Clinical Characteristics, Outcomes, Disposition, and Acute Care of Children and Adolescents Treated for Acetaminophen Toxicity.
Acetaminophen is a common cause of intentional and inadvertent overdoses among children and adolescents worldwide. Little is known about characteristics and clinical outcomes of these youths. The primary goal of this naturalistic study was to describe the psychiatric characteristics, medical management, outcomes, and dispositions of children and adolescents evaluated for excessive acetaminophen exposure. The Rochester Epidemiology Project database was searched for all patients ages 0-18 treated for excessive acetaminophen exposure in Olmsted County, Minnesota, during a 7-year period (2004-2010). Demographic factors, overdose intentionality, medical and psychiatric treatment, mental health and addiction history, and disposition from the emergency department (ED) were documented. Of 110 cases of acetaminophen overdose (89 female patients and 21 male patients), 97 (88%) were intentional and 13 (12%) were unintentional. Fifteen patients (14%) were discharged from the ED, and 69 (63%) required admission to a medical unit. Sixty-four (59%) received N-acetylcysteine. Ninety-eight (89%) were evaluated by psychiatry, and 80 (73%) were admitted for psychiatric hospitalization. Most had at least one psychiatric diagnosis, most commonly depression (55%); 22 (20%) had a prior suicide attempt. Substance use was common, notably alcohol dependence (N=16, 15%), alcohol abuse (N=18, 16%), and cannabis abuse (N=18, 16%). All survived and recovered without liver transplant. Among pediatric patients with acetaminophen overdoses, psychiatric comorbidities and substance use were common. Most received both inpatient medical and psychiatric treatment. Interventions that restrict acetaminophen access are needed for this population, as are suicide risk reduction interventions for delivery in emergency settings.


Role of 5-hydroxytryptamine in toxaemia of pregnancy.
5-HT concentration in blood of 24 randomly selected pregnant women presenting with signs and symptoms of toxaemia of pregnancy were estimated and compared with 30 normal pregnant women. As such 5-HT level increases with the progress of pregnancy and in toxaemia group in comparison to normal pregnancy. A change in the degree of oedema from moderate to severe could bring a statistically significant change in blood pressure and serum 5-HT level. Increased 5-HT plays a role in toxaemia as well as in normal pregnancy and some of the toxic effects observed in toxaemia of pregnancy are due to the effects of 5-HT.


Recognition of mos-related proteins with an antiserum to a peptide of the v-mos gene product.
A mos-specific antiserum was generated by injection of rabbits with a peptide predicted from the sequence of the v-mos gene of Moloney murine sarcoma virus (MuSV) strain 124. The peptide is composed of amino acids 37-55 (cyclized at the cysteine residues) conjugated to keyhole limpet haemocyanin. This serum [anti-mos(37-55c)] specifically recognized p37mos in MuSV-124 acutely infected NIH-3T3 cells, P85gag-mos in 6m2 cells, an NRK clone infected with the temperature-sensitive mutant (ts110) of Moloney MuSV, and P100gag-mos in 54-5A4 cells, an NRK clone infected with a spontaneous revertant of ts110. An additional protein of Mr 55000 from uninfected cells was recognized by this serum. Reactivity of the serum toward the v-mos-containing proteins and the 55K protein was completely inhibited by prior incubation with free peptide. The 55K protein was not recognized by antisera made from synthetic peptides prepared from the C-terminal eight or 12 amino acids of v-mos.


Timolol maleate: efficacy and safety.
A randomized, double-masked trial of various concentrations of timolol maleate ophthalmic solution (0.1%, 0.25%, 0.5%, and 1.0%) vs placebo demonstrated that all concentrations of timolol effectively lowered intraocular pressure (IOP). A 0.5% solution of timolol was as effective in reducing IOP as the 1.0% concentration. Blood pressure, visual acuity, and pupillary diameter were not altered significantly by any concentration of timolol tested during this study. There was a dose-dependent decrease in resting pulse rate with increasing concentrations of timolol. No objective signs of drug intolerance were found on external ocular examination, nor were any subjective symptoms elicited on questioning the subjects. Timolol applied topically twice daily in concentrations of 0.1% to 0.5% appeared to be an effective and safe ocular hypotensive agent.


Reaching the Unreached: Bridging Islam and Science to Treat the Mental Wounds of War.
Radical new paradigms are needed to equip non-professionals and leverage community faith-based infrastructure to address the individual and communal wounds of war- and conflict-related trauma. Muslims in war-torn regions like Somalia experience high rates of trauma and posttraumatic stress; yet, lack of providers, potential stigma, and lack of integration with one's faith are substantial barriers to care. In this pre-post feasibility clinical trial (NCT03761732), mosque leaders implemented a brief, group- and mosque-based intervention, Islamic Trauma Healing, targeting trauma-related psychopathology and community reconciliation for trauma survivors (N = 26) in Somaliland, Somalia. Leaders were trained in a brief 2-day training, with supervision provided remotely via WhatsApp. This six-session intervention combines empirically-supported trauma-focused psychotherapy and Islamic principles, focusing on wisdom from the lives of the Prophets and turning to Allah in dua about trauma. There were large, clinically meaningful effects for PTSD (g = 1.91), depression (g = 2.00), somatic symptoms (g = 2.73), and well-being (g = 1.77). Qualitative data from group members highlighted how well the program was aligned with their Islamic faith, built community, and need to expand the program. These results highlight the feasibility of this non-expert, easily up-scalable mental health approach in war-torn Muslim regions and refugee communities. This program has the potential to provide a low-cost, self-sustaining, Islam-based intervention addressing the psychological wounds of war consistent with the IOM's call to develop novel approaches to address unmet clinical needs. ClinicalTrials.gov Identifier: NCT03761732.


