the influence of the host cell on the inhibition of virus protein synthesis in cells double infected with vesicular stomatitis virus and mengovirus.
The ability of mengovirus to inhibit the synthesis of vesicular stomatitis virus (VSV) proteins and of VSV to inhibit the synthesis of mengovirus proteins during double infection in three different cell lines was investigated. Although cellular protein synthesis was inhibited after infection of cells by each virus, the ability of one virus to decrease translation of the mRNA species of the co-infecting virus varied with the cell type. Superinfection of mengovirus-infected L-929 cells by VSV resulted in essentially no inhibition in the synthesis of either mengovirus or VSV proteins. In HeLa cells and CHO cells the synthesis of both VSV and mengovirus proteins was inhibited under conditions of simultaneous or sequential infection. The inhibition of VSV protein synthesis after infection of HeLa cells by mengovirus was not a result of a modification or inactivation of virus mRNAs. When extracted from double infected cells, the VSV mRNAs manifested normal biological activity, as determined by their ability to stimulate the synthesis of VSV proteins in a micrococcal nuclease-treated cell-free system from L cells. The interference of non-interference of one virus by another in different cell lines was also measured by quantifying the number of infectious particles produced in each cell line. The results were similar to those reported above for protein synthesis inhibition. These experiments suggest that the interference of mengovirus with VSV mRNA translation in HeLa cells is not necessarily reflective of the mechanism by which mengovirus inhibits cellular protein synthesis. Also, the host cell appears to influence the extent or nature of the interference of one virus by the other.


Expression of the v-src or v-fps oncogene increases fructose 2,6-bisphosphate in chick-embryo fibroblasts. Novel mechanism for the stimulation of glycolysis by retroviruses.
The concentration of fructose 2,6-bisphosphate and the activity of 6-phosphofructo-2-kinase are increased after infection of chick-embryo fibroblasts with the Rous sarcoma virus, or with a temperature-sensitive mutant of this virus at the permissive, but not at the non-permissive, temperature. This is observed after transformation by retroviruses carrying either the v-src or v-fps, but not the v-mil and/or v-myc, oncogenes. Comparison of the effects of the Rous sarcoma virus with those of phorbol myristate acetate on fructose 2,6-bisphosphate suggests that both result from the stimulation of a step which is rate-limiting for 6-phosphofructo-2-kinase activation and which is also controlled by protein kinase C.


A Qualitative Exploration of Sport and Social Pressures on Elite Athletes in Relation to Disordered Eating.
Introduction: Athletes are at increased risk of disordered eating compared to non-athletes. Inspired by previous investigation into quantitative work on an etiological model of disordered eating in athletes, the current study aimed to explore a problematic aspect of the model: athletes' lived experiences of social and sport pressures in relation to the onset of disordered eating and differing eating behaviors. Methods: Nine (N = 9) male and female athletes representing a range of endurance sports took part in semi-structured interviews. Thematic analysis was utilized. Analysis: Analysis revealed two main themes each with two corresponding subthemes (1) Conflating physical appearance and sporting ability with the subthemes of (1a) social comparison in a sporting world and (1b) societal notions of "the athlete body" and (2) Living as an athlete with the corresponding subthemes of (2a) discipline and sacrifice and (2b) the balancing act. Discussion: It is the complex interaction between societal expectations as lived out in social messages and comparisons, and sport pressures that contributes to the development of disordered eating behaviors. These findings suggest that prevention and treatment of disordered eating in athletes can be applied from those already established in non-sporting realm.


Co-occurrence of an intraventricular meningioma and cholesterol granuloma of the choroid plexus in a cat.
A 12-year-old domestic shorthair cat was presented with neurologic signs localized to the forebrain. Magnetic resonance imaging (MRI) of the brain revealed a space occupying lesion within the third and the lateral ventricles. The lesion had areas of disparate signal characteristics and exerted a mass effect on the surrounding parenchyma and ventricular system. The histologic examination identified the co-existence of two intraventricular masses: a meningioma and a choroid plexus cholesterol granuloma.


Relationship between Personality and Insomnia in Panic Disorder Patients.
Panic disorder (PD) is frequently comorbid with insomnia, which could exacerbate panic symptoms and contribute to PD relapse. Research has suggested that characteristics are implicated in both PD and insomnia. However, there are no reports examining whether temperament and character affect insomnia in PD. Thus, we examined the relationship between insomnia and personality characteristics in PD patients. Participants were 101 patients, recruited from 6 university hospitals in Korea, who met the DSM-IV-TR criteria for PD. We assessed sleep outcomes using the sleep items of 17-item Hamilton Depression Rating Scale (HAMD-17)(item 4=onset latency, item 5=middle awakening, and item 6=early awakening) and used the Cloninger's Temperament and Character Inventory-Revised-Short to assess personality characteristics. To examine the relationship between personality and insomnia, we used analysis of variance with age, sex, and severity of depression (total HAMD scores minus sum of the three sleep items) as the covariates. There were no statistical differences (p>0.1) in demographic and clinical data between patients with and without insomnia. Initial insomnia (delayed sleep onset) correlated to a high score on the temperamental dimension of novelty seeking 3 (NS3)(F(1,96)=6.93, p=0.03). There were no statistical differences (p>0.1) in NS3 between patients with and without middle or terminal insomnia. The present study suggests that higher NS3 is related to the development of initial insomnia in PD and that temperament and character should be considered when assessing sleep problems in PD patients.


[A case of Diphyllobothrium nihonkaiense identified by virtual enterography and virtual enteroscopy].
In October 2007, a woman in her early 30s presented, complaining of worm discharge in her stool. We identified it as Diphyllobothrium nihonkaiense, and identified it by virtual enterography and virtual enteroscopy. It was treated by 1500 mg/day praziquantel orally. We think these methods, of pathology as well as capsule enteroscopy and enteroscopy, are useful for the searching of the small intestinal lesions. We hope these examinations will become more widespread with reference to these cases.


Diagnostic applications of cystatin C.
Cysteine proteases are proteolytic enzymes involved in many pathological processes and found in the lysosomes of cells; examples include the cathepsins B, H and L. The role of cysteine proteases is crucial in normal cellular metabolism, being fundamental to intracellular protein turnover, degradation of collagen, and cleaving of precursor proteins. Cysteine protease inhibitors, of which the cystatin superfamily are one example, constitute the final regulatory step in the control of cysteine proteases. Currently, cystatin C is the most frequently investigated family member and is involved in processes such as tumour invasion and metastasis, inflammatory processes and some neurological diseases. In such diseases the emphasis is placed on the fine balance and regulation of both the cysteine proteases and their inhibitors, with an imbalance resulting in a pathological state. In addition, the constant serum concentration of cystatin C means it has possible application as a replacement for creatinine in the measurement of glomerular filtration rate. To date, several assays have been developed and studies show a promising future for its use in the medical laboratory, and not just as a research tool. This review of cystatin C includes a brief history of its discovery and characterisation, provides a guide to some of the processes in which its role is fundamental, and highlights developments in its use as a clinical biomarker in the disease processes discussed.


Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement.
Recombinant human soluble thrombomodulin (ART-123) is composed of the active, extracellular, domain of thrombomodulin. ART-123 binds to thrombin and this complex converts protein C into the natural anticoagulant activated protein C. This study was performed to identify an effective and safe dose of ART-123 for prevention of venous thromboembolism after elective, unilateral total hip replacement. An open-label, sequential, dose-ranging study was performed in which 312 patients received either 0.3 mg kg(-1) or 0.45 mg kg(-1) of ART-123, subcutaneously, 2-4 h after surgery (day 1). Those who received 0.3 mg kg(-1) were given a second dose of 0.3 mg kg(-1) on day 6, and the first 29 of these patients also used intermittent pneumatic compression devices. Those who received 0.45 mg kg(-1) were not given a second dose. Primary efficacy outcome was all deep vein thrombosis on mandatory bilateral venography performed on day 9 +/- 2 and symptomatic venous thromboembolism up to day 11. Primary safety outcome was major bleeding up to day 11. Among patients who did not use intermittent pneumatic compression, venous thromboembolism occurred in 3.4% of 116 evaluable patients in the 0.3 mg kg(-1) group and 0.9% of 111 patients in the 0.45 mg kg(-1) group. Major bleeding occurred in 1.4% of 139 patients in the 0.3 mg kg(-1) group and 6.3% of 144 patients in the 0.45 mg kg(-1) group. ART-123 is a highly effective antithrombotic agent that should be directly compared with current methods of prophylaxis in patients who have major orthopedic surgery.


Emergence of the giant weak component in directed random graphs with arbitrary degree distributions.
The weak component generalizes the idea of connected components to directed graphs. In this paper, an exact criterion for the existence of the giant weak component is derived for directed graphs with arbitrary bivariate degree distributions. In addition, we consider a random process for evolving directed graphs with bounded degrees. The bounds are not the same for different vertices but satisfy a predefined distribution. The analytic expression obtained for the evolving degree distribution is then combined with the weak-component criterion to obtain the exact time of the phase transition. The phase-transition time is obtained as a function of the distribution that bounds the degrees. Remarkably, when viewed from the step-polymerization formalism, the new results yield Flory-Stockmayer gelation theory and generalize it to a broader scope.


Totally Implantable Venous-Access Device Infection Causing Hematogenous Prosthetic Joint Infection: A Retrospective Case Series.
Introduction: Prosthetic joint infections (PJIs) can be acquired hematogenously from a distant site or device. Notably, 30%-40% of patients with PJIs have Staphylococcus aureus bacteremia. No case reports or series of PJIs acquired from totally implantable venous-access device (TIVAD) infection or colonization have been published. This study was undertaken to describe epidemiological, clinical, microbiological and radiological characteristics of such PJIs, their treatments and outcomes. Methods: This retrospective study included all patients, identified in a prospective French Bone-and-Joint Infections Referral Center cohort treated between 2004 and 2017, with PJI secondary to TIVAD infection, with the same microbiologically documented microorganism isolated from both. Results: We describe six consecutive hematogenous PJIs (4 women, 2 men; median age: 66.5 years) acquired from TIVAD primary infections. The main infection risk factors were malignancy (n=5) and prior septic arthritis (n=2). Four participants' TIVADs were implanted for chemotherapy, preceding the prosthesis for one patient. The median TIVAD-implantation-to-symptom-onset interval was 12 months. Microorganisms were Staphylococcus epidermidis (n=4), Staphylococcus capitis (n=1) and Staphylococcus aureus (n=1). All TIVADs were removed. Five participants received curative treatment, with a median of 12 weeks of antibiotics. After median follow-up of 42 months, none have relapsed. Conclusions: When PJI occurs in a patient with a TIVAD, the latter must be tested as a potential source of the prosthesis infection. Conversely, PJIs must sought in all patients with bacteremia.


