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This study evaluated the potential of low-glycoalkaloid potato haulm (LGPH) as a high-quality feed for ruminants. The low-glycoalkaloid potato plants were grown in a net house following standard agricultural practices. Dehaulming was performed a fortnight before the harvest of the tubers, as commercially practiced. Four healthy female lambs (aged 4 months) were employed in a 4×4 Latin square feeding experiment design. The lambs were fed with either a maintenance diet consisting of 73% roughage (control), or treatment diets with supplementation of 10% (P10), 15% (P15), and 20% (P20) LGPH on a dry matter (DM) basis for a period of 21 days, including 14 days of adaption and 7 days of sampling. Refusals and feces were collected for 6 days and pooled followed by a 24 h urine collection on the 7th day. On the 6th day, an hour after morning feeding, blood, and rumen liquid samples were collected. All the samples were analysed, and the data generated were analysed using ANOVA with diet and period as fixed effects and sheep as a random effect. Orthogonal contrasts were used to detect linear and quadratic effects of LGPH in the diet. Linear or polynomial equations were produced to extract the nutrient digestibility and metabolizable energy (ME) of LGPH. No toxicological clinical signs were observed, and the haematology profiles were normal throughout the trial. LGPH did not affect the daily intake of nutrients and energy. However, the apparent digestibility of DM, organic matter (OM), crude protein (CP), and gross energy increased (P= 0.01) linearly (P< 0.01) with supplementation of LGPH in the diet. The inclusion of LGPH had a quadratic effect on neutral detergent fiber (NDF) digestibility (P= 0.027), reaching a peak of 54.8 % at 12.3 % LGPH supplement on a DM basis. The N retention in lambs fed with the P20 diet was nearly twice that of the control diet (P= 0.032; 19.1 vs. 10.2 g/d). The computed digestibility values of DM, OM, CP, and NDF for LGPH were 76.1, 79.7, 84.2, and 72.1 %, respectively, and ME was 2.62 Mcal/kg DM. Conclusively, by significantly reducing the glycoalkaloids’ content in potato haulm, we can safely repurpose the currently wasted foliage as a new source of high-quality roughage feed for ruminants, equivalent to alfalfa hay, without imposing any additional environmental burden. However, further research is necessary to assess impact of LGPH on growth performance, and milk productivity before practical application on commercial farms.

Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na+, K+-ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na+, K+-ATPase are present in the brain. Previous studies have supported the involvement of the Na+, K+-ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1+/− mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1+/− but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na+, K+-ATPase activity in wt and α1+/− mice. The serum ECS was lower in α1+/− than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na+, K+-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na+, K+-ATPase/ECS system participates in the etiology of BD.

The tumor suppressor p53 is mutated in more than half of human cancers and the compound methylene quinuclidinone (MQ) was shown to reactivate p53 mutants by binding covalently to cysteine residues. Here, the authors present crystal structures of wild-type and cancer related p53 mutant core domains bound to MQ alone and in complex with their DNA response elements and observe that MQ is bound to several cysteine residues located at the surface of the core domain.

Most insights on DNA-mediated allostery upon transcription factor (TF) binding were either based on artificial promoters or found to be short-ranged. Here authors use single-molecule FRET and cryo-EM to show that Bacillus subtilis bacteria utilize long-range allostery in a stochastic and reversible phenotype switch.

Actin-based tunneling nanotubes are a means of intercellular communication between remote cells. In the last decade, this type of nanotube was described in a wide variety of cell types and it became widely accepted that communication through these nanotubes is related to response to environmental changes. Few reports, however, are available regarding the expression of similar nanotubes in vivo or in primary cells. Moreover, the functional significance of this intercellular communication for health and disease is largely unknown. In this context, and as a first step in unraveling these questions, we examined the formation of similar nanotubes in primary peripheral human monocytes. To that end, we combined the use of a live cell imaging system along with advanced methods of fluorescent and scanning electron microscopy. This experimental approach reveals for the first time that the bacterial lipopolysaccharide endotoxin induces a transient expression of an unexpected abundance of actin-based tunneling nanotubes associated with vesicles. In addition, it was found that a similar response can be achieved by treating human monocytes with various bacterial and yeast membrane components, as well as with a viral component analog. In all these cases, this response is mediated by distinct complexes of toll-like receptors. Therefore, we suggest that the observed phenomena are related to a broad type of monocyte pathogen response, and raise the possibility that the phenomena described above may be involved in many clinical situations related to inflammation as a new topic of study.