Identification and Antifungal Susceptibility of Penicillium-Like Fungi from Clinical Samples in the United States.
Penicillium species are some of the most common fungi observed worldwide and have an important economic impact as well as being occasional agents of human and animal mycoses. A total of 118 isolates thought to belong to the genus Penicillium based on morphological features were obtained from the Fungus Testing Laboratory at the University of Texas Health Science Center in San Antonio (United States). The isolates were studied phenotypically using standard growth conditions. Molecular identification was made using two genetic markers, the internal transcribed spacer (ITS) and a fragment of the β-tubulin gene. In order to assess phylogenetic relationships, maximum likelihood and Bayesian inference assessments were used. Antifungal susceptibility testing was performed according to CLSI document M38-A2 for nine antifungal drugs. The isolates were identified within three genera, i.e., Penicillium, Talaromyces, and Rasamsonia The most frequent species in our study were Penicillium rubens, P. citrinum, and Talaromyces amestolkiae The potent in vitro activity of amphotericin B (AMB) and terbinafine (TRB) and of the echinocandins against Penicillium and Talaromyces species might offer a good therapeutic alternative for the treatment of infections caused by these fungi.


Short-term methionine supplementation during the early post-partum period in primiparous rabbits improves prolificacy associated with an increase in serum concentrations of IGF-I.
The aim of this study was to evaluate the effects of methionine supplementation on energy metabolism and reproductive performance during the early post-partum period in primiparous does. Forty nulliparous New Zealand White does were used. Females were randomized in two groups at calving: the control group (n = 20) was fed with the basal diet, and the methionine group (n = 20) was fed the basal diet plus 1 g/animal/day of methionine from the day of calving to 4 days post-partum. Results showed that methionine supplementation increased (p = 0.032) the concentration of insulin-like growth factor-1 with respect to control group 4 days post-partum. It similarly increased the prolificacy (p = 0.03), the number of kits born alive per litter (p = 0.06) and the body gain weight of the litter during supplementation (p = 0.035). These results were observed despite the does in the methionine group having a deeper negative energy balance than the does in the control group. Finally, methionine supplementation did not affect receptivity (p = 0.23), fertility (p = 0.49), the number of kits born dead per litter (p = 0.86) insulin and metabolites as glucose, non-esterified fatty acids and triglycerides. In conclusion, our results show that methionine supplementation during the first 4 days of the post-partum period in rabbits increases total litter size and the corporal weight of kits and is associated with an increase in blood concentration of IGF-1.


Transplantation into the anterior chamber of the eye for longitudinal, non-invasive in vivo imaging with single-cell resolution in real-time.
Intravital imaging has emerged as an indispensable tool in biological research. In the process, many imaging techniques have been developed to study different biological processes in animals non-invasively. However, a major technical limitation in existing intravital imaging modalities is the inability to combine non-invasive, longitudinal imaging with single-cell resolution capabilities. We show here how transplantation into the anterior chamber of the eye circumvents such significant limitation offering a versatile experimental platform that enables non-invasive, longitudinal imaging with cellular resolution in vivo. We demonstrate the transplantation procedure in the mouse and provide representative results using a model with clinical relevance, namely pancreatic islet transplantation. In addition to enabling direct visualization in a variety of tissues transplanted into the anterior chamber of the eye, this approach provides a platform to screen drugs by performing long-term follow up and monitoring in target tissues. Because of its versatility, tissue/cell transplantation into the anterior chamber of the eye not only benefits transplantation therapies, it extends to other in vivo applications to study physiological and pathophysiological processes such as signal transduction and cancer or autoimmune disease development.


Radical hysterectomy: a randomized study comparing two techniques for resection of the cardinal ligament.
To compare two different surgical techniques for the resection of the cardinal ligaments during radical operation for cervical cancer, 84 patients with locally advanced cervical cancer (FIGO stages IB-IIA > or = 4 cm, IIB-III) primarily treated with chemotherapy and then eligible for radical surgery underwent radical hysterectomy. Lateral parametria were resected by using the Meigs technique or a modified Magara technique. The procedure to be performed on the right hand side was randomly chosen, consequently the left cardinal ligament was resected with the other technique. Evaluation of the first 35 cases showed that the median size of the parametria resected with the modified Magara technique (52 mm) was significantly greater than that removed with the Meigs technique (34 mm) (P < 0.05). Therefore hemoclips were routinely adopted in the following 49 cases. In 11% of cases hemoclips could not be used due to a deep and narrow pelvis or varicosities of the hypogastric plexus, therefore clamps were necessary. Bleeding complicating parametrial dissection occurred independently of the adopted technique. Five-years DFS is 100, 80, and 52% for stage IB-IIA > 4 cm, IIB and III, respectively. The study showed that the modified Magara technique is feasible and safe and allows for a more radical resection of the parametrial tissue. Furthermore, this approach seems to improve the local control of disease.


Pitfalls in the diagnosis of hypereosinophilic syndrome: a report of two cases.
The idiopathic hypereosinophilic syndrome is empirically defined as the presence of prolonged eosinophilia without identifiable underlying cause, and with evidence of end-organ dysfunction. Virtually any organ system may be involved, most frequently the heart, the central and peripheral nervous system, the lungs and the skin. We report two cases where the diagnosis of hypereosinophilic syndrome was proposed although the classic criteria were not met. In the first case total peripheral eosinophil counts were relatively low, but pathological evidence clearly showed infiltration of eosinophils in the damaged tissues. An hypothesis to explain this discrepancy is formulated. The second case did not fulfil the first feature either, although the clinical presentation and disease course corresponded well with other cases reported in the literature. The delay in diagnosis was caused by early institution of corticosteroids, clearing all evidence of eosinophil involvement in the observed tissue damage.