Protective molecular mechanisms of resveratrol in UVR-induced Skin carcinogenesis.
Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis.


[The status of dog dental pulp after preparation for metalloceramic crowns using temporary fixative cement containing calcium hydroxide].
Morphologic investigation of the condition of the pulp of teeth in 15 dogs in the use of different kinds of temporary fixing cements after preparation for meta-ceramic crowns. It was determined microscopically that the use of the temporary fixing cement Provicol considerably diminishes inflammatory changes in the pulp of the prepared teeth and it assists the much quicker restoration of its normal histophysiology (normalization of oxidation-reduction processes, cellular elements of the pulp and especially the layer of the odontoblasts, their participation in formation of the replacing dentin).


PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer.
Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.


Plate-slide for the culture and morphological observation of fungi.
Adaptation of a polystyrene plate-slide is extremely well suited for the simultaneous macroscopic and microscopic diagnosis of fungi. This technique obviates the disorientation of identifying structures when cultures are mechanically disaggregated during preparation of slides for microscopy.


A model for fibrinogen: domains and sequence.
Electron microscopy of rotary-shadowed fibrinogen demonstrates that the molecules modified for crystallization by limited cleavage with a bacterial protease retain the major features of the native structure. This evidence, together with image processing and x-ray analysis of the crystals and of fibrin, has been used to develop a three-dimensional low resolution model for the molecule. The data indicate that the two large end domains of the molecule would be composed of the carboxyl-terminus of the B beta chain (proximal) and gamma chain (distal), respectively; the carboxyl-terminus of the A alpha chain would fold back to form an additional central domain. On this basis, the carboxyl-terminal region of each of the three chains of fibrinogen is folded independently into a globular domain.


Flavonoids of Lonchocarpus montanus A.M.G. Azevedo and biological activity.
The analysis of root extracts from Lonchocarpus montanus A.M.G. Azevedo resulted in the isolation of twenty three compounds chiefly flavonoids of which five (four flavonoids and one benzophenone) are described for the first time. The molecular structures of the new compounds (1-5) were determined through spectral analysis (UV, IR, MS and NMR) as being: 2'-hydroxy-8-(alpha,alpha-dimethylallyl)-2", 2"-dimethylpyrano-(5",6":3',4')-dibenzoylmethane (1), 2'-methoxy-8-(alpha,alpha-dimethylallyl)-2", 2"-dimethylpyrano-(5",6":3',4')-dibenzoylmethane (2), 4'-methoxy-2",2"-dimethylpyrano-(5",6":8,7)-flavone (3), 2"-(1-hydroxy-1-methylethyl)-furano-(4",5":8,7)-flavone (4) and [2'-methoxy-furano-(4",5":3',4')-phenyl]-phenylmethanone (5). Additionally, fifteen fatty acids were detected through GC-MS analysis of the corresponding methyl esters [(CH3)2CH(CH2)8COOH and CH3(CH2)nCOOH (n = 6, 12-24)]. Quantitative RP-HPLC showed that the most abundant flavonoids in the petroleum ether and dichloromethane extracts were pongamol (19%) and lanceolatine B (8.0%), respectively. In the bioautography assay, the extracts, pongamol (9), lanceolatine B (10), isolonchocarpin (14), derriobtusone A (17) and medicarpine (18) were active against Staphylococcus aureus whereas 9 also against Bacillus subtilis and Cladosporium cladosporioides. Compound 1, 2",2"-dimethylpyrano-(5",6":8,7)-flavone (11) and furano-(1200,1300:7,8)- 4'-methoxy flavone (12) were active against Fusarium oxysporium whereas 11 also against Rhizopus orizae. The extracts, compounds 9, 10, 17 and (E)-7-O-methoxypongamol (23) displayed high toxicity in the brine shrimp lethality assay.


[Features of lipid metabolism in patients of different sexes and ages with dyscirculatory encephalopathy].
Lipid metabolism was studied in 312 males and females of young, middle, elderly and senile ages with dyscirculatory Stage I and II encephalopathy induced by atherosclerosis, arterial hypertension, or their combination. The control group was composed of 216 clinically healthy age-matched subjects. Marked hyperlipidemic shifts in the form of hypertriglyceridemia (HTG), hypercholesterolemia (HC) and hyperbetalipoproteinemia (HBL) were found in patients of both sexes under 45 years of age: HC and marked HTG were significantly more frequent in males. In middle-aged patients marked HTG was more common in males and HC in females. Elderly and senile patients as compared with young and middle-aged ones were characterized by a low cholesterol coefficient of atherogenicity and high levels of high density lipoproteins with antiatherogenic action. The most frequent type of hyperlipidemias in patients of all age groups was IIa, Types IIb and IV were observed less commonly.


A rapid appraisal of access to and utilisation of psychotropic medicines in Bihar, India.
A major aspect of providing mental healthcare is access to and use of psychotropic medications. Bihar is a state in northeast India with limited mental healthcare provision; consequently access to and utilisation of psychotropic medications are likely to be limited. However, to date there has been no research assessing the situation. This study therefore aims to analyse the psychotropic medications management cycle (selection, procurement, distribution and use), and identify the barriers to access and utilisation, and their underlying causes. A rapid appraisal method was used in which primary and secondary data sources were collected and analysed. Semi-structured interviews were conducted with twenty-two stakeholders and twenty-one service users from the government, non-governmental organisation (NGO) and private sectors. The qualitative data collected was analysed using a comparative thematic approach. The research was supported by the NGOs BasicNeeds and Nav Bharat Jagriti Kendra. Availability, distance and cost were the main barriers to access and utilisation. At the medical college hospital level a lack of supply appears to be due to a discrepancy between orders made by the hospital and medications supplied by the manufacturers. At the primary health centre and district hospital level the main barrier is a cycle between lack of demand for treatments for mental illness by doctors and patients. Further investigation and monitoring is necessary to ensure the availability of psychotropic medications at the medical college hospital level. In addition, implementation of the District Mental Health Programme is likely to address the access and utilisation barriers due to its potential to break the current cycle of lack of demand.


Executive control training for adolescents with ADHD: Study protocol for a randomized controlled trial.
Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental conditions diagnosed during childhood and adolescence. In addition to the commonly observed symptoms of inattention, hyperactivity, and impulsivity, individuals with ADHD often experience impairments in executive functions (EFs). Goal management training (GMT) is a cognitive remediation intervention targeting EFs, with empirical support from studies with adult populations, including ADHD. The objective of the upcoming trial is to examine the effectiveness of GMT for adolescents with ADHD. This pre-registered protocol outlines a multi-centre randomized controlled trial (RCT) comparing GMT to treatment as usual (TAU) to improve EFs. We aim to recruit 120 participants, aged 12 to 18 years, recently diagnosed with ADHD. Participants will be randomly allocated to the group-based GMT intervention in addition to TAU, or the TAU condition, through block randomization with age and site stratification. GMT will be delivered in groups of four to six participants, with weekly two-hour sessions for seven weeks, complemented by separate parent and teacher sessions. TAU is standard community mental health treatment. The primary outcome measure will be parent-reported EF assessed with the Behaviour Rating Inventory of Executive Function 2 (BRIEF-2). Secondary outcomes will include ADHD symptom measures, social functioning, quality of life, and neuropsychological tests (attention span, inhibition, working memory, and visuo-motor speed). The outcome assessments will be conducted at baseline, 12 weeks, 12 months, and 24 months post-treatment. The study findings will contribute to determine the effectiveness of a non-pharmacological ADHD treatment, including outcome trajectories up to 24 months post-treatment.


Effect of inosine in the normal and reperfused rat heart.
Inosine is a positive inotropic agent and dilates coronary blood vessels. During ischemia, inosine infusion increases blood flow, resulting in decreased myocardial damage. We wished (a) to determine inosine's effect in isolated rat hearts and (b) to determine if inosine attenuates myocardial dysfunction after transient global ischemia. Developed left ventricular pressure (LVP), LV dP/dt, and coronary perfusion pressure were monitored in hearts receiving Krebs-Henseleit buffer (KHB) (n = 10) or KHB + 2 mM inosine (n = 4). KHB + 2 mM inosine significantly reduced coronary perfusion pressure by 21% but had no effect on developed LVP or LV dP/dt. Hearts receiving KHB (n = 6) or KHB + 2 mM inosine (n = 5) were subjected to 15-min global ischemia followed by 30-min reperfusion with KHB. Recovery of LVP, LV dP/dt, the incidence of arrhythmias, and the time to peak recovery of developed LVP was not different between groups. In two additional hearts, KHB + 2 mM inosine administered during reperfusion had no effect on developed LVP, LV dP/dt, or coronary perfusion pressure. Thus, unlike other preparations, inosine pretreatment did not significantly affect the time course of postischemic functional recovery of rat myocardium.


Renal papillary necrosis in children with chronic arthritis.
Five ambulatory children with various types of chronic arthritis developed renal papillary necrosis (RPN), as documented by intravenous pyelography. Each child was being treated with nonsteroidal anti-inflammatory drugs (NSAIDs) at the time of diagnosis of RPN and had had episodes of gross or microscopic hematuria for several months prior to diagnosis. In each child hematuria was associated with more than one NSAID, and three of the five children also had ingested acetaminophen intermittently. Glomerular function has remained normal and hypertension has not developed, but management of these children has necessitated reduction or elimination of NSAIDs. As evidenced by these five cases, microscopic or gross hematuria in a child with chronic arthritis treated with anti-inflammatory drugs should raise the possibility of RPN.


