U content. Most importantly, features that contribute to U2AF(59) insensitivity of an intron unexpectedly reside in its 5'-most 30 nucleotides. These include the 5' splice site, a guanosine at position 7, and the 5' splice site-to-branch point sequence context. A differential requirement (similar to U2AF(59)) for introns may also apply to other general splicing factors (e.g., prp10). Our combined results indicate that U2AF insensitivity is a common phenomenon and that varied intron features support the existence of unrecognized aspects of spliceosome assembly.


Role of urinary bikunin in the inhibition of calcium oxalate crystallization.
Several urinary macromolecules are known to modulate calcium oxalate (CaOx) crystallization. One of these is urinary bikunin, the light chain of inter-alpha-inhibitor. Bikunin has been demonstrated to be an efficient inhibitor of CaOx crystal growth; however, its inhibitory activity against other events in CaOx crystallization has not been fully investigated. To assess the potential of urinary bikunin as an effective inhibitor, its effects on CaOx crystal nucleation and aggregation were evaluated. Nucleation and aggregation of CaOx crystals were studied by measuring turbidity at 620 nm. In the nucleation assay, crystallization was induced by mixing calcium chloride and sodium oxalate, at final concentrations of 3 and 0.5 mM, respectively. Both solutions were buffered with 0.05 M Tris, 0.15 M NaCl, pH 6.5. Nucleation measurements were performed at 37 degrees C, with stirring at 800 rpm. Inhibition of nucleation was estimated by comparing the induction time in the presence of the inhibitor with control values. In the aggregation assay, the optical density of the solution containing CaOx monohydrate crystals was monitored. Inhibition of aggregation was evaluated by comparing the turbidity slope in the presence of the inhibitor with control values. The data showed that urinary bikunin, at concentrations of 2.5 to 20 microg/ml, retarded crystal nucleation by 67 to 58% and inhibited crystal aggregation by 59 to 80%. According to these results, it seems that urinary bikunin is an efficient inhibitor of crystal nucleation and aggregation. Its presence in the kidneys and urine may protect subjects against CaOx crystallization and kidney stone formation.


Effects of music therapy on psychological health of women during pregnancy.
The purpose of this study was to examine the effects of music therapy on stress, anxiety and depression in Taiwanese pregnant women. The value of music therapy is slowly being realized by nurses in various clinical areas, including obstetrics. Previous studies have demonstrated a high prevalence of psychological stress during pregnancy. Few studies have examined the effects of music therapy on reducing psychological stress during pregnancy. A randomized experimental study design was developed and implemented. Two hundred and thirty-six pregnant women were randomly assigned to music therapy (n = 116) and control (n = 120) groups. The music therapy group received two weeks of music intervention. The control group received only general prenatal care. Psychological health was assessed using three self-report measures: Perceived Stress Scale (PSS), State Scale of the State-Trait Anxiety Inventory (S-STAI) and Edinburgh Postnatal Depression Scale (EPDS). In a paired t-test, the music therapy group showed significant decrease in PSS, S-STAI and EPDS after two weeks. The control group only showed a significant decrease in PSS after two weeks. This decrease was not as substantial as in the experimental group. An ancova test with the pretest scores as the control revealed that the changes in PSS, S-STAI and EPDS after two weeks were significantly decreased in the experimental group compared with the control group. This controlled trial provides preliminary evidence that two-week music therapy during pregnancy provides quantifiable psychological benefits. The findings can be used to encourage pregnant women to use this cost-effective method of music in their daily life to reduce their stress, anxiety and depression. Further research is needed to test the long-term benefits.


Cerebral vein and dural sinus thrombosis in Portugal: 1980-1998.
There is insufficient information on the prognosis and safety of anticoagulation in acute cerebral vein and dural sinus thrombosis (CVDST). To describe the clinical aspects and medical management of CVDST in Portuguese hospitals, to evaluate the safety of anticoagulation in this setting, and to identify subgroups of CVDST patients with different prognoses, we registered symptomatic CVDST patients admitted to Portuguese hospitals since 1980. Cases were collected from file review up to 6/95 and from consecutively admitted patients from 6/95 to 6/98. One hundred and forty-two patients were included from 20 centers (51 retrospectively and 91 prospectively). One hundred and twelve patients (79%) were anticoagulated. There were only 6 new intracranial hemorrhages (4 in anticoagulated patients) and 2 systemic hemorrhages. Nine (6%) patients died. At discharge, 96 (68%), had recovered completely and only 6 (4%) were dependent (Rankin > or = 3). Significant multivariate predictors of death/dependency were central nervous system infection as a predisposing cause (odds ratio, OR = 15.4; 95% confidence interval CI = 111-1.1), encephalopathy on admission (OR = 5.2; 95% CI = 18.7-1.5) and hemorrhage on admission CT/MR (OR = 3.6; 95% CI = 12.9-1). Significant predictors of complete recovery were no encephalopathy on admission (OR = 5; 95% CI = 12.5-2.1), age < 45 years (OR = 3.8; 95% CI = 9.2-1.6) and anticoagulation (OR = 3.8; 95% CI = 9.6-1.5). It is possible to identify CVDST patients with potential bad or good prognosis in the acute phase. Anticoagulation was safe and a predictor of complete recovery in acute CVDST.