RESEARCH AND THERAPEUTICS.
Progressive therapeutics depends on research, but at the same time it is a marked stimulant for promoting research. Through research will come much of the post-war advancement which may occur in medicine and allied sciences, drug manufacturing and educational centers. Success and survival will depend not only on cooperation, leadership and a shrewd business sense but on an adequate appreciation of opportunities, limitations and the value of fostering research by providing grants and fellowships. Much material assistance can be provided with mutual gain for all participants when such fellowships are established. This gain may extend past current problems into lifelong associations. If the manufacturer recognizes his opportunities and obligations and forges ahead to challenge or accept them instead of remaining on the defensive, there will be less likelihood of being fettered by purblind policies. Each one interested in research and therapeutics has responsibilities peculiar to himself, but there are few, regardless of occupation, who, at the completion of a job well done, does not feel as Pasteur, who said of the researcher: It is indeed a hard task when you believe you have found an important scientific fact and are feverishly anxious to publish it, to constrain yourself for days, weeks, years sometimes, to fight with yourself, to try to ruin your own experiments and only to proclaim your discovery after having exhausted all contrary hypotheses. But when, after so many efforts, you have at last arrived at certainty, your joy is one of the greatest which can be felt by a human soul, and the thought that you will have contributed to the honor of your country renders that joy still deeper.


[Evaluation of therapeutic effect of new Russian drug semax in optic nerve disease].
Semax is a synthetic analog of adrenocorticotropic hormone 4-10 with a pronounced nootropic effect. It was used in the treatment of vascular, toxic allergic, and inflammatory diseases of the optic nerve and partial atrophy of the optic nerve in parallel with basic neurotrophic and antiinflammatory therapy. For evaluating the drug efficiency, the patients were divided into 3 groups, administered the drug via different routes. In group 1 semax was administered intransally as nasal drops, in group 2 by endonasal electrophoresis, and group 3 was control. Addition of semax to therapeutic complex in patients with diseases of the optic nerve had a favorable impact on the intensity and rate of recovery and improved the visual functions. Semax effectively protected nervous tissue from aftereffects of injury, particularly during the acute stage of optic nerve disease: it stimulated positive changes in the clinical picture, which were evaluated by improvement of visual acuity, extension of the total visual field, increase in the electric sensitivity and conductivity of the optic nerve, and improvement of color vision.


Psychometric Examination of the Abbreviated Version of the Dual School Climate and School Identification Measure-Student (SCASIM-St15) in a Sample of Chilean Adolescents.
School climate is a multidimensional construct that has been related to a series of psychological, social, and school variables. The dual school climate and school identification measure-student (SCASIM-St) is a measure that has a multidimensional factor structure, with four first-order factors and a second-order factor, plus an independent factor that evaluates school identification. However, the SCASIM-St is long, with 38 items measuring school climate. The first objective of this study was to examine the psychometric properties of reliability and validity of the abbreviated version of the dual school climate and school identification measure-student (SCASIM-St-15), for use in contexts with time limitations or for explanatory studies that need to apply multiple instruments simultaneously. The second objective was to analyze the degree of invariance for the groups: sex, type of education, and age. The sample was made up of 2,044 students of both sexes (49.1% women and 50.9% men), with a mean age of 14.64 (SD = 0.718), representing 27 secondary schools in Chile. The results indicated that the SCASIM-St15 presents adequate indicators of reliability and construct validity. Evidence of external criterion validity confirmed significant associations with the Attitudes to Institutional Authority in Adolescence Scale measure. The results of the factorial invariance analysis indicate that the SCASIM-St15 remains stable up to the level of metric invariance for the variable sex and the level of scalar invariance for the variables type of education and age. The study concluded that despite the significant decrease in the number of items, the SCASIM-St15 measures school climate in a reliable and valid way, without losing its theoretical and conceptual robustness.


Palladium-catalyzed intermolecular transthioetherification of aryl halides with thioethers and thioesters.
Functional group transfer reactions are an important synthetic tool in modern organic synthesis. Herein, we developed a new palladium-catalyzed intermolecular transthioetherification reaction of aryl halides with thioethers and thioesters. The synthetic utility and practicality of this catalytic protocol are demonstrated in a wide range of successful transformations (>70 examples). This catalytic protocol is applicable in carbonylative coupling processes as well, and the first example of carbonylative methylthioesterification of aryl halides has been achieved. Notably, this work also provides an approach to using natural products, such as methionine and selenomethionine, as the functional group sources.


Familial aggregation of Parkinson's disease in the Faroe Islands.
The Faroe Islands are a geographic population isolated in the North Atlantic with a high prevalence of Parkinson's disease (PD). Although environmental risk factors are well described, the familial aggregation of PD on the Islands has yet to be explored. Complete ascertainment of all patients with PD was performed, including 217 cases and 251 control subjects. All patients were neurologically assessed and diagnosed using UK Brain Bank criteria and Hohn and Yahr staging. Comprehensive genealogical and detailed cartographic analyses were performed. Relative risk and risk ratios were calculated with respect to the general population. Patients with PD in the Faroes have a higher age at symptom onset and diagnosis than for neighboring countries. Clinically, patients are similar; however, they are more likely to have affected relatives than randomly selected control subjects, matched by sex and age. Disease is most prevalent within two geographic regions. Overall, the relative risk for PD was 2.3 (95% confidence interval [CI], 1.2-4.3; P = 0.008) for siblings and 1.4 (95% CI, 1.01-1.99, P = 0.04) for first cousins. The etiology and excess prevalence of PD on the Faroes is complicated. Regional and familial clustering, and subsequent segregation analysis, suggests the disease best fits a genetic etiology with limited support for an environmental contribution. Pedigree-based analysis of PD on the Faroe Islands which has few founders and a relatively homogeneous background may elaborate on these possibilities and their joint contribution.


Why do larger mothers produce larger offspring? A test of classic theory.
Across a wide range of taxa, larger mothers produce larger offspring. Theory assumes that larger, more fecund mothers create higher local densities of siblings, and so larger mothers produce larger offspring to offset sibling competition. This assumption has been debated for over 30 yr, but direct empirical tests are surprisingly rare. Here, we test two key assumptions of classic theories that predict sibling competition drives maternal-size-offspring-size (MSOS) correlations: (1) independent effects of offspring size and sibling density on offspring performance or (2) as a product of an interaction between these two factors. To simultaneously test these alternative assumptions, we manipulate offspring size and sibling density in the marine invertebrate, Bugula neritina, and monitor offspring performance in the field. We found that, depending on the fitness metric being considered, offspring size and sibling density can either independently or interactively affect offspring performance. Yet sibling density did not affect offspring performance in the ways that classic theories assume. Given our results, it is unlikely that sibling competition drives the positive MSOS correlation observed in this species. Empirical support for these classic theories remains lacking, suggesting alternative explanations are necessary.


Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease.
Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.


Hydraulic fracturing volume is associated with induced earthquake productivity in the Duvernay play.
A sharp increase in the frequency of earthquakes near Fox Creek, Alberta, began in December 2013 in response to hydraulic fracturing. Using a hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We show that induced earthquakes are associated with completions that used larger injection volumes (104 to 105 cubic meters) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have an insignificant association with seismic response. Further findings suggest that geological factors play a prominent role in seismic productivity, as evidenced by spatial correlations. Together, volume and geological factors account for ~96% of the variability in the induced earthquake rate near Fox Creek. This result is quantified by a seismogenic index-modified frequency-magnitude distribution, providing a framework to forecast induced seismicity.


Australian graduating nurses' knowledge, intentions and beliefs on infection prevention and control: a cross-sectional study.
In recent year, national bodies have been actively addressing the increasing concern on the spread of healthcare-associated infections (HAIs). The current study measures the knowledge, intentions and beliefs of third-year Australian nursing students on key infection prevention and control (IPC) concepts. A cross-sectional study of final-year undergraduate nursing students from Schools of Nursing at six Australian universities was undertaken. Students were asked to participate in an anonymous survey. The survey explored knowledge of standard precautions and transmission based precautions. In addition intentions and beliefs towards IPC were explored. 349 students from six universities completed the study. 59.8% (95% CI 58.8-60.8%) of questions were answered correctly. Significantly more standard precaution questions were correctly answered than transmission-based precaution questions (p < 0.001). No association was found between self-reported compliance with IPC activities and gender or age. Certain infection control issues were correlated with the percentage of correctly answered transmission-based precaution questions. The participants were most likely to seek infection control information from an infection control professional. Knowledge on transmission-based precautions was substandard. As transmission-based precautions are the foundation of IPC for serious organisms and infections, education institutions should reflect on the content and style of educational delivery on this topic.


The Next Era: Deep Learning in Pharmaceutical Research.
Over the past decade we have witnessed the increasing sophistication of machine learning algorithms applied in daily use from internet searches, voice recognition, social network software to machine vision software in cameras, phones, robots and self-driving cars. Pharmaceutical research has also seen its fair share of machine learning developments. For example, applying such methods to mine the growing datasets that are created in drug discovery not only enables us to learn from the past but to predict a molecule's properties and behavior in future. The latest machine learning algorithm garnering significant attention is deep learning, which is an artificial neural network with multiple hidden layers. Publications over the last 3 years suggest that this algorithm may have advantages over previous machine learning methods and offer a slight but discernable edge in predictive performance. The time has come for a balanced review of this technique but also to apply machine learning methods such as deep learning across a wider array of endpoints relevant to pharmaceutical research for which the datasets are growing such as physicochemical property prediction, formulation prediction, absorption, distribution, metabolism, excretion and toxicity (ADME/Tox), target prediction and skin permeation, etc. We also show that there are many potential applications of deep learning beyond cheminformatics. It will be important to perform prospective testing (which has been carried out rarely to date) in order to convince skeptics that there will be benefits from investing in this technique.


Autonomic effects of refractory epilepsy on heart rate variability in children: influence of intermittent vagus nerve stimulation.
Vagus nerve stimulation (VNS) is a therapeutic option for individuals with refractory epilepsy. Individuals with refractory epilepsy are prone to dysfunction of the autonomic nervous system. Reduced heart rate variability is a marker of dysfunction of the autonomic nervous system. Our goal was to study heart rate variability in children with refractory epilepsy and the influence of VNS on this parameter. In 17 children (13 male; four female; mean age 7 y 6 mo; age range 3-16 y) with refractory epilepsy, electroencephalographic and electrocardiographic data were obtained before and after implantation of VNS during stage 2 and slow-wave sleep. Time and frequency domain parameters were calculated and the results were compared with an age- and sex-matched group of individuals without refractory epilepsy. Our results show that autonomic cardiac control is affected in individuals with refractory epilepsy. There is a striking reduction in vagal tone during slow-wave sleep and modulation capacity is smaller than in individuals without refractory epilepsy. Implantation of VNS induces a shift in sympathovagal balance towards sympathetic predominance and an improvement in autonomic modulation. Heart rate variability is affected in children with refractory epilepsy, and changes after implantation of VNS. The observed changes could be of importance in the cardiac complications of individuals with epilepsy and should be explored in more detail.


Soybean ureases, but not that of Bradyrhizobium japonicum, are involved in the process of soybean root nodulation.
Ureases are abundant in plants, bacteria, and in the soil, but their role in signaling between soybean and soil microorganisms has not been investigated. The bacterium Bradyrhizobium japonicum forms nitrogen-fixing nodules on soybean roots. Here, we evaluated the role(s) of ureases in the process of soybean nodulation. Chemotaxis assays demonstrated that soybean and jack bean ureases were more chemotactic toward bacterial cells than the corresponding plant lectins. The eu1-a,eu4 soybean, deficient in urease isoforms, formed fewer but larger nodules than the wild-type, regardless of the bacterial urease phenotype. Leghemoglobin production in wild-type plants was higher and peaked earlier than in urease-deficient plants. Inhibition of urease activity in wild-type plants did not result in the alterations seen in mutated plants. We conclude that soybean urease(s) play(s) a role in the soybean-B. japonicum symbiosis, which is independent of its ureolytic activity. Bacterial urease does not play a role in nodulation.