Fish oil supplementation ameliorates fructose-induced hypertriglyceridemia and insulin resistance in adult male rhesus macaques.
Fish oil (FO) is a commonly used supplemental source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2 n-3 (ω-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a variety of health benefits considered to be protective against cardiometabolic diseases. Although the effects of EPA and DHA on lipid metabolism have been extensively studied, not all of the metabolic effects of FO-derived n-3 PUFAs have been characterized. Our laboratory recently showed that a high-fructose diet in rhesus monkeys induces the features of metabolic syndrome (MetS) similar to those observed in humans. Thus, we specifically wanted to evaluate the effects of FO in rhesus monkeys fed a high-fructose diet and hypothesized that FO supplementation would mitigate the development of fructose-induced insulin resistance, dyslipidemia, and other cardiometabolic risk factors. In this study, adult monkeys (aged 12-20 y) received either a standard unpurified diet plus 75 g fructose/d (control group; n = 9) or a standard unpurified diet, 75 g fructose/d, and 4 g FO (16% EPA + 11% DHA)/d (treatment group; n = 10) for 6 mo. Importantly, our results showed that daily FO supplementation in the monkeys prevented fructose-induced hypertriglyceridemia and insulin resistance as assessed by intravenous-glucose-tolerance testing (P ≤ 0.05). Moreover, FO administration in the monkeys prevented fructose-induced increases in plasma apolipoprotein (Apo)C3, ApoE, and leptin concentrations and attenuated decreases in circulating adropin concentrations (P ≤ 0.05). No differences between the control and FO-treated monkeys were observed in body weight, lean mass, fat mass, or fasting glucose, insulin, and adiponectin concentrations. In conclusion, FO administration in a nonhuman primate model of diet-induced MetS ameliorates many of the adverse changes in lipid and glucose metabolism induced by chronic fructose consumption.


Economic Impact of a Bluetongue Serotype 8 Epidemic in Germany.
Background and Objectives: Germany was affected by Bluetongue virus serotype 8 (BTV-8) from 2006 to 2009 and recorded new cases since December 2018. We assessed the economic impact of the epidemic from the first cases in 2006 until 2018. Direct costs include production losses, animal deaths, and veterinary treatment. Indirect costs include surveillance, additional measures for animal export, disease control (preventive vaccination and treatment with insecticides), vector monitoring, and administration. Methodology: To estimate the financial impact of BTV-8 on different species and production types at the animal level, we performed a gross margin analysis (GMA) for dairy and beef cattle, and sheep. To estimate the impact on the national level, we used a modified framework described by Rushton et al. (1) and applied a methodology described by Bennett (2). Both the GMA and the economic model on national level were implemented in Excel and the Excel Add-in @Risk. The tools, which are widely applicable, also for other diseases, are made available here. Results: The financial impact of a BTV-8 infection at the animal level was estimated at 119-136 Euros in dairy cattle, at 27 Euros in beef cattle, and at 74 Euros in sheep. At the national level, the impact of the BTV-8 epidemic ranged between 157 and 203 million Euros (mean 180 million Euros). This figure consisted of 132 (73%) and 48 (27%) million Euros for indirect and direct costs. Indirect costs included 89 million Euros (67%) for vaccination, 18 million Euros (14%) for insecticide treatment, 15 million Euros (11%) for diagnostic testing of animals dispatched for trade, 8 million Euros (6%) for monitoring and surveillance, and 3 million Euros (2%) for administration. The highest costs were induced by a compulsory vaccination campaign in 2008 (51 million Euros; 28% of the total costs) and the disease impact on cattle in 2007 (30 million Euros; 17%). Discussion: We compare the outcome of our study with economic analyses of Bluetongue disease in other countries, and discuss the suitability of GMA and the developed tools for a wider application in veterinary economics.


Methods for the synthesis of 5,6,7,8-tetrahydro-1,8-naphthyridine fragments for alphaVbeta3 integrin antagonists.
The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the synthesis of alpha(V)beta(3) antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3'-pyridine-2,5-diyldipropan-1-amines 9a/9b.


Wide local en bloc excision of subungual melanoma in situ.
Subungual melanoma is a rare but lethal form of melanoma. Amputation at the level of the interphalangeal joint or proximal has been described as appropriate surgical management for all stages of subungal melanoma. In cases of subungual melanoma in situ (SMIS), wide local excision can improve functional and aesthetic outcomes. We reviewed our experience of wide local excision for the treatment of SMIS. Between 2003 and 2010, we treated 9 cases of SMIS. We performed a retrospective review of this series looking at the primary outcomes of recurrence or metastasis. Average age was 40 years (range, 5-65 years). Presenting lesions were on the thumb (5) and index finger (4). All patients underwent definitive reconstruction with a combination of full-thickness skin graft (8) and paronychial advancement flap (6). Reexcision was performed when disease-free margins could not be confirmed. To date, there have been no cases of metastasis or local recurrence in any of our 9 patients (mean follow-up time of more than 4 years). Wide local excision can improve functional and aesthetic outcomes with similar success in rates of local recurrence and metastasis when compared to treatment by amputation in SMIS.


Leishmaniases of the New World: current concepts and implications for future research.
Recent epidemiologic studies indicate that leishmaniasis in the Americas is far more abundant and of greater public health importance than was previously recognized. The disease in the New World is caused by a number of different parasite species that are capable of producing a wide variety of clinical manifestations. The outcome of leishmanial infection in humans is largely dependent on the immune responsiveness of the host and the virulence of the infecting parasite strain. This article reviews current concepts of the clinical forms, immunology, pathology, laboratory diagnosis, and treatment of the disease as well as aspects of its epidemiology and control. Recommendations for future research on the disease and its control are made.


Binding and degradation of angiotensin II by mesenteric artery subcellular membranes.
Rat mesenteric artery microsomes were previously reported to degrade 125I-angiotensin II (AII). It is now shown here that washing the membranes with EDTA and including EGTA in the assay media reduces the 125I-AII degradation to very low levels without reducing the specific binding of 125I-AII. Using EDTA wash and including 5 mM MgCl2 and 0.2 mM EGTA the following characteristics of the binding were observed: microscopic association rate constant (k1) = 1.3 to 2.2 X 10(5) M-1 s-1, microscopic dissociation rate constant (k-1) = 3.8 to 6.4 X 10(-4) s-1, equilibrium dissociation constant (Kd) = 1.8 nM and number of binding sites (Bmax) = 193 fmol/mg protein. The subcellular distribution of the specific binding of 125I-AII at 0.16 nM and 1.63 nM was studied along with the distribution of the marker enzymes. The specific binding paralleled the plasma membrane marker (5'-nucleotidase), but not the putative endoplasmic reticulum marker (NADPH-cyt. c-reductase) or the inner mitochondrial marker (cyt. c-oxidase). Thus the binding to the plasma membrane-enriched fraction F2 occurred with a similar affinity (Kd = 2.2 nM) but with higher number of binding sites (420 fmol/mg protein). This study establishes the 125I-AII binding method suitable for determining the changes in the angiotensin receptor characteristics in the pathophysiology of the vascular smooth muscle.


Incidental mastoid effusion diagnosed on imaging: Are we doing right by our patients?
To investigate whether radiologist-produced imaging reports containing the terms mastoiditis or mastoid opacification clinically correlate with physical examination findings of mastoiditis. Additionally, to investigate whether and how often otolaryngology was unnecessarily consulted and inappropriate antibiotic therapy was initiated. Retrospective chart review within a large community hospital setting. A retrospective review of 160 patients who had imaging tests performed for nonotolaryngology indications from January 2011 to March 2017 at our facility. Indications, patient demographics, otolaryngology consultations, and new antibiotics started were recorded. Physical examinations were documented. Physical examination revealed that only 14 of 160 patients (8.8%) had clinical evidence of otologic disease. However, of the 160 patients meeting the inclusion criteria, 18 (11.3%) received an otolaryngology consultation, and 18 (11.3%) had antibiotics started. Eleven of the 18 patients in each group (61.1%) had a normal physical examination, two (11.1%) had serous otitis media, one (5.6%) had chronic otitis media, and four (22.2%) had acute otitis media. No patients were found to have clinical mastoiditis. χ2 analysis revealed no significance in the radiologic diagnosis of mastoiditis versus mastoid opacification in relation to physicians requesting otolaryngology consultations (P = .241) or starting patients on antibiotics (P = .951). This study highlights the prevalence of incidental but clinically insignificant opacification of the mastoid cavity. We believe that nonotolaryngology physicians are, overall, competent to correlate such radiologic findings clinically and to prevent unnecessary consultations and inappropriate treatment, which add significant costs to our overstretched healthcare system. 4 Laryngoscope, 129:852-857, 2019.


Nursing students' understanding of factors influencing ethical sensitivity: A qualitative study.
Ethical sensitivity is considered as a component of professional competency of nurses. Its effects on improvement of nurses' ethical performance and the therapeutic relationship between nurses and patients have been reported. However, very limited studies have evaluated ethical sensitivity. Since no previous Iranian research has been conducted in this regard, the present study aimed to review nursing students' understanding of effective factors on ethical sensitivity. This qualitative study was performed in Kerman, Iran, during 2009. It used semi-structured individual interviews with eight MSc nursing students to assess their viewpoints. It also included two focus groups. Purposive sampling was continued until data saturation. Data were analyzed using manifest content analysis. The students' understanding of factors influencing ethical sensitivity were summarized in five main themes including individual and spiritual characteristics, education, mutual understanding, internal and external controls, and experience of an immoral act. The findings of this study create a unique framework for sensitization of nurses in professional performance. The application of these factors in human resource management is reinforcement of positive aspects and decrease in negative aspects, in education can use for educational objectives setting, and in research can designing studies based on this framework and making related tools. It is noteworthy that presented classification was influenced by students themselves and mentioned to a kind of learning activity by them.