Leishmaniasis is a parasitic disease transmitted by the bite of infected sand flies. Here the authors describe an atomic resolution cryo-EM structure of the Leishmania ribosome in complex with the recently approved drug paromomycin (PAR) and highlight conserved elements in the drug binding pocket that mediate PAR deleterious effects on the parasite.

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Leishmania is a single-cell eukaryotic parasite of the Trypanosomatidae family, whose members cause an array of tropical diseases. The often fatal outcome of infections, lack of effective vaccines, limited selection of therapeutic drugs, and emerging resistant strains, underline the need to develop strategies to combat these pathogens. The Trypanosomatid ribosome has recently been highlighted as a promising therapeutic target due to structural features that are distinct from other eukaryotes. Here, we present the 2.8-Å resolution structure of the Leishmania donovani large ribosomal subunit (LSU) derived from a cryo-EM map, further enabling the structural observation of eukaryotic rRNA modifications that play a significant role in ribosome assembly and function. The structure illustrates the unique fragmented nature of leishmanial LSU rRNA and highlights the irregular distribution of rRNA modifications in Leishmania, a characteristic with implications for anti-parasitic drug development.

Bipolar disorder is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the world’s population. Its biological basis is unknown, and its treatment is unsatisfactory. The α1, α2, and α3 isoforms of the Na+, K+-ATPase, an essential membrane transporter, are vital for neuronal and glial function. The enzyme and its regulators, endogenous cardiac steroids like ouabain and marinobufagenin, are implicated in neuropsychiatric disorders, bipolar disorder in particular. Here, we address the hypothesis that the α isoforms of the Na+, K+-ATPase and its regulators are altered in the prefrontal cortex of bipolar disease patients. The α isoforms were determined by Western blot and ouabain and marinobufagenin by specific and sensitive immunoassays. We found that the α2 and α3 isoforms were significantly higher and marinobufagenin levels were significantly lower in the prefrontal cortex of the bipolar disease patients compared with those in the control. A positive correlation was found between the levels of the three α isoforms in all samples and between the α1 isoform and ouabain levels in the controls. These results are in accordance with the notion that the Na+, K+-ATPase-endogenous cardiac steroids system is involved in bipolar disease and suggest that it may be used as a target for drug development.

Aims: To determine the appropriateness of the acute otitis media antibiotic treatment prescribed in the community in relation to the therapeutic guidelines. Methods: Children aged 3 months–3 years diagnosed with simple uncomplicated acute otitis media in 6 community primary care clinics were enrolled. Data on the antibiotic treatment were collected using computerized medical files. Results: 689 simple uncomplicated acute otitis media patients were enrolled; 597 (86.9%) were treated with antibiotics by 38 family medicine practitioners, 12 pediatricians and 7 general practitioners. 461 (77.2%) patients were 2 years of age received an inappropriate antibiotic treatment. Conclusions: The majority of primary care physicians treat simple uncomplicated acute otitis media with the recommended antibiotic drug. However, incorrect dosage and shorter than recommended duration of therapy may jeopardize the quality of care in children with simple uncomplicated acute otitis media. Keywords: Acute otitis media, Antibiotics, Physicians, Community

Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD.