Effectiveness and cost-effectiveness of duloxetine added to usual care for patients with chronic pain due to hip or knee osteoarthritis: protocol of a pragmatic open-label cluster randomised trial (the DUO trial).
Osteoarthritis (OA) is a highly prevalent painful condition of the musculoskeletal system. The effectiveness of current analgesic options has proven to be limited and improved analgesic treatment is needed. Several randomised placebo-controlled trials have now demonstrated the efficacy of duloxetine, an antidepressant with a centrally acting effect, in the treatment of OA pain. The aim of the current study is to investigate if duloxetine is effective and cost-effective as a third-choice analgesic added to usual care for treating chronic pain compared with usual care alone in general practice. A pragmatic open, cluster randomised trial is conducted. Patients with pain due to hip or knee OA on most days of the past 3 months with insufficient benefit of non-steroidal anti-inflammatory drugs or contraindications or intolerable side effects are included. General practices are randomised to either (1) duloxetine and usual care or (2) usual care only. Primary outcome is pain at 3 months measured on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Secondary outcomes at 3 months and 1 year are pain (WOMAC, at 1 year), function (WOMAC), adverse reactions, quality of life and modification of the response to treatment by the presence of centrally sensitised pain (modified PainDETECT). At 1 year, medical and productivity costs will be assessed. Analyses will be performed following the intention-to-treat principle taking the cluster design into account. The study is approved by the local Medical Ethics Committee (2015-293). Results will be published in a scientific peer-reviewed journal and will be communicated at conferences. Dutch Trial Registry(ntr4798); Pre-results.


Dynamic buckling of an inextensible elastic ring: Linear and nonlinear analyses.
Slender elastic objects such as a column tend to buckle under loads. While static buckling is well understood as a bifurcation problem, the evolution of shapes during dynamic buckling is much harder to study. Elastic rings under normal pressure have emerged as a theoretical and experimental paradigm for the study of dynamic buckling with controlled loads. Experimentally, an elastic ring is placed within a soap film. When the film outside the ring is removed, surface tension pulls the ring inward, mimicking an external pressurization. Here we present a theoretical analysis of this process by performing a postbifurcation analysis of an elastic ring under pressure. This analysis allows us to understand how inertia, material properties, and loading affect the observed shape. In particular, we combine direct numerical solutions with a postbifurcation asymptotic analysis to show that inertia drives the system towards higher modes that cannot be selected in static buckling. Our theoretical results explain experimental observations that cannot be captured by a standard linear stability analysis.


Phase II trial of pegylated interferon-alpha 2b in patients with advanced renal cell carcinoma.
Pegylated interferon (IFN) has a longer serum half-life compared with standard IFN, and this allows for weekly dosing. In this study, the efficacy and toxicity of pegylated IFN was assessed in patients with metastatic renal cell carcinoma (mRCC). Thirty-two patients with previously untreated mRCC were treated with pegylated IFN-alpha 2b in a prospective, single-arm phase II trial. Pegylated IFN was given by subcutaneous administration on a weekly schedule at a dose of 4.5 microg/kg. Of the 32 assessable patients, 29 (91%) had a nephrectomy previously, and none had been treated previously with systemic therapy. Forty-one percent had good-risk, 53% had intermediate-risk, and 6% had poor-risk features per Memorial Sloan-Kettering Cancer Center risk criteria. The best response was a complete response (CR) in 1 patient (3%). Nine patients (28%) had a partial response. Fifteen patients (47%) had stable disease. The median progression-free survival (PFS) was 5 months (95% CI, 3-7 months), and median overall survival was 31 months (95% CI, 18 months to not reached). Five patients had a prolonged PFS of > or = 17 months, 1 of whom achieved a CR. There were no grade 4 toxicities; primary grade 3 toxicities were hematologic (11 of 32 patients; 34%) and fatigue (4 of 32 patients; 13%). Pegylated IFN administered weekly has antitumor activity in patients with mRCC with predominantly good- and intermediate-risk features. This study suggests comparable efficacy and safety compared with standard IFN-alpha.


Diffraction symmetry of binary Fourier elements with feature sizes on the order of the illumination wavelength and effects of fabrication errors.
When building spot array binary Fourier diffractive optical elements (DOEs) having feature sizes on the order of the wavelength, we noticed remarkable variations in the experimental diffraction efficiency compared to the simulation results. Even with the use of high-cost electron beam lithography and rigorous Fourier modal method simulations, there appear to be no publications, to the best of our knowledge, showing close agreement in diffraction efficiency between the simulation and experimental results. In this Letter, we show that the diffraction symmetry of binary Fourier DOEs can be an efficient and consistent metric for evaluating the limit of the thin-element approximation and the effects of fabrication errors.


Biological effects of hydrogen peroxide administered intratumorally with or without irradiation in murine tumors.
Despite insufficient laboratory data, radiotherapy after intratumoral injection of hydrogen peroxide (H2 O2 ) is increasingly being used clinically for radioresistant tumors. Especially, this treatment might become an alternative definitive treatment for early and advanced breast cancer in patients who refuse any type of surgery. The purpose of this study was to investigate the biological effects and appropriate combination methods of irradiation and H2 O2 in vivo. SCCVII tumor cells transplanted into the legs of C3H/HeN mice were used. Chronological changes of intratumoral distribution of oxygen bubbles after injection of H2 O2 were investigated using computed tomography. The effects of H2 O2 alone and in combination with single or five-fraction irradiation were investigated using a growth delay assay. The optimal timing of H2 O2 injection was investigated. Immunostaining of tumors was performed using the hypoxia marker pimonidazole. Oxygen bubbles decreased gradually and almost disappeared after 24 h. Administration of H2 O2 produced 2-3 days' tumor growth delay. Tumor regrowth was slowed further when H2 O2 was injected before irradiation. The group irradiated immediately after H2 O2 injection showed the longest tumor growth delay. Dose-modifying factors were 1.7-2.0 when combined with single irradiation and 1.3-1.5 with fractionated irradiation. Pimonidazole staining was weaker in tumors injected with H2 O2 . H2 O2 injection alone had modest antitumor effects. Greater tumor growth delays were demonstrated by combining irradiation and H2 O2 injection. The results of the present study could serve as a basis for evaluating results of various clinical studies on this treatment.