Different nature of the interactions between anions and HAT(CN)6: from reversible anion-π complexes to irreversible electron-transfer processes (HAT(CN)6 = 1,4,5,8,9,12-hexaazatriphenylene).
We report experimental evidence indicating that the nature of the interaction established between HAT(CN)(6), a well-known strong electron acceptor aromatic compound, with mono- or polyatomic anions switches from the almost exclusive formation of reversible anion-π complexes, featuring a markedly charge transfer (CT) or formal electron-transfer (ET) character, to the quantitative and irreversible net production of the anion radical [HAT(CN)(6)](•-) and the dianion [HAT(CN)(6)](2-) species. The preferred mode of interaction is dictated by the electron donor abilities of the interacting anion. Thus, weaker Lewis basic anions such as Br(-) or I(-) are prone to form mainly anion-π complexes. On the contrary, stronger Lewis basic F(-) or (-)OH anions display a net ET process. The ET process can be either thermal or photoinduced depending on the HOMO/LUMO energy difference between the electron donor (anion) and the electron acceptor (HAT(CN)(6)). These ET processes possibly involve the intermediacy of anion-π complexes having strong ET character and producing an ion-pair radical complex. We hypothesize that the irreversible dissociation of the pair of radicals forming the solvent-caged complex is caused by the reduced stability (high reactivity) of the radical resulting from the anion.


Whole-genome sequence of Bacillus velezensis strain R22 isolated from Oryza sativa rhizosphere in Bulgaria.
Bacillus velezensis R22 was isolated from a rice rhizosphere in Bulgaria. Its genome (assembled into 14 scaffolds) has a size of 4.08 Mbp and a G + C content of 46.35%. Nine full biosynthetic clusters for antimicrobials were predicted, among them two new gene clusters probably encoding polyketides named macrolactin R22 and velezensin.


Endogenous formation of dimethylamine.
An understanding of the biosynthesis and metabolism of dimethylamine (DMA) is important because it is a precursor of dimethylnitrosamine (nitroso-DMA). DMA is the major short-chain aliphatic amine in human and rat urine. DMA is formed from trimethylamine (TMA), which, in turn, is a breakdown product of dietary choline. Enzymes within gut bacteria catalyse both of these reactions; it is not known whether mammalian cells can form DMA. To determine the relative importance of dietary choline, bacteria and other mechanisms for the formation of DMA, we measured DMA excretion in the urine of rats fed on a diet devoid of choline, and in urine of rats with no bacterial colonization of the intestines. We also describe an improved gas-chromatographic method for the measurement of methylamines in biological fluids. In control rats there were significant amounts of DMA within several biological fluids [urine, 54.2 +/- 3.0 mumol/kg body wt. per 24 h (556.2 +/- 37.5 nmol/ml); blood, 18.8 +/- 1.9 nmol/ml; gastric juice, 33.5 +/- 10.5 nmol/ml; means +/- S.E.M.]. Animals eating a diet containing no choline excreted as much MMA and DMA as did choline-supplemented rats (25-35 mumol/kg per 24 h), and they excreted slightly less TMA (2 versus 2.5 mumol/kg per 24 h). Rats with no gut bacteria excreted the same amount of DMA in their urine as did the control animals (45-55 mumol/kg per 24 h). They excreted much less MMA (16.3 +/- 1.5 versus 40.3 +/- 2.6 mumol/kg per 24 h; mean +/- S.E.M.; P less than 0.01), TMA (0.7 +/- 0.2 versus 2.5 +/- 0.5 mumol/kg per 24 h; mean +/- S.E.M.; P less than 0.01) and piperidine (2.0 +/- 0.3 versus 6.3 +/- 0.6 mumol/kg per 24 h; mean +/- S.E.M.; P less than 0.01) in their urine. From our studies we conclude that DMA is present in significant amounts within gastric fluid, an environment that is ideal for nitrosamine formation (under acidic conditions, nitroso-DMA is chemically formed by the reaction of nitrite with DMA). Results also indicate that dietary choline was not the sole precursor for DMA formation and that gut bacteria are not essential for the formation of DMA. Hence in mammals there must be endogenous pathways that are capable of forming DMA; however, these endogenous mechanisms remain unidentified.


Identification and characterization of pseudo-recombinants of red clover mottle comovirus.
cDNA clones specific for the two genomic RNAs of strain O of the comovirus red clover mottle virus (RCMV) were constructed. Using these clones, in conjunction with clones specific for RNAs of RCMV strain S, local lesion isolates containing reciprocal pseudo-recombinants between strains S and O were identified. Investigation of the biological properties of these pseudo-recombinants showed that the ability of RCMV to infect Chenopodium quinoa is determined by B RNA. The results also suggest that both RNAs are involved in symptom formation in Pisum sativum. Analysis of the strain O clones enabled the sequences at the 3' ends of both genomic RNAs of strain O to be determined. Comparison of these sequences with the corresponding region of the strain S RNAs suggests that the 3' terminal sequences critical for replicase recognition may lie somewhat upstream of the poly(A) tract.


[Dextrals and sinistrals (right-handers and left-handers): specificity of interhemispheric brain asymmetry and EEG coherence parameters].
Data of literature about morphological, functional and biochemical specificity of the brain interhemispheric asymmetry of healthy right-handers and left-handers and about peculiarity of dynamics of cerebral pathology in patients with different individual asymmetry profiles are presented at the present article. Results of our investigation by using coherence parameters of electroencephalogram (EEG) in healthy right-handers and left-handers in state of rest, during functional tests and sleeping and in patients with different forms of the brain organic damage were analyzed too. EEG coherence analysis revealed the reciprocal changing of alpha-beta and theta-delta spectral bands in right-handers whilein left-handers synchronous changing of all EEG spectral bands were observed. Data about regional-frequent specificity of EEG coherence, peculiarity of EEG asymmetry in right-handers and left-handers, aslo about specificity of EEG spectral band genesis and point of view about a role of the brain regulator systems in forming of interhemispheric asymmetry in different functional states allowed to propose the conception about principle of interhermispheric brain asymmetry formation in left-handers and left-handers. Following this conception in dextrals elements of concurrent (summary-reciprocal) cooperation are predominant at the character of interhemispheric and cortical-subcortical interaction while in sinistrals a principle of concordance (supplementary) is preferable. These peculiarities the brain organization determine, from the first side, the quicker revovery of functions damaged after cranio-cerebral trauma in left-handers in comparison right-handers and from the other side - they determine the forming of the more expressed pathology in the remote terms after exposure the low dose of radiation.


Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation.
Glutamine addiction is an important phenotype displayed in some types of cancer. In these cells, glutamine depletion results in a marked reduction in the aggressive cancer phenotype. Mesothelioma is an extremely aggressive disease that lacks effective therapy. In this study, we show that mesothelioma tumors are glutamine addicted suggesting that glutamine depletion may be a potential therapeutic strategy. We show that glutamine restriction, by removing glutamine from the medium or treatment with inhibitors that attenuate glutamine uptake (V-9302) or conversion to glutamate (CB-839), markedly reduces mesothelioma cell proliferation, spheroid formation, invasion, and migration. Inhibition of the SLC1A5 glutamine importer, by knockout or treatment with V-9302, an SLC1A5 inhibitor, also markedly reduces mesothelioma cell tumor growth. A relationship between glutamine utilization and YAP1/TEAD signaling has been demonstrated in other tumor types, and the YAP1/TEAD signaling cascade is active in mesothelioma cells and drives cell survival and proliferation. We therefore assessed the impact of glutamine depletion on YAP1/TEAD signaling. We show that glutamine restriction, SLC1A5 knockdown/knockout, or treatment with V-9302 or CB-839, reduces YAP1 level, YAP1/TEAD-dependent transcription, and YAP1/TEAD target protein (e.g., CTGF, cyclin D1, COL1A2, COL3A1, etc.) levels. These changes are observed in both cells and tumors. These findings indicate that mesothelioma is a glutamine addicted cancer, show that glutamine depletion attenuates YAP1/TEAD signaling and tumor growth, and suggest that glutamine restriction may be useful as a mesothelioma treatment strategy.


Nanostrategy of Targeting at Embryonic Trophoblast Cells Using CuO Nanoparticles for Female Contraception.
Effective contraceptives have been comprehensively adopted by women to prevent the negative consequences of unintended pregnancy for women, families, and societies. With great contributions of traditional hormonal drugs and intrauterine devices (IUDs) to effective female contraception by inhibiting ovulation and deactivating sperm, their long-standing side effects on hormonal homeostasis and reproductive organs for females remain concerns. Herein, we proposed a nanostrategy for female contraceptives, inducing embryonic trophoblast cell death using nanoparticles to prevent embryo implantation. Cupric oxide nanoparticles (CuO NPs) were adopted in this work to verify the feasibility of the nanostrategy and its contraceptive efficacy. We carried out the in vitro assessment on the interaction of CuO NPs with trophoblast cells using the HTR8/SVneo cell line. The results showed that the CuO NPs were able to be preferably uptaken into cells and induced cell damage via a variety of pathways including oxidative stress, mitochondrial damage, DNA damage, and cell cycle arrest to induce cell death of apoptosis, ferroptosis, and cuproptosis. Moreover, the key regulatory processes and the key genes for cell damage and cell death caused by CuO NPs were revealed by RNA-Seq. We also conducted in vivo experiments using a rat model to examine the contraceptive efficacy of both the bare CuO NPs and the CuO/thermosensitive hydrogel nanocomposite. The results demonstrated that the CuO NPs were highly effective for contraception. There was no sign of disrupting the homeostasis of copper and hormone, or causing inflammation and organ damage in vivo. In all, this nanostrategy exhibited huge potential for contraceptive development with high biosafety, efficacy, clinical translation, nonhormonal style, and on-demand for women.