AIMS:The aim of this study was to compare in patients presenting with acute chest pain the clinical outcomes and cost-effectiveness of an accelerated diagnostic protocol utilizing contemporary technology in a chest pain unit versus routine care in an internal medicine department. METHODS AND RESULTS:Hospital and 90-day course were prospectively studied in 585 consecutive low-moderate risk acute chest pain patients, of whom 304 were investigated in a designated chest pain center using a pre-specified accelerated diagnostic protocol, while 281 underwent routine care in an internal medicine ward. Hospitalization was longer in the routine care compared with the accelerated diagnostic protocol group (p

The aim of this study was to determine if handgrip strength might be used as a diagnostic tool in musculoskeletal disorders of the upper extremities in women working in an industrial environment. The setting was an electronic factory with four groups of women (n = 101) in a factory assembling electronic components. Handgrip strength was measured using a Jamar® hydraulic hand dynamometer. The study investigated grip strength in managers-engineers, cable wiring, circuit board assembly, integrated circuits women at 90? elbow flexion and 180? elbow extension. Women seeking or receiving medical care for musculoskeletal disorders of the upper extremities or neck showed significant declines (p < 0.01) in handgrip strength and these also related to the type of work and the level of perceived physical exertion. Women in the managerial-engineering group showed fewer musculoskeletal disorders of the upper extremity compared with the other groups and also had significantly stronger handgrip. Our findings encourage us to recommend hand dynamometer testing as a useful diagnostic tool to determine loss of handgrip strength.

OBJECTIVE: To describe the daily work practice under the threat of defensive medicine among obstetricians and gynecologists. STUDY DESIGN: A prospective cross-sectional survey of obstetricians and gynecologists working at tertiary medical centers in Israel. RESULTS: Among the 117 obstetricians and gynecologists who participated in the survey, representing 10% of the obstetricians and gynecologists registered by the Israel Medical Association, 113 (97%) felt that their daily work practice is influenced by concern about being sued for medical negligence and not only by genuine medical considerations. As a result, 102 (87%) physicians are more likely to offer the cesarean section option, even in the absence of a clear medical indication, 70 (60%) follow court rulings concerning medical practices, and 85 (73%) physicians mentioned that discussions about medical negligence court rulings are included in their departments' meetings. CONCLUSIONS: Defensive medicine is a well-embedded phenomenon affecting the medical decision process of obstetricians and gynecologists.

Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of “pathogen-specific antibiotics,” in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification.

OBJECTIVE: We explored whether financial incentives have a role in patients' decisions to accept (purchase) a continuous positive airway pressure (CPAP) device in a healthcare system that requires cost sharing. DESIGN: Longitudinal interventional study. PATIENTS: The group receiving financial incentive (n = 137, 50.8±10.6 years, apnea/hypopnea index (AHI) 38.7±19.9 events/hr) and the control group (n = 121, 50.9±10.3 years, AHI 39.9±22) underwent attendant titration and a two-week adaptation to CPAP. Patients in the control group had a co-payment of $330-660; the financial incentive group paid a subsidized price of $55. RESULTS: CPAP acceptance was 43% greater (p = 0.02) in the financial incentive group. CPAP acceptance among the low socioeconomic strata (n = 113) (adjusting for age, gender, BMI, tobacco smoking) was enhanced by financial incentive (OR, 95% CI) (3.43, 1.09-10.85), age (1.1, 1.03-1.17), AHI (>30 vs. 30 vs. 30 vs.

BACKGROUND: Defensive medicine is the practice of diagnostic or therapeutic measures conducted primarily as a safeguard against possible malpractice liability. We studied the extent, reasons, and characteristics of defensive medicine in the Israeli health care system. METHODS AND FINDINGS: Cross-sectional study performed in the Israeli health care system between April and July 2008 in a sample (7%) of board certified physicians from eight medical disciplines (internal medicine, pediatrics, general surgery, family medicine, obstetrics and gynecology, orthopedic surgery, cardiology, and neurosurgery). A total of 889 physicians (7% of all Israeli board certified specialists) completed the survey. The majority [60%, (95%CI 0.57-0.63)] reported practicing defensive medicine; 40% (95%CI 0.37-0.43) consider every patient as a potential threat for a medical lawsuit; 25% (95%CI 0.22-0.28) have previously been sued at least once during their career. Independent predictors for practicing defensive medicine were surgical specialty [OR=1.6 (95%CI 1.2-2.2), p=0.0004], not performing a fellowship abroad [OR=1.5 (95%CI 1.1-2), p=0.027], and previous exposure to lawsuits [OR=2.4 (95%CI 1.7-3.4), p

Vacuolar H + -ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1 R741Q ) and A512P (Atp6v0a1 A512P ) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1 A512P/A512P mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.