Pregnancy rates after in-vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies.
This meta-analysis was intended to evaluate differences in pregnancy rates after in-vitro fertilization (IVF) in tubal fertility with and without hydrosalpinx. It examined nine published retrospective comparative series and five series published as abstracts for which additional information was obtained. In all, these studies involved 5592 patients (1004 with hydrosalpinx and 4588 with tubal infertility without hydrosalpinx). The main outcome measures were rates of pregnancy, implantation, live delivery, and early pregnancy loss. Pregnancy rates were significantly lower in the presence of hydrosalpinx: 31.2% for the tubal sterility group without hydrosalpinx and 19.7% for the group with hydrosalpinx (odds ratio: 0.64; 95% confidence interval: 0.56, 0.74). Similarly, the implantation rate and the delivery rate per transfer in the hydrosalpinx group were only slightly more than half those of the non-hydrosalpinx group (implantation: 8.5 and 13.7%, respectively; delivery: 13.4 and 23.4%). The incidence of early pregnancy loss was also higher in the hydrosalpinx group (43.7%) than in the control group (31.1%). This meta-analysis makes it clear that hydrosalpinx present during IVF-embryo transfer has negative consequences on the rates of pregnancy, implantation, live delivery, and early pregnancy loss. It would be premature, nonetheless, to conclude that routine salpingectomy should be performed on all patients with hydrosalpinx.


Emotional eccrine sweating. A heritable disorder.
A family with hereditary emotional hyperhidrosis is described. The inheritance pattern is autosomal dominant. A simple quantitative palmar sweat test was used to objectively confirm historical data. Of two family members tested, both had a marked decrease in palmar sweat secretion during administration of diltiazem, a calcium-channel blocker. Additional studies in a large group of patients are needed to extend this observation.


Efficacy of Clonidine as an Adjuvant to Ropivacaine in Transversus Abdominis Plane Block in Adult Renal Transplant Recipients: A Double-blinded Randomized Controlled Trial.
Transversus abdominis plane (TAP) block has been used to provide analgesia in renal transplant surgery with varying results. This study was designed to assess if the addition of clonidine in TAP block would decrease 24-h postoperative morphine consumption in adult renal transplant recipients. Forty adult patients undergoing renal transplantation under general anesthesia in a tertiary care hospital were randomized into either group RC (TAP block with 20 mL of 0.5% ropivacaine plus 2 μg.kg-1 clonidine) or group R (TAP block with 20 mL 0.5% ropivacaine) after induction of anesthesia. Postoperative analgesia was provided using patient-controlled morphine. The primary outcome was 24-h patient-controlled morphine consumption. The secondary outcomes were a) intraoperative hemodynamics, b) fentanyl and ephedrine requirement, c) postoperative pain using the Visual Analog Scale at 0, 2, 6, 12 and 24 hours, d) time to first postoperative analgesia, e) postoperative hemodynamics, and f) side effects. There was no significant difference in postoperative morphine consumption between the groups (25 mg in group RC vs. 28.5 mg in group R) (median interquartile range) (P = 0.439). Postoperative pain scores were comparable between the groups. Intraoperatively, fewer patients required rescue fentanyl in group RC (7 patients) as compared to group R (17 patients) (P = 0.003). Significantly more patients in group RC required ephedrine boluses as compared to group R (9 patients in group RC vs. 2 in group R, P = 0.014). The addition of 2 μg.kg-1 clonidine to ropivacaine in TAP block did not reduce 24-h postoperative morphine consumption after renal transplantation. It reduced the need for intraoperative analgesics but increased the need for intraoperative ephedrine administration.


Nonthermal Electron Energization from Magnetic Reconnection in Laser-Driven Plasmas.
The possibility of studying nonthermal electron energization in laser-driven plasma experiments of magnetic reconnection is studied using two- and three-dimensional particle-in-cell simulations. It is demonstrated that nonthermal electrons with energies more than an order of magnitude larger than the initial thermal energy can be produced in plasma conditions currently accessible in the laboratory. Electrons are accelerated by the reconnection electric field, being injected at varied distances from the X points, and in some cases trapped in plasmoids, before escaping the finite-sized system. Trapped electrons can be further energized by the electric field arising from the motion of the plasmoid. This acceleration gives rise to a nonthermal electron component that resembles a power-law spectrum, containing up to ∼8% of the initial energy of the interacting electrons and ∼24% of the initial magnetic energy. Estimates of the maximum electron energy and of the plasma conditions required to observe suprathermal electron acceleration are provided, paving the way for a new platform for the experimental study of particle acceleration induced by reconnection.


Glutamatergic and nonglutamatergic neurons of the ventral tegmental area establish local synaptic contacts with dopaminergic and nondopaminergic neurons.
The ventral tegmental area (VTA) contributes to reward and motivation signaling. In addition to the well established populations of dopamine (DA) or GABA VTA neurons, glutamatergic neurons were recently discovered in the VTA. These glutamatergic neurons express the vesicular glutamate transporter 2, VGluT2. To investigate whether VTA glutamatergic neurons establish local synapses, we tagged axon terminals from resident VTA neurons by intra-VTA injection of Phaseolus vulgaris leucoagglutinin (PHA-L) or an adeno-associated virus encoding wheat germ agglutinin (WGA) and by immunoelectron microscopy determined the presence of VGluT2 in PHA-L- or WGA-positive terminals. We found that PHA-L- or WGA-positive terminals from tagged VTA cells made asymmetric or symmetric synapses within the VTA. VGluT2 immunoreactivity was detected in the vast majority of PHA-L- or WGA-positive terminals forming asymmetric synapses. These results indicate that both VTA glutamatergic and nonglutamatergic (likely GABAergic) neurons establish local synapses. To examine the possible DAergic nature of postsynaptic targets of VTA glutamatergic neurons, we did triple immunolabeling with antibodies against VGluT2, tyrosine hydroxylase (TH), and PHA-L. From triple-labeled tissue, we found that double-labeled PHA-L (+)/VGluT2 (+) axon terminals formed synaptic contacts on dendrites of both TH-positive and TH-negative cells. Consistent with these anatomical observations, in whole-cell slice recordings of VTA neurons we observed that blocking action potential activity significantly decreased the frequency of synaptic glutamatergic events in DAergic and non-DAergic neurons. These observations indicate that resident VTA glutamatergic neurons are likely to affect both DAergic and non-DAergic neurotransmission arising from the VTA.