Associations Between Religiosity, Perceived Social Support, and Stimulant Use in an Untreated Rural Sample in the U.S.A.
Religiosity and perceived social support (SS) may serve as protective factors for more severe substance use in adults. This study sought to examine whether aspects of religiosity and SS are associated with longitudinal reductions in stimulant use over three years in an untreated sample of rural drug users. Respondent-driven sampling was used to recruit stimulant users (N = 710) from Arkansas, Kentucky, and Ohio. Follow-up interviews were conducted at 6-month intervals for 36 months. Our bivariate findings indicate that higher religiosity was associated with lower odds and fewer days of methamphetamine and cocaine use. After controlling for covariates, higher religiosity was associated with fewer days of crack cocaine use, but more days of methamphetamine use among a small sample of users in the two final interviews. Higher SS from drug-users was also associated with higher odds and days of methamphetamine and powder cocaine use, while higher SS from nondrug users was associated with fewer days of methamphetamine use. Our bivariate findings suggest that higher levels of religiosity may be helpful for some rural individuals in reducing their drug use over time. However, our multivariate findings suggest a need for further exploration of the potential effects of religiosity on longer-term drug use, especially among those who continue to use methamphetamine and/or remain untreated. Our findings also highlight the potential deleterious effect of SS from drug users on the likelihood and frequency of methamphetamine and powder cocaine use over time among untreated rural drug users.


The natural history and management of intracranial dural arteriovenous fistulae. Part 2: aggressive lesions.
The natural history of aggressive intracranial dural arteriovenous fistulae (ICDAVF) is unknown. Despite this, the recently proposed classification scheme of Borden et al (Borden(*)) has the potential to predict aggressive lesion behavior after presentation for any lesion, but has so far been untested. In addition, they discuss a new but logical treatment strategy for aggressive ICDAVF based on the elimination of retrograde leptomeningeal venous drainage (RLVD). Our similar philosophy and substantial experience with these lesions, provides a unique opportunity to test these hypotheses. A cohort of 46 Borden(*) grade II and III ICDAVF was selected from a series of 102 ICDAVF seen at a single institution between 1984 and 1995. Patients with these lesions, presumed to have an aggressive course were all offered treatment. Conservative therapy was chosen by 14 (30%) patients, 22 (47%) had surgery, and 20 (43%) had embolisation either as sole treatment or prior to surgery. During the follow-up period (249 lesion months) for the conservatively treated group, Jour (29%) patients died. Excluding presentation, these patients were observed to have interval rates of intracranial hemorrhage (ICH), non haemorrhagic neurological deficit (NHND), and mortality, of 19.2%, 10.9%, and 19.3% / lesion year respectively. The 11 patients who had embolisation alone were followed for a total of 344 months after treatment. All nine patients who had lesion obliteration, or subtotal obliteration with elimination of RLVD, as confirmed by angiography, experienced improvement or complete clinical recovery. Two patients had subtotal obliteration without elimination of RLVD. One died from interval ICH and the other experienced a delayed NHND. Twenty-five surgical operations were performed on 23 ICDAVF in 22 patients. Resection of the ICDAVF was performed in 9 patients, and 16 patients were treated with surgical disconnection alone. Complications occurred in 3/9 (33%) patients who had their lesions resected and none of the disconnected group. Failure to achieve angiographic obliteration of RLVD in 2 patients treated with resection was associated with an adverse outcome in both cases (death, and interval NHND). All 16 (100%) of the disconnected group were shown to have undergone angiographic obliteration with excellent clinical outcome. Untreated, Borden(*) grade II and III ICDAVF have a poor natural history. Also, persistence of RLVD after inadequate treatment results in adverse outcomes. Embolisation usually improves the safety of surgical access and may lead to obliteration on its own in some cases. For the aggressive ICDAVF, surgery is required in most cases, and our data confirm that surgical disconnection alone results in cure of all Borden(*) grade III ICDAVF, and in grade II lesions, ifnot cure, conversion to a benign grade I lesion.


Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.
Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.


The plant-specific SR45 protein negatively regulates glucose and ABA signaling during early seedling development in Arabidopsis.
The plant-specific SR45 belongs to the highly conserved family of serine/arginine-rich (SR) proteins, which play key roles in precursor-mRNA splicing and other aspects of RNA metabolism. An Arabidopsis (Arabidopsis thaliana) loss-of-function mutant, sr45-1, displays pleiotropic phenotypes, such as defects in flower and leaf morphology, root growth, and flowering time. Here, we show that the sr45-1 mutation confers hypersensitivity to glucose (Glc) during early seedling growth in Arabidopsis. Unlike wild-type plants, the sr45-1 mutant displays impaired cotyledon greening and expansion as well as reduced hypocotyl elongation of dark-grown seedlings when grown in the presence of low (3%) Glc concentrations. In addition, SR45 is involved in the control of Glc-responsive gene expression, as the mutant displays enhanced repression of photosynthetic and nitrogen metabolism genes and overinduction of starch and anthocyanin biosynthesis genes. Like many other sugar response mutants, sr45-1 also shows hypersensitivity to abscisic acid (ABA) but appears to be unaffected in ethylene signaling. Importantly, the sr45-1 mutant shows enhanced ability to accumulate ABA in response to Glc, and the ABA biosynthesis inhibitor fluridone partially rescues the sugar-mediated growth arrest. Moreover, three ABA biosynthesis genes and two key ABA signaling genes, ABI3 and ABI5, are markedly overinduced by Glc in sr45-1. These results provide evidence that the SR45 protein defines a novel player in plant sugar response that negatively regulates Glc signaling during early seedling development by down-regulating both Glc-specific ABA accumulation and ABA biosynthesis and signaling gene expression.


Dynamical patterns of epidemic outbreaks in complex heterogeneous networks.
We present a thorough inspection of the dynamical behavior of epidemic phenomena in populations with complex and heterogeneous connectivity patterns. We show that the growth of the epidemic prevalence is virtually instantaneous in all networks characterized by diverging degree fluctuations, independently of the structure of the connectivity correlation functions characterizing the population network. By means of analytical and numerical results, we show that the outbreak time evolution follows a precise hierarchical dynamics. Once reached the most highly connected hubs, the infection pervades the network in a progressive cascade across smaller degree classes. Finally, we show the influence of the initial conditions and the relevance of statistical results in single case studies concerning heterogeneous networks. The emerging theoretical framework appears of general interest in view of the recently observed abundance of natural networks with complex topological features and might provide useful insights for the development of adaptive strategies aimed at epidemic containment.


Vertebrates on the brink as indicators of biological annihilation and the sixth mass extinction.
The ongoing sixth mass species extinction is the result of the destruction of component populations leading to eventual extirpation of entire species. Populations and species extinctions have severe implications for society through the degradation of ecosystem services. Here we assess the extinction crisis from a different perspective. We examine 29,400 species of terrestrial vertebrates, and determine which are on the brink of extinction because they have fewer than 1,000 individuals. There are 515 species on the brink (1.7% of the evaluated vertebrates). Around 94% of the populations of 77 mammal and bird species on the brink have been lost in the last century. Assuming all species on the brink have similar trends, more than 237,000 populations of those species have vanished since 1900. We conclude the human-caused sixth mass extinction is likely accelerating for several reasons. First, many of the species that have been driven to the brink will likely become extinct soon. Second, the distribution of those species highly coincides with hundreds of other endangered species, surviving in regions with high human impacts, suggesting ongoing regional biodiversity collapses. Third, close ecological interactions of species on the brink tend to move other species toward annihilation when they disappear-extinction breeds extinctions. Finally, human pressures on the biosphere are growing rapidly, and a recent example is the current coronavirus disease 2019 (Covid-19) pandemic, linked to wildlife trade. Our results reemphasize the extreme urgency of taking much-expanded worldwide actions to save wild species and humanity's crucial life-support systems from this existential threat.


Prevalence and significance of risk enhancing biomarkers in the United States population at intermediate risk for atherosclerotic disease.
Pooled cohort equations (PCEs) estimate 10-year risk for atherosclerotic cardiovascular disease (ASCVD) in US adults. One use is to guide statin eligibility. However, PCEs risk estimate is inaccurate in some US subpopulations. Recent cholesterol guidelines proposed addition of risk enhancing factors to improve risk assessment for selection of statin therapy. This study examines frequencies of several risk enhancing biomarkers in NHANES subjects at intermediate risk (7.5 -<20% 10-year risk for ASCVD) and considers how they may be used to better assess risk for individuals. Prevalence of the following biomarkers were determined; elevations in apolipoprotein B-containing lipoproteins, i.e., LDL cholesterol (LDL-C) (160-189 mg/dL), non-HDL-cholesterol (non-HDL-C) (190-219 mg/dL), or total apolipoprotein B (apoB) (≥ 130 mg/dL), serum triglyceride (≥175 mg/dL), hemoglobin A1c (5.7-6.4%), high sensitivity C-reactive protein (2-10 mg/L), and waist circumference ≥ 102 cm, and abnormal estimated glomerular filtration rate (15 - ≤ 60 mg/min/1.73 m2). 25% of NHANES population had intermediate risk. In this subpopulation, 85% had ≥ 1 biomarkers-similarly in women and men-with a third having ≥3 abnormal markers. Frequencies were not age-related, except in those 40-49 years, in whom > 40% had ≥3 abnormal biomarkers. It made little difference whether LDL-C, non-HDL-C or apoB was used as the atherogenic lipoprotein. Three or more enhancing risk factors in intermediate risk subjects can complement PCE-estimated 10-year risk and guide the patient-provider discussion toward use of lipid-lowering medication. Future research is needed to integrate risk estimates by PCE and multiple risk enhancers.