Artificial intelligence (AI) is defined as the ability of machines to perform tasks that are usually associated with intelligent beings. Argument and debate are fundamental capabilities of human intelligence, essential for a wide range of human activities, and common to all human societies. The development of computational argumentation technologies is therefore an important emerging discipline in AI research 1 . Here we present Project Debater, an autonomous debating system that can engage in a competitive debate with humans. We provide a complete description of the system's architecture, a thorough and systematic evaluation of its operation across a wide range of debate topics, and a detailed account of the system's performance in its public debut against three expert human debaters. We also highlight the fundamental differences between debating with humans as opposed to challenging humans in game competitions, the latter being the focus of classical 'grand challenges' pursued by the AI research community over the past few decades. We suggest that such challenges lie in the 'comfort zone' of AI, whereas debating with humans lies in a different territory, in which humans still prevail, and for which novel paradigms are required to make substantial progress.

p21-activated kinases (PAKs) are protein serine/threonine kinases stimulated by Rho-family p21 GTPases such as CDC42 and RAC. PAKs have been implicated in several human disorders, with pathogenic variants in PAK3 associated with intellectual disability and several PAK members, especially PAK1 and PAK4, overexpressed in human cancer. Recently, de novo PAK1 variants were reported to be causative of neurodevelopmental disorder (ND) with secondary macrocephaly in three patients. We herein report a fourth patient with ND, epilepsy, and macrocephaly caused by a de novo PAK1 missense variant. Two previously reported missense PAK1 variants functioned as activating alleles by reducing PAK1 homodimerization. To examine the pathogenicity of the identified novel p.Ser110Thr variant, we carried out in silico structural analysis. Our findings suggest that this variant also prevents PAK1 homodimerization, leading to constitutive PAK1 activation.

Solitary fibrous tumours are a rare group of tumours that originate from connective tissues such as the pleura and mediastinum. When growing within the thoracic cavity these tumours exert pressure on vital organs and large vessels. We have successfully operated on two patients with large solitary fibrous tumours and managed the pathophysiological changes manifested as superior vena cava syndrome resulting from these tumours., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Schizophrenia may follow a course of amelioration, deterioration or stability. It is possible that deterioration at the aggregate level may be due to a sub-group of patients with a tendency to deteriorate., Aims: To examine the course of schizophrenia in a national population-based cohort., Methods: All first admissions for schizophrenia in Israel 1978-1986 were followed for readmissions in the Israeli psychiatric hospitalization registry for 10 years (n=6865). Readmission rates were examined using cluster analysis. This was followed by an examination of changes in readmission patterns., Results: Cluster analysis identified a small cluster of patients who spent more days in the hospital over time and two clusters that improved. A priori classification of the patients into deteriorating, improving and stable (based on days hospitalized per year) revealed that approximately 75% of patients improved over time., Conclusions: Over time a majority of patients appear to improve and a minority appear to deteriorate.

Studies suggest that better premorbid functioning is associated with better outcomes in chronic schizophrenia. Yet first admission studies, which are more appropriate to examine this, are less conclusive. Also, little attention has been given to whether these findings hold for other psychoses. We examined the relationship of premorbid functioning using the Premorbid Adjustment Scale and outcomes in first admission psychoses (schizophrenia, N = 177; bipolar disorder, N = 106; major depression, N = 68) in the Suffolk County-wide mental health project. Poor premorbid functioning was associated with worse outcomes in all three diagnostic groups. Specifically, it was associated with more negative symptoms early in the course of illness, less improvement in negative symptoms, poorer overall clinical functioning, and poorer social functioning. Consistent with new epidemiological research, early assessment of premorbid functioning could provide an avenue for targeted interventions that might improve outcomes.