RimNet: A deep 3D multimodal MRI architecture for paramagnetic rim lesion assessment in multiple sclerosis.
In multiple sclerosis (MS), the presence of a paramagnetic rim at the edge of non-gadolinium-enhancing lesions indicates perilesional chronic inflammation. Patients featuring a higher paramagnetic rim lesion burden tend to have more aggressive disease. The objective of this study was to develop and evaluate a convolutional neural network (CNN) architecture (RimNet) for automated detection of paramagnetic rim lesions in MS employing multiple magnetic resonance (MR) imaging contrasts. Imaging data were acquired at 3 Tesla on three different scanners from two different centers, totaling 124 MS patients, and studied retrospectively. Paramagnetic rim lesion detection was independently assessed by two expert raters on T2*-phase images, yielding 462 rim-positive (rim+) and 4857 rim-negative (rim-) lesions. RimNet was designed using 3D patches centered on candidate lesions in 3D-EPI phase and 3D FLAIR as input to two network branches. The interconnection of branches at both the first network blocks and the last fully connected layers favors the extraction of low and high-level multimodal features, respectively. RimNet's performance was quantitatively evaluated against experts' evaluation from both lesion-wise and patient-wise perspectives. For the latter, patients were categorized based on a clinically relevant threshold of 4 rim+ lesions per patient. The individual prediction capabilities of the images were also explored and compared (DeLong test) by testing a CNN trained with one image as input (unimodal). The unimodal exploration showed the superior performance of 3D-EPI phase and 3D-EPI magnitude images in the rim+/- classification task (AUC = 0.913 and 0.901), compared to the 3D FLAIR (AUC = 0.855, Ps < 0.0001). The proposed multimodal RimNet prototype clearly outperformed the best unimodal approach (AUC = 0.943, P < 0.0001). The sensitivity and specificity achieved by RimNet (70.6% and 94.9%, respectively) are comparable to those of experts at the lesion level. In the patient-wise analysis, RimNet performed with an accuracy of 89.5% and a Dice coefficient (or F1 score) of 83.5%. The proposed prototype showed promising performance, supporting the usage of RimNet for speeding up and standardizing the paramagnetic rim lesions analysis in MS.


Kynurenine pathway metabolic balance influences microglia activity: Targeting kynurenine monooxygenase to dampen neuroinflammation.
Chronic stress or inflammation increases tryptophan metabolism along the kynurenine pathway (KP), and the generation of neuroactive kynurenine metabolites contributes to subsequent depressive-like behaviors. Microglia regulate KP balance by preferentially producing oxidative metabolites, including quinolinic acid. Research has focused on the interplay between cytokines and HPA axis-derived corticosteroids in regulating microglial activity and effects of KP metabolites directly on neurons; however, the potential role that KP metabolites have directly on microglial activity is unknown. Here, murine microglia were stimulated with lipopolysaccharide(LPS). After 6 h, mRNA expression of interleukin(IL)-1β, IL-6, tumor necrosis factor(TNF)-α and inducible nitric oxide synthase(iNOS) was dose-dependently increased along with the rate-limiting enzymes for oxidative KP metabolism, indoleamine-2,3-dioxygenase(IDO)-1 and kynurenine 3-monooxygenase(KMO). By 24 h post-LPS, kynurenine and quinolinic acid in the media was elevated. Inhibiting KMO with Ro 61-8048 during LPS challenge attenuated extracellular nitrite accumulation and expression of KMO and TNF-α in response to LPS. Similarly, primary microglia isolated from KMO-/- mice exhibited a significantly reduced pro-inflammatory response to LPS compared to WT controls. To determine whether the substrate (kynurenine) or end product (quinolinic acid) of KMO-dependent metabolism modulates the LPS response, microglia were treated with increasing concentrations of L-kynurenine or quinolinic acid in combination with LPS or saline. Interestingly, quinolinic acid did not impact the microglial LPS response. However, L-kynurenine had dose-dependent inhibitory effect on the LPS response. These data are the first to show an anti-inflammatory effect of KMO inhibition on microglia during immune challenge and suggest that KP metabolic balance may play a direct role in regulating microglia activity.


Cold-Atmospheric Plasma Induces Tumor Cell Death in Preclinical In Vivo and In Vitro Models of Human Cholangiocarcinoma.
Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a rare and very aggressive cancer emerging from the biliary tree with few efficient treatments. In the present study, we aimed at deciphering the molecular mechanisms underlying the antitumor effects of CAP towards CCA in both an in vivo and in vitro context. In vivo, using subcutaneous xenografts into immunocompromised mice, CAP treatment of CCA induced DNA lesions and tumor cell apoptosis, as evaluated by 8-oxoguanine and cleaved caspase-3 immunohistochemistry, respectively. The analysis of the tumor microenvironment showed changes in markers related to macrophage polarization. In vitro, the incubation of CCA cells with CAP-treated culture media (i.e., plasma-activated media, PAM) led to a dose response decrease in cell survival. At molecular level, CAP treatment induced double-strand DNA breaks, followed by an increased phosphorylation and activation of the cell cycle master regulators CHK1 and p53, leading to cell cycle arrest and cell death by apoptosis. In conclusion, CAP is a novel therapeutic option to consider for CCA in the future.