[Transnasal endoscopic surgery of the sellar region: study of the first 100 cases].
An endoscopic endonasal transsphenoidal approach to the sella was performed in 100 consecutive patients, with a follow up from 3 to 55 months: 57 females and 43 males, age ranging from 14 and 70 years. 76 cases pituitary adenomas: 22 were acromegaly (7 microadenomas and 15 macroadenomas); 21 null cell adenomas (3 microadenomas and 18 macroadenomas); 19 Cushing disease (11 microadenomas and 8 macroadenomas), 10 prolactinomas (6 microadenomas and 4 macroadenomas), and 4 LH adenomas (4 macroadenomas). In this serie, remission was achieved in 44.8% for macroadenomas, 60% for acromegaly, 27.7% for null cell adenoma, 50% for Cushing disease, 50% for prolactinomas and 50% for LH adenomas, and 81.4% for microadenomas 85% for acromegaly, 100% for null cell adenoma, 81.8% for Cushing disease, 66% for prolactinoma. We had also four craniopharyngiomas, four sphenoidal mucocele, three sphenoidal aspergillus, one Rathke cyst, one hypophysitis, one cavernous aneurysm, one encefalocele, one intrasellar meningioma, one intrasellar tuberculoma and a sphenoid fibrous dysplasia. In this series we also had six fistulas of the anterior base that were completely cured. We had a mortality of 2, one null cell giant adenoma in a 57 years old man and another patient, 38 years old, with a giant craniopharyngioma. The morbidity was: two cured meningitis, three cured fistulas, and two permanent diabetes insipidus. Endoscopic endonasal transsphenoidal surgery in this series resulted with comparable surgical outcomes to conventional microscopic transsphenoidal surgery. The advantages of this technique have been represented by an easier access to the lesion, better visualisation and increased illumination of the surgical sites, microdissection of the tumor with maximum preservation of the pituitary function, and reduction of hospitalization times and coasts. The main limits have been the reduction of field depth, constant need of manual control of the endoscope, and required experience of the endoscope technique.


Senning repair for transposition of the great arteries in the first week of life.
Infants with D-loop transposition of the great arteries (D-TGA) may have unacceptable results after the balloon septostomy while awaiting surgery. It has been our policy to repair defects in infants with D-TGA and intact ventricular septum or small ventricular septal defect at the time of diagnosis. We report our experience with the Senning operation in 18 newborns less than 1 week of age. The mean age at operation was 3 days (range 12 hr to 7 days) and the mean weight was 3.5 kg (range 2.8 to 4.8). There were two early postoperative deaths (11%) and one late death (5%). Early mortality was associated with preoperative acidosis and congestive heart failure. Late mortality was associated with severe left ventricular outflow tract obstruction (LVOTO). The 15 long-term survivors have been followed for an average of 27 months and 11 of the 16 perioperative survivors have undergone postoperative catheterizations. There was no evidence of systemic or pulmonary venous obstruction. One patient developed LVOTO that led to his death. Two patients had residual atrial shunts. Electrocardiograms revealed no major arrhythmias. All patients are clinically asymptomatic. Good hemodynamic, electrocardiographic, and clinical results can be obtained with correction of D-TGA in the first week of life.


ProBDNF inhibits proliferation, migration and differentiation of mouse neural stem cells.
ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), is an important regulator of neurodegeneration, hippocampal long-term depression, and synaptic plasticity. ProBDNF and its receptors pan-neurotrophin receptor p75 (p75NTR), vps10p domain-containing receptor Sortilin and tropomyosin receptor kinase B (TrkB) are expressed in neuronal and glial cells. The role of proBDNF in regulation of neurogenesis is not fully defined. This study aims to uncover the function of proBDNF in regulating the differentiation, migration and proliferation of mouse neural stem cells (NSCs) in vitro. We have found that proBDNF and its receptors are constitutively expressed in NSCs when assessed by immunocytochemistry and western blotting. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay showed that exogenous proBDNF treatment reduced mouse NSCs viability by 38% at 10ng/mL. The migration of NSCs was also reduced by exogenous proBDNF treatment in a concentration-dependent manner (by 90% at 10ng/mL) but increased by anti-proBDNF antibody treatment (by 50%). BrdU (5-Bromo-2'-Deoxyuridine) incorporation was performed for detection of newborn cells. We have found that proBDNF significantly inhibited proliferation of NSCs and reduced the number of differentiated neurons, oligodendrocytes and astrocytes, while anti-proBDNF antibody treatment promoted proliferation and differentiation of NSCs. In conclusion, proBDNF may oppose the functions of mature BDNF by inhibiting the proliferation, differentiation and migration of NSCs during development. Conversely, anti-proBDNF antibody treatment promoted proliferation and differentiation of NSCs.


Northern African strains of human T-lymphotropic virus type 1 arose from a recombination event.
Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for human T-lymphotropic virus type 1 (HTLV-1), the first isolated human-pathogenic retrovirus. Different genotypes exist for HTLV-1: Genotypes b and d to g are restricted to central Africa, while genotype c is only endemic in Australo-Melanesia. In contrast, the cosmopolitan genotype a is widely distributed. We applied a combination of phylogenetics and recombination analysis approaches to a set of new HTLV-1 sequences, which we collected from 19 countries throughout Africa, the continent where the virus has the largest endemic presence. This led us to demonstrate the presence of recombinants in HTLV-1. Indeed, the HTLV-1 strains currently present in North Africa have originated from a recombinant event between strains from Senegal and West Africa. This recombination is estimated to have occurred around 4,000 years ago. This recombination seems to have been generated during reverse transcription. In conclusion, we demonstrate that, albeit rare, recombination can occur in HTLV-1 and may play a role in the evolution of this retrovirus. A number of HTLV-1 subtypes have been described in different populations, but none of the genetic differences between these subtypes have been ascribed to recombination events. Here we report an HTLV-1 recombinant virus among infected individuals in North Africa. This demonstrates that, contrary to what was thought, recombination can occur and could play a role in the evolution of HTLV-1.


[Blocking action of adenosine and ATP on synaptic transmission in isolated slices of the rat brain].
Effects of ATP and adenosine on the background activity, orthodromic responses of single neurons and focal potentials were investigated in neocortex, hippocampus, fascia dentata and cerebellum slices in vitro. Both agents exerted a double action: excitatory and inhibitory. Excitation was observed only at large concentrations of ATP (10(-2)-10(-3)M), and it was insignificant for adenosine. It was apparently due to a direct depolarizing action of those agents on cell membrane. Similar inhibitory effects of both ATP and adenosine were observed at concentrations as low as 10(-6)-10(-7)M and were manifested in depression of evoked unit responses and their background activity at a presynaptic level. Hippocampal neurons proved to be the most sensitive to these agents, while the cerebellar neurons displayed the lowest sensitivity to them. Apamine did not effect the inhibitory action of ATP. The data obtained indicate that ATP and adenosine cannot be considered as central neurotransmitters. Their possible role as modulators of synaptic transmission in the CNS is discussed.


Improved tools for the Brainbow toolbox.
In the transgenic multicolor labeling strategy called 'Brainbow', Cre-loxP recombination is used to create a stochastic choice of expression among fluorescent proteins, resulting in the indelible marking of mouse neurons with multiple distinct colors. This method has been adapted to non-neuronal cells in mice and to neurons in fish and flies, but its full potential has yet to be realized in the mouse brain. Here we present several lines of mice that overcome limitations of the initial lines, and we report an adaptation of the method for use in adeno-associated viral vectors. We also provide technical advice about how best to image Brainbow-expressing tissue.


The implementation of quantitative electromyographic neuromuscular monitoring in an academic anesthesia department.
Although experts agree on the importance of quantitative neuromuscular blockade monitoring, particularly for managing reversal, such monitoring is not in widespread use. We describe the processes and results of our departmental experience with the introduction of such quantitative monitoring. In mid-2010, the senior authors became concerned about the management of nondepolarizing neuromuscular blockers (NMB) by providers within the department, based on personal observations and on a review of a departmental quality assurance/adverse event database. This review indicated the occurrence of 2 to 4 reintubations/year in the postanesthesia care unit (PACU) that were deemed to be probably or possibly related to inadequate reversal. In response, quantitative blockade equipment (Datex-Omeda ElectroSensor™ EMG system) was installed in all our main operating rooms in January 2011. This introduction was accompanied by an extensive educational effort. Adoption of the system was slow; by mid-2011, the quantitative system was being used in <50% of cases involving nondepolarizing relaxants and adverse NMB-related events continued to occur. Therefore, starting in August 2011 and extending over the next 2 years, we performed a series of 5 separate sampling surveys in the PACU in which train-of-four (TOF) ratios were recorded in 409 tracheally extubated adult patients who had received nondepolarizing NMB (almost exclusively rocuronium) as well as in 73 patients who had not received any nondepolarizing NMB. After each survey, the results were presented to the entire department, along with discussions of individual cases, reviews of the recent literature regarding quantitative monitoring and further education regarding the use of the quantitative system. In the initial (August 2011) PACU survey of 96 patients receiving nondepolarizing NMBs, 31% had a TOF ratio of ≤0.9, 17% had a ratio of ≤0.8, and 4 patients (4%) had ratios of ≤0.5. A record review showed that the quantitative monitoring system had been used to monitor reversal in only 51% of these patients, and 23% of patients had no evidence of any monitoring, including qualitative TOF assessment. By December of 2012 (after 2 interim PACU monitoring surveys), a fourth survey showed 15% of 101 monitored patients had a TOF ratio ≤0.9, and only 5% had ratios ≤0.8. (P < 0.05 vs August 2011). Clear documentation of reversal using the quantitative system was present in 83% of cases (P < 0.05 vs August 2011). A final survey in July 2013 showed nearly identical values to those from December 2012. The lowest TOF ratio observed in any patient not receiving a nondepolarizing NMB was 0.92. There were no changes in the patterns of either rocuronium or neostigmine use over the duration of the project (through December 2012), and there have been no cases of NMB-related reintubations in the PACU during the last 2 years. Implementation of universal electromyographic-based quantitative neuromuscular blockade monitoring required a sustained process of education along with repeated PACU surveys and feedback to providers. Nevertheless, this effort resulted in a significant reduction in the incidence of incompletely reversed patients in the PACU.


Tricyclic antidepressant therapy for peptic ulcer disease.
The role of tricyclic antidepressants (TCAs) as agents for treatment of peptic ulcer disease is of growing interest. In both placebo-controlled clinical trials and comparative studies with cimetidine, TCAs have proved effective and safe as ulcer-healing agents. The mechanism of action by which TCAs produce healing has not been fully elucidated. In vivo studies in man have generally shown that TCAs decrease gastric acid secretion. In addition to their well-known anticholinergic properties, in vitro studies have indicated potent H1- and H2-receptor blocking activities for these agents. Separate from these effects on acid output, the antipain/depression effect of TCAs may be of benefit in certain patients with ulcers. Other advantages of these agents include their long half-lives, low cost, and readily available serum monitoring. Further clinical studies with detailed physiologic and psychologic observations and serum monitoring using TCAs in patients with peptic ulcer disease are needed.