Isotretinoin-associated acne fulminans: A multicentre, retrospective study of the European Academy of Dermatology and Venereology Task Force on Acne, Rosacea and Hidradenitis Suppurativa.
Acne fulminans (AF) is a rare severe acne entity. Although occasionally reported, it is unclear whether AF development is associated with oral isotretinoin treatment. To investigate the occurrence of isotretinoin-associated AF, clinical characteristics and prognosis at follow-up. An international, multicentre, retrospective study was performed in eight hospitals following the call of the EADV Task Force on Acne, Rosacea and Hidradenitis Suppurativa (ARHS). Characteristics of patients treated with isotretinoin before the development of AF (isotretinoin-associated acne fulminans, IAF) were compared with non-IAF (NAF). Forty-nine patients diagnosed with AF from 2008 to 2022 were included (mean age 16.4 years, SD 2.9, 77.6% male). Αrthralgias/arthritis occurred in 11 patients (22.9%). AF occurred without any previous acne treatment in 26.5% of the patients. Overall, 28 patients (57.1%) developed AF after oral isotretinoin intake (IAF group), while the remaining 21 patients (42.9%) developed AF without previous oral isotretinoin administration (NAF group). IAF occurred after a median duration of isotretinoin treatment of 45 days (IQR: 30, 90). Patients with IAF were more frequently male compared to patients with NAF (89.3% vs. 61.9%, respectively, p = 0.023). There were no differences in patients with IAF versus NAF in patient age, the duration of pre-existing acne, a family history of AF, the distribution of AF lesions or the presence of systemic symptoms or arthralgias. Regarding the management of AF, patients with IAF were treated more frequently with prednisolone (96.2%) compared to those with NAF (70%; p = 0.033) and less frequently with isotretinoin (32.1%) compared to NAF (85.7%; p < 0.001). At a median follow-up of 2.2 years, 76.4% of patients were free of AF and scarring was present in all patients. No specific clinical or demographic characteristics of IAF compared with NAF could be detected, a fact that does not support IAF as a district clinical entity.


Scrotoschisis in a neonate with meconium peritonitis and periorchitis.
We present the case of an infant born with scrotoschisis and evidence of meconium periorchitis and peritonitis. A scrotal defect was noted with exposure of the left testis and spermatic cord. Meconium peritonitis and periorchitis were confirmed on operative exploration. Given the history, cystic fibrosis was suspected, but initial screening and diagnostic tests were negative.


Mutation analysis of glial cell line-derived neurotrophic factor, a ligand for an RET/coreceptor complex, in multiple endocrine neoplasia type 2 and sporadic neuroendocrine tumors.
Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-alpha, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-alpha are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.


The driving effects of common atmospheric molecules for formation of prenucleation clusters: the case of sulfuric acid, formic acid, nitric acid, ammonia, and dimethyl amine.
How secondary aerosols form is critical as aerosols' impact on Earth's climate is one of the main sources of uncertainty for understanding global warming. The beginning stages for formation of prenucleation complexes, that lead to larger aerosols, are difficult to decipher experimentally. We present a computational chemistry study of the interactions between three different acid molecules and two different bases. By combining a comprehensive search routine covering many thousands of configurations at the semiempirical level with high level quantum chemical calculations of approximately 1000 clusters for every possible combination of clusters containing a sulfuric acid molecule, a formic acid molecule, a nitric acid molecule, an ammonia molecule, a dimethylamine molecule, and 0-5 water molecules, we have completed an exhaustive search of the DLPNO-CCSD(T)/CBS//ωB97X-D/6-31++G** Gibbs free energy surface for this system. We find that the detailed geometries of each minimum free energy cluster are often more important than traditional acid or base strength. Addition of a water molecule to a dry cluster can enhance stabilization, and we find that the (SA)(NA)(A)(DMA)(W) cluster has special stability. Equilibrium calculations of SA, FA, NA, A, DMA, and water using our quantum chemical ΔG° values for cluster formation and realistic estimates of the concentrations of these monomers in the atmosphere reveals that nitric acid can drive early stages of particle formation just as efficiently as sulfuric acid. Our results lead us to believe that particle formation in the atmosphere results from the combination of many different molecules that are able to form highly stable complexes with acid molecules such as SA, NA, and FA.