Background: Kraepelin and Blueler suggested that subtle manifestations of schizophrenia are present in some persons for many years before formal diagnosis and that the severity of these is associated with outcomes in schizophrenia. Empirical support for this hypothesis comes primarily from small samples using retrospectively collected data., Aims: We tested this hypothesis, for the first time, using a population-based cohort., Method: The Israeli Draft Board Registry, which contains measures of intellectual and behavioral functioning for the unselected population of 17-year-olds, was merged with the National Psychiatric Hospitalization Case Registry that contains data on all psychiatric hospitalizations. The database was used to identify adolescents assessed by the draft board at least 1 year prior to their first hospitalization for schizophrenia (n=996) or affective disorder (n=335)., Results: Poorer social functioning and organizational ability prior to first admission were associated with more days per year in the hospital for the male schizophrenia group. There were no significant correlations between days per year in the hospital and any of the behavioral functioning measures for the affective group. Among females the higher the previous level of intellectual functioning the fewer the days per year in the hospital in both the schizophrenia group and affective groups. For males no such correlations were evident. The comparisons between patients who had one as opposed to more than one admission found that in both diagnostic groups female patients with one admission had higher pre-first hospitalization intellectual functioning., Conclusions: Gender and disease specific premorbid deficits have may have differential prognostic value for outcomes in schizophrenia and affective disorders.

Commercial sex work has many medical and psychiatric implications. In recent years many papers on this matter have been published. However, many of these articles are based on opinions rather then on empiric fieldwork. Sex workers in the western world are not a major source of spread of venereal diseases. Nonetheless, it is important for medical decision makers to be aware of the health risks related to commercial sex work habits: for example. avoidance of condoms for oral sex, might be a risk factor for gonorrhea transmission. In field studies in Israel and abroad, it has been shown that sex workers are not always drug addicts or mentally ill; many of them see it as a legitimate form of work that is dictated by their needs, their social, personal and familial background. Commercial sex workers frequently suffer from emotional and somatic health problems that are often neglected. This review intends to examine the few empirical works that have been conducted on commercial sex workers. including our recent study performed in Israel.

Phytoplasmas are unculturable, insect-transmissible plant pathogens belonging to the class Mollicutes. To be transmitted, the phytoplasmas replicate in the insect body and are delivered to the insect's salivary glands, from where they are injected into the recipient plant. Because phytoplasmas cannot be cultured, any attempt to recover phytoplasmal DNA from infected plants or insects has resulted in preparations with a large background of host DNA. Thus, studies of the phytoplasmal genome have been greatly hampered, and aside from the rRNA genes, only a few genes have hitherto been isolated and characterized. We developed a unique method to obtain host-free phytoplasmal genomic DNA from the insect vector's saliva, and we demonstrated the feasibility of this method by isolating and characterizing 78 new putative phytoplasmal open reading frames and their deduced proteins. Based on the newly accumulated information on phytoplasmal genes, preliminary characteristics of the phytoplasmal genome are discussed.

Studies have shown that it is difficult for psychiatrists to accurately predict which patients will be violent while hospitalized. The authors compared the predictions of 14 psychiatrists and nine psychiatric nurses who independently evaluated 308 patients consecutively admitted to a hospital in Israel and rated their likelihood of becoming violent. The psychiatrists and nurses also completed a general questionnaire about the criteria they used to predict violence. No significant differences were found in the accuracy of predictions between the two professional groups or in the criteria they used to predict violence. The total predictive value, or proportion of all cases predicted correctly, was 82 percent for the psychiatrists and 84 percent for the nurses. The predictions of the two groups coincided for 83 percent of the patients. The results suggest that psychiatrists and psychiatric nurses make similarly accurate predictions of violence and use similar criteria for making them.