Single-Molecule Imaging Uncovers Rules Governing Nonsense-Mediated mRNA Decay.
Nonsense-mediated decay (NMD) is a surveillance system that degrades mRNAs containing a premature termination codon (PTC) and plays important roles in protein homeostasis and disease. The efficiency of NMD is variable, impacting the clinical outcome of genetic mutations. However, limited resolution of bulk analyses has hampered the study of NMD efficiency. Here, we develop an assay to visualize NMD of individual mRNA molecules in real time. We find that NMD occurs with equal probability during each round of translation of an mRNA molecule. However, this probability is variable and depends on the exon sequence downstream of the PTC, the PTC-to-intron distance, and the number of introns both upstream and downstream of the PTC. Additionally, a subpopulation of mRNAs can escape NMD, further contributing to variation in NMD efficiency. Our study uncovers real-time dynamics of NMD, reveals key mechanisms that influence NMD efficiency, and provides a powerful method to study NMD.


Recovery of contagious equine metritis organisms and development of lesions in experimental infection of mares.
Twenty-three of 24 mares were infected experimentally with contagious equine metritis organisms by intrauterine inoculation, and killed 2-116 days later. From mares killed within 14 days after infection the organism could be recovered from many sites in the uterus, and most sites in the cervix, a few sites in the vagina and oviduct and from one clitoral sinus. At this time the endometrial folds were swollen and there were 10-20 ml of fluid in the uterus. In mares killed after 14 days, the organism was recovered from the ovarian surface (1 mare), oviduct (4 mares), uterus (2 mares) and the clitoral sinus (3 mares). Severe diffuse endometritis and cervicitis was initially acute, and became more severe subacute and predominantly plasmacytic by 14 days, then declined but persisted throughout the experiment.


Search for B0s-->micro+micro- and B0d-->micro+micro- decays in pp collisions at square root s = 1.96 TeV.
We report on a search for B(0)(s)-->micro(+)micro(-) and B(0)(d)-->micro(+)micro(-) decays in pp collisions at square root of s=1.96 TeV using 171 pb(-1) of data collected by the CDF II experiment at the Fermilab Tevatron Collider. The decay rates of these rare processes are sensitive to contributions from physics beyond the standard model. One event survives all our selection requirements, consistent with the background expectation. We derive branching ratio limits of B(B(0)(s)-->micro(+)micro(-))<5.8x10(-7) and B(B(0)(d)-->micro(+)micro(-))<1.5x10(-7) at 90% confidence level.


SWOG S0925: A Randomized Phase II Study of Androgen Deprivation Combined With Cixutumumab Versus Androgen Deprivation Alone in Patients With New Metastatic Hormone-Sensitive Prostate Cancer.
Cixutumumab, formerly IMC-A12, is a recombinant human monoclonal immunoglobulin G1 antibody that targets insulin-like growth factor I receptor (IGF-IR). Cixutumumab was synergistic with castration in a hormone-sensitive prostate cancer xenograft model. Patients with new metastatic prostate cancer were randomly assigned within 30 days of initiating androgen deprivation (AD) to cixutumumab added to a luteinizing hormone-releasing hormone agonist with bicalutamide versus AD alone. With 180 patients and one-sided alpha of 0.10, there would be 90% power to detect an absolute 20% difference in undetectable prostate-specific antigen (PSA; ≤ 0.2 ng/mL) rate at 28 weeks (relative risk, 1.44); this end point was previously strongly correlated with survival. Secondary end points included the proportion of patients with PSA > 4.0 ng/mL, safety and tolerability, circulating tumor cell (CTC) levels, and seven plasma IGF-IR biomarkers. Fisher's exact test was used for the primary end point, and extended Mantel-Haenszel χ(2) test was used for three PSA response categories. The trial accrued 210 eligible patients (105 randomly assigned to each arm). Patient characteristics were similar in both arms. Undetectable PSA rate was 42 (40.0%) of 105 for cixutumumab plus AD and 34 (32.3%) of 105 for AD alone (relative risk, 1.24; one-sided P = .16). Lower baseline CTCs (0 v 1 to 4 v ≥ 5/7.5 mL whole blood) were associated with higher rate of PSA response (three categories; P = .036) in 39 evaluable patients. IGF-IR biomarkers were not correlated with PSA outcome, and cixutumumab did not significantly change these biomarker levels. Cixutumumab plus AD did not significantly increase the undetectable PSA rate in men with new metastatic hormone-sensitive prostate cancer. CTCs at baseline may carry prognostic value.


Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations.
The genetic heterogeneity of non-syndromic hearing loss (NSHL) has hampered the identification of its pathogenic mutations. Several recent studies applied targeted genome enrichment (TGE) and massively parallel sequencing (MPS) to simultaneously screen a large set of known hearing loss (HL) genes. However, most of these studies were focused on familial cases. To evaluate the effectiveness of TGE and MPS on screening sporadic NSHL patients, we recruited 63 unrelated sporadic NSHL probands, who had various levels of HL and were excluded for mutations in GJB2, MT-RNR1, and SLC26A4 genes. TGE and MPS were performed on 131 known HL genes using the Human Deafness Panel oto-DA3 (Otogenetics Corporation., Norcross, GA). We identified 14 pathogenic variants in STRC, CATSPER2, USH2A, TRIOBP, MYO15A, GPR98, and TMPRSS3 genes in eight patients (diagnostic rate = 12.7%). Among these variants, 10 were novel compound heterozygous mutations. The identification of pathogenic mutations could predict the progression of HL, and guide diagnosis and treatment of the disease.


External fluorescence retention of calcein-marked juvenile brown trout Salmo trutta raised in natural and artificial environments.
The fluorescence retention and intensity of juvenile brown trout Salmo trutta marked during their first summer were monitored in a hatchery and in four natural streams. A handheld detector was used for direct examination. In the hatchery, three marking treatments (T) were compared: 3·5 min in a 0·5% calcein solution (T0·5-3·5), 7 min in a 0·5% calcein solution (T0·5-7) and 3·5 min in a 1% calcein solution (T1-3·5). The fish were raised indoors for 11 months and then outdoors until 18 months. The fluorescence retention rate was 100% in all treatments at 11 months, although T1-3·5 showed the highest mean fluorescence intensity, followed by T0·5-7 and T0·5-3·5. The fluorescence intensity was not correlated with the final total length (L(T)) of the fish in two treatments, although it significantly decreased with increasing L(T) in T1-3·5. At 18 months, <30% of the fish were still slightly fluorescent, suggesting a negative effect of sunlight exposure. In stream studies, the fluorescence intensity did not significantly differ according to final L(T); an overall mean ± s.d. retention rate of 70·7 ± 26·6% was measured at 12 months with a decrease to 48·6 ± 24·6% at 24 months. Significant differences amongst streams and within reaches of the same stream were observed. Because of a significant positive effect of the shading index on the fluorescence intensity, the use of calcein should be restricted to streams unexposed to direct sunlight. Consequently, the marking method would be reliable for 1 year monitoring studies in shaded streams.


Adipose tissue and volumetric bone mineral density of older Afro-Caribbean men.
Although low body weight is a risk factor for osteoporosis-related fractures, conflicting data exist for the association between adiposity and bone mineral density (BMD). Studies examining these relationships have measured body fat and BMD with dual-energy X-ray absorptiometry (DXA), which cannot distinguish subcutaneous adipose tissue area (SAT) from total adiposity or trabecular from cortical bone. To investigate the relationship between adiposity and BMD further, we analyzed body composition and adipose tissue distribution by quantitative computed tomography (QCT) in 1829 Afro-Caribbean men aged 40 years and older from a population-based sample. Cortical volumetric BMD, muscle cross-sectional area, total adipose tissue area (TAT), and percentage SAT were measured at the proximal tibia. Trabecular volumetric BMD was measured at the distal tibia. We used analysis of covariance to test for associations between quartile of the adipose tissue measures and BMD, adjusting for anthropometric, health, and lifestyle factors. Higher TAT was associated with lower cortical BMD in both unadjusted and adjusted models (p < .001). Men with a higher percentage SAT had greater cortical BMD (p < .001). Similar associations were seen between percent SAT and trabecular BMD at the distal tibia. These results indicate that total adiposity is a potentially important correlate of bone mass in older men and that different fat depots may have opposing associations with bone mass. Additional research is needed to better understand the mechanisms underlying the relationship between body fat distribution and bone mass.


Femtosecond optoinjection of intact tobacco BY-2 cells using a reconfigurable photoporation platform.
A tightly-focused ultrashort pulsed laser beam incident upon a cell membrane has previously been shown to transiently increase cell membrane permeability while maintaining the viability of the cell, a technique known as photoporation. This permeability can be used to aid the passage of membrane-impermeable biologically-relevant substances such as dyes, proteins and nucleic acids into the cell. Ultrashort-pulsed lasers have proven to be indispensable for photoporating mammalian cells but they have rarely been applied to plant cells due to their larger sizes and rigid and thick cell walls, which significantly hinders the intracellular delivery of exogenous substances. Here we demonstrate and quantify femtosecond optical injection of membrane impermeable dyes into intact BY-2 tobacco plant cells growing in culture, investigating both optical and biological parameters. Specifically, we show that the long axial extent of a propagation invariant ("diffraction-free") Bessel beam, which relaxes the requirements for tight focusing on the cell membrane, outperforms a standard Gaussian photoporation beam, achieving up to 70% optoinjection efficiency. Studies on the osmotic effects of culture media show that a hypertonic extracellular medium was found to be necessary to reduce turgor pressure and facilitate molecular entry into the cells.