The effects of calcium channel blocking agents on cardiovascular function.
The hemodynamic effects of calcium blocking agents are a composite of the various direct and indirect cardiac and peripheral vascular actions of these drugs on the individual determinants of left ventricular pump function. Calcium antagonists have been shown to have a direct negative inotropic effect, a direct negative chronotropic effect and a direct effect to produce relaxation of vascular smooth muscle and vasodilation. These agents may also elicit important indirect effects by an anti-ischemic action referable to both coronary arterial dilation and reduction in myocardial oxygen demand, as well as a baroreceptor-mediated reflex increase in beta adrenergic tone in response to vasodilation. The net result of these direct and indirect actions on cardiocirculatory dynamics is also dependent upon the individual calcium blocking agent administered, the dose and route of administration, and the underlying status of left ventricular function. Available data do not lead to a clear definition of the hemodynamic effects referable to calcium blocking agents that may be produced by the interaction of all variable factors. At present, however, it would appear that the direct negative inotropic and chronotropic actions of the calcium antagonists are offset by the reflex increase in beta adrenergic tone, in combination with the reduction in afterload produced by the peripheral vascular effects of these agents. Preliminary data suggest that certain calcium inhibiting agents may be useful in the vasodilator therapy of congestive heart failure. Nevertheless, the direct negative inotropic effects of these agents have resulted in clinically evident decompensation in cardiac performance in patients with advanced left ventricular dysfunction, and caution is warranted in the application of calcium blocking agents in this setting.


Hip revision arthroplasty for failed osteosynthesis in periprosthetic Vancouver type B1 fractures using a cementless, modular, tapered revision stem.
To evaluate the hypothesis that failed osteosynthesis of periprosthetic Vancouver type B1 fractures can be treated successfully with stem revision using a transfemoral approach and a cementless, modular, tapered revision stem with reproducible rates of fracture healing, stability of the revision stem, and clinically good results. A total of 14 patients (11 women, three men) with a mean age of 72.4 years (65 to 90) undergoing revision hip arthroplasty after failed osteosynthesis of periprosthetic fractures of Vancouver type B1 were treated using a transfemoral approach to remove the well-fixed stem before insertion of a modular, fluted titanium stem which obtained distal fixation. These patients were clinically and radiologically followed up for a mean 52.2 months (24 to 144). After a mean of 15.5 weeks (standard deviation (sd) 5.7) all fractures had healed. No stems subsided and bony-ingrowth fixation had occurred according to the classification of Engh et al. The mean Harris Hip Score increased from a pre-operative score of 22.2 points (sd 9.7) to 81.5 points (sd 16.8) 24 months post-operatively. All hips had obtained an excellent result according to the classification of Beals and Tower. The technique described here for stem revision provides reproducibly good results in the treatment of failed osteosynthesis for Vancouver types B1 periprosthetic fractures of the hip. Cite this article: Bone Joint J 2017;99-B(4 Supple B):11-16.


Aspiration thrombectomy in ST-elevation myocardial infarction.
The major challenge in the treatment of ST-elevation myocardial infarction (STEMI) is not only restoration of normal coronary blood flow but also microvascular perfusion. In fact, both electrocardiographic (ST segment resolution) and angiographic measures of myocardial perfusion (myocardial blush grade) have been shown to predict mortality after primary percutaneous coronary intervention (PPCI). Initial enthusiasm for manual thrombectomy arose after the apparent mortality benefit observed in the TAPAS trial (N=1,071). Meta-analyses of small trials suggest that manual thrombectomy improves epicardial and microvascular perfusion with trends towards benefit for survival. On the other hand, meta-analyses of small trials of mechanical thrombectomy show improvement in ST resolution without an effect on survival. Recently, the TASTE trial (N=7,244) showed no reduction in mortality with manual thrombectomy but trends toward reduction in rates of rehospitalisation for recurrent MI and stent thrombosis. The interpretation of TASTE should be cautious given that the trial had a much lower than expected mortality, and modest but important treatment effects cannot be excluded (20-30%). The largest trial, the ongoing TOTAL trial (N=10,700), will help determine the effect of manual thrombectomy for important clinical outcomes. A planned individual patient meta-analysis of the TOTAL and TASTE trials will have approximately 17,000 patients to examine the effect on clinical outcomes.


Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma.
Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma. In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence. TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the α(-) and β(-)-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024). Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma.


[Enantiomeric monoterpenes in ether oil from Achillea millefolium s. I.--a taxonomically useful marker?].
The Achillea millefolium complex is a group of taxonomically hardly separable species. Yarrow has the tendency to hybridize and to vary in phenotype. An obvious characterization of the species or hybrids is not just important for the taxonomical distinction but also for a reliable assessment of herbal drug quality. Most of the Achillea plants are still gathered from natural populations. According to the variation in phenotype, mixtures with Achillea species, which contain allergy setting compounds, often cannot be determined. Morphometric investigations exclusively do not replace a further chemical characterization. Therefore we tried to assess the composition of the chiral monoterpenes alpha-pinene, beta-pinene and sabinene. They were selected because of their frequency in the essential oil of Achillea species. By method of M.C.S.S. (Moving Capillary Stream Switching) the differentiation of stereoisomeres succeeded directly from the essential oil, which was distilled or extracted by headspace trapping at room temperature. The enantiomeric distribution neither depends on the method of extraction, nor on the habitat or the developmental stage of Yarrow. Since the compositions of enantiomeres from several Achillea species and their hybrides are of different pattern, it seemed to represent an additional marker. Though investigations of all species within the Achillea millefolium group and possibly of further chiral compounds are necessary to ensure these results.