[Anxiety--historical and clinical aspects of the problem].
Working on the principle that anxiety is interpreted as a sorrowful and uncanny experience of being fundamentally imperiled, the clinical phenomena of anxiety are examined taking into account the historical aspects of the problem of anxiety. As a nosological term anxiety implies the establishment of anxiety diseases such as anxiety neuroses and the manifold phobiae. Anxiety can generally be understood as the dynamic basis of neurotic diseases. In the assessment of the range of this problem in a scientific way, the development of psychoanalytical theories plays an important role. There is also a level of symptomatology where the importance of anxiety in the pattern of symptoms belonging to various mental illnesses must be given consideration. This is where the phenomenon of anxiety as part of a psychosis becomes a crucial psychopathological problem which, in its complexity, is taken care of rather insufficiently in current psychiatric discussions. The possibilities offered by a phenomenological and hermeneutic approach are pointed out, leading to the fundamental importance of anxiety that structures human experience in psychosis. The clinical empiricism of the phenomena of anxiety gives rise to first attempts to formulate a theory and a concept of anxiety: Side by side with the somatological constructions and psychoanalytical theorems, there is the approach of a psychiatry drawing from the fields of philosophical anthropology aiming at understanding. The attention paid to anxiety by psychiatry during the Romantic era before Griesinger, as well as the reasons for the differentiation between anxiety and fear, owing to the history of thought and concept, are dealt with separately. Looking at the history of the problem of anxiety, where psychiatric science always maintains its links with prevalent concepts of its era, we can recognize the continuity of the ever identical transhistorical problem structures of anxiety in their relevance for the questions formulated by today's psychiatry. Since it enables us to differentiate between what can be scientifically elucidated and what evades the grasp of science, it is quite evident that psychiatric thinking guided by philosophic interpretation remains a necessity even today--not least with regard to the attitude towards the patient suffering from anxiety.


Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly(ADP-ribose) polymerase inhibitor in a novel drug combination.
Floxuridine (5-fluorodeoxyuridine, FdUrd), a U.S. Food and Drug Administration-approved drug and metabolite of 5-fluorouracil, causes DNA damage that is repaired by base excision repair (BER). Thus, poly(ADP-ribose) polymerase (PARP) inhibitors, which disrupt BER, markedly sensitize ovarian cancer cells to FdUrd, suggesting that this combination may have activity in this disease. It remains unclear, however, which DNA repair and checkpoint signaling pathways affect killing by these agents individually and in combination. Here we show that depleting ATR, BRCA1, BRCA2, or RAD51 sensitized to ABT-888 (veliparib) alone, FdUrd alone, and FdUrd + ABT-888 (F+A), suggesting that homologous recombination (HR) repair protects cells exposed to these agents. In contrast, disabling the mismatch, nucleotide excision, Fanconi anemia, nonhomologous end joining, or translesion synthesis repair pathways did not sensitize to these agents alone (including ABT-888) or in combination. Further studies demonstrated that in BRCA1-depleted cells, F+A was more effective than other chemotherapy+ABT-888 combinations. Taken together, these studies 1) identify DNA repair and checkpoint pathways that are important in ovarian cancer cells treated with FdUrd, ABT-888, and F+A, 2) show that disabling HR at the level of ATR, BRCA1, BRCA2, or RAD51, but not Chk1, ATM, PTEN, or FANCD2, sensitizes cells to ABT-888, and 3) demonstrate that even though ABT-888 sensitizes ovarian tumor cells with functional HR to FdUrd, the effects of this drug combination are more profound in tumors with HR defects, even compared with other chemotherapy + ABT-888 combinations, including cisplatin + ABT-888.


Added Value of Xpert MTB/RIF Ultra for Diagnosis of Pulmonary Tuberculosis in a Low-Prevalence Setting.
Xpert MTB/RIF (Xpert) for direct molecular detection of Mycobacterium tuberculosis and rifampin resistance from clinical specimens has dramatically improved the diagnosis of tuberculosis (TB). Xpert MTB/RIF Ultra (Ultra) is proposed as a substitute of Xpert with increased sensitivity and improved rifampin resistance detection. We evaluated the diagnostic performance of Ultra and Xpert for pulmonary TB diagnosis in a low-TB-burden setting. Performance of Ultra and Xpert were compared to culture on respiratory specimens from patients with suspected pulmonary TB (November 2016 to August 2018; n = 196) in Lausanne (Switzerland). Clinical data were used to investigate discrepant results. Correlation between semiquantitative result of Ultra and smear microscopy status for the detection of acid-fast bacilli (AFB) was established. The sensitivities of Xpert and Ultra were 82.9% (39/47) and 95.8% (45/47), respectively, when considering all culture-positive specimens, 100% (23/23) for both assays on smear-positive specimens, and 66.7% (16/24) and 91.7% (22/24) on smear-negative specimens. Using culture as gold standard, the specificities of Xpert and Ultra were 97.3% (145/149) and 96.64% (144/149), respectively. All the patients with Ultra-positive results with the new category "trace" were diagnosed with active TB based on clinical findings and microbiological culture. The semiquantitative results of both Xpert and of Ultra positively correlated with the semiquantitative result of AFB detection. Our data support an increased sensitivity of Ultra compared to Xpert in a low-prevalence setting. Correlation between the Ultra semiquantitative result and AFB burden can help in evaluating a patient's transmission potential.


Localisation and immunological properties of a 24-kDa surface protein of Haemophilus ducreyi.
The cell wall and outer structures of Haemophilus ducreyi bacteria were investigated. The 24-kDa outer protein from two strains was purified with an SDS-PAGE preparative continuous-elution electrophoresis cell. The protein was further characterised by SDS-PAGE and immunoblotting, and the immunological properties were investigated by ELISA. Localisation on the bacterial surface was investigated by immuno-electron-microscopy with a polyclonal antiserum raised against the purified protein. A triple-laminar cell wall typical of gram-negative bacteria, close cellular contact between bacterial cells and outer blebs were seen on thin sections. An additional high mol. wt band of c. 165 kDa was seen when not treated by heating to 100 degrees C. A high density fibrilla-like material was detected on the bacterial cell and in the environment by negative staining and immuno-electron-microscopy with antisera specific for the 24-kDa protein. The surface localisation of the 24-kDa protein was confirmed by an ELISA technique with the specific antiserum and whole bacterial cells as antigen. The presence of antibodies to the 24-kDa protein was demonstrated in antisera to 13 strains of H. ducreyi, indicating antigenic identity or within-species cross-reactivity. Low titres of antibodies to this protein were also detected in 19 antisera raised against different strains of gram-negative bacteria, indicating cross-reactivity with other species. Antibody response to the 24-kDa protein in rabbits immunised subcutaneously with live bacteria resulted in a secondary IgG response. Of 28 sera from patients with culture-verified chancroid, 26 manifested high titres of IgG antibodies to the 24-kDa protein, thus indicating the involvement of this antigen in the disease process in man.


Extensive CD44-dependent hyaluronan coats on human bone marrow-derived mesenchymal stem cells produced by hyaluronan synthases HAS1, HAS2 and HAS3.
Hyaluronan (HA), a natural extracellular matrix component, has been considered as an important constituent of the stem cell niche, and successfully used as 3D scaffolds for the chondrogenic differentiation of stem cells. However, the expression levels of HA synthases (HAS1, 2 and 3) and the synthesis of HA by stem cells have remained unknown, and were studied here in the human bone marrow-derived mesenchymal stem cells (hMSCs). Nine hMSCs from different donors were cultured as monolayers with MSC culture medium supplemented with FGF-2. The amount of HA secreted into medium was studied by an ELISA-type assay, and HA bound to cell surface by live cell microscopy. The expression of HASs was analyzed by real time RT-PCR and immunostainings. The HA receptor CD44 was studied by immunocytochemistry. An intense HA coat surrounded the plasma membrane and its protrusions in all nine hMSCs. Displacement assay with HA oligosaccharides indicated that HA coat was at least partly dependent on CD44, which showed similar, relatively high expression in all hMSCs. All HAS isoenzymes were detected, HAS1 showing the largest and HAS3 the smallest range of expression levels between the hMSCs. The secretion of HA ranged between 22.5 and 397.4 ng/10,000 cells/24h, and could not be clearly assigned to the mRNA level of a certain HAS, or a combination of the isoenzymes. This suggests that post-transcriptional and post-translational factors were involved in the adjustment of the HA secretion. In conclusion, all hMSCs expressed high levels of HAS1-3, secrete large amounts of HA, and surround themselves with a thick HA coat bound to CD44. The results suggest that hMSC has the potential for autocrine maintenance of the HA niche, important for their stemness.


Increased presence of mammal-eating killer whales in the Salish Sea with implications for predator-prey dynamics.
The inland waters of Washington State and southern British Columbia, collectively known as the Salish Sea, comprise key habitat for two regional populations of killer whales (Orcinus orca): the mammal-eating West Coast Transients and the endangered fish-eating Southern Residents. These two populations are genetically distinct and may avoid each other. Transient killer whale usage of the Salish Sea has been previously assessed over two seven-year time periods, showing an increase from 1987 to 2010. We documented a continued significant increase in mammal-eating killer whale presence in the Salish Sea from 2011 to 2017, with intra- and inter-annual variability and with record sightings in 2017. This continued increase, likely in response to abundant marine mammal prey, is related to both a growing population and an increase in the number of West Coast Transients visiting the area. Additionally, a negative binomial regression shows that absence of Southern Residents is correlated to transient presence. Finally, both populations of killer whales have been linked to regional harbor seal populations; harbor seals are salmonid-eating competitors of the Southern Residents and are prey for the mammal-eating transients. With Southern Residents listed as endangered, culling harbor seals has been proposed as a measure to help in their recovery. With this in mind, we developed an energetic model to assess the minimum number of harbor seals consumed by transient killer whales. Using the actual number of whales present in each age-sex class for each day of the year, we estimate that, at a minimum, transients in the Salish Sea consumed 1090 seals in 2017. This is more than 2% of the 2014 estimated harbor seal population the Salish Sea. The population controlling effects of transient killer whale predation on harbor seals should be considered when evaluating any pinniped management actions in the Salish Sea.