Transforming Growth Factor Beta Receptor 3 (TGFBR3)-Associated Membranous Nephropathy.
Membranous lupus nephritis (MLN) comprises 10%-15% of lupus nephritis and increases morbidity and mortality of patients with SLE through complications of nephrotic syndrome and chronic kidney failure. Identification of the target antigens in MLN may enable noninvasive monitoring of disease activity, inform treatment decisions, and aid in prognostication, as is now possible for idiopathic MN caused by antibodies against the phospholipase A2 receptor. Here, we show evidence for type III TGF-β receptor (TGFBR3) as a novel biomarker expressed in a subset of patients with MLN. Mass spectrometry was used for protein discovery through enrichment of glomerular proteins by laser capture microdissection and through elution of immune complexes within MLN biopsy specimens. Colocalization with IgG within glomerular immune deposits from patients and disease controls was evaluated by confocal microscopy. Immunostaining of consecutive case series was used to determine the overall frequency in MN and MLN. TGFBR3 was found to be enriched in glomeruli and coimmunoprecipitated with IgG within a subset of MLN biopsy specimens by mass spectrometry. Staining of consecutive MN cases without clinical evidence of SLE did not show TGFBR3 expression (zero of 104), but showed a 6% prevalence in MLN (11 of 199 cases). TGFBR3 colocalized with IgG along the glomerular basement membranes in TGFBR3-associated MN, but not in controls. Positive staining for TGFBR3 within glomerular immune deposits represents a distinct form of MN, substantially enriched in MLN. A diagnosis of TGFBR3-associated MN can alert the clinician to search for an underlying autoimmune disease.


Immune Profiling of Polysaccharide Submicron Vesicles.
Alginate (ALG) and chitosan (CS) have been extensively used for biomedical applications; however, data relative to immune responses exerted by them are scarce. We synthesized a submicron vesicle system (SV) displaying a CS shell over an ALG core. Intravenous injection of these promising carriers could be a possible route of delivery; therefore, we evaluated their impact on human peripheral blood mononuclear cells (PBMCs). By this ex vivo approach, we established how SV chemical-physical characteristics affected the immune cells in terms of cellular uptake, viability, and state of activation. By flow cytometry, we demonstrated that SVs were internalized by PBMCs with differential trends. No substantial necrotic and apoptotic signals were recorded, and SVs weakly affected activation status of PBMCs (concerning the markers CD69, CD25, CD80, and the cytokines TNF-α and IL-6), showing high immune biocompatibility and low immunomodulating properties. Our findings gain particular value toward the biomedical applications of SVs and make these polymer-based structures more attractive for translation into clinical uses.


[Expression of tenascin, laminin and fibronectin following traumatic rupture of the anterior cruciate ligament].
In the present study, the pattern of some extracellular matrix glycoproteins was determined in traumatic anterior cruciate ligament ruptures (n = 17) and in normal ligaments (n = 11). 6 microns cryo-sections were incubated with monoclonal antibodies recognizing tenascin, laminin, and fibronectin, and FITC-labeled secondary antibodies. Immunohistochemistry revealed that tenascin, fibronectin and laminin are sparsely distributed in normal anterior cruciate ligaments, but strongly expressed in ruptured ligaments with a time-restricted pattern. The de novo-expression of tenascin appeared before laminin but later than fibronectin. The data suggest that fibronectin and tenascin are important, partially antagonistic components during healing processes after anterior cruciate ligament ruptures.


Improved prediction of response to antiretroviral combination therapy using the genetic barrier to drug resistance.
The outcome of antiretroviral combination therapy depends on many factors involving host, virus, and drugs. We investigate prediction of treatment response from the applied drug combination and the genetic constellation of the virus population at baseline. The virus's evolutionary potential for escaping from drug pressure is explored as an additional predictor. We compare different encodings of the viral genotype and antiretroviral regimen including phenotypic and evolutionary information, namely predicted phenotypic drug resistance, activity of the regimen estimated from sequence space search, the genetic barrier to drug resistance, and the genetic progression score. These features were evaluated in the context of different statistical learning procedures applied to the binary classification task of predicting virological response. Classifier performance was evaluated using cross-validation and receiver operating characteristic curves on 6,337 observed treatment change episodes from the Stanford HIV Drug Resistance Database and a large US clinic-based patient population. We find that the choice of appropriate features affects predictive performance more profoundly than the choice of the statistical learning method. Application of the genetic barrier to drug resistance, which combines phenotypic and evolutionary information, outperformed the genetic progression score, which uses exclusively evolutionary knowledge. The benefit of phenotypic information in predicting virological response was confirmed by using predicted fold changes in drug susceptibility. Moreover, genetic barrier and predicted phenotypic drug resistance were found to be the best encodings across all datasets and statistical learning methods examined. THEO (THErapy Optimizer), a prototypical implementation of the best performing approach, is freely available for research purposes at http://www.geno2pheno.org.


Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations.
The aims of this study were to develop a population pharmacokinetic model of vancomycin in adult patients, to use this model to develop dosage guidelines targeting vancomycin trough concentrations of 10-15 mg/L and to evaluate the performance of these new guidelines. All data analyses were performed using NONMEM. A population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected during routine therapeutic drug monitoring in 398 patients, then new vancomycin dosage guidelines were devised by using the model to predict vancomycin trough concentrations in a simulated dataset. Individual estimates of CL and V1 were then obtained in an independent group of 100 patients using the population model and the POSTHOC option. These individual estimates were used to predict vancomycin trough concentrations and steady-state AUC(24)/MIC ratios using the current and new dosage guidelines. The population analysis found that the vancomycin data were best described using a bi-exponential elimination model with a typical CL of 3.0 L/h that changed by 15.4% for every 10 mL/min difference from a CL(CR) of 66 mL/min. V(ss) was 1.4 L/kg. The proposed dosage guidelines were predicted to achieve 55% of vancomycin troughs within 10-15 mg/L and 71% within 10-20 mg/L, which is significantly higher than current guidelines (19% and 22%, respectively). The proportion of AUC(24)/MIC ratios above 400 was also higher, 87% compared with 58%. New vancomycin dosage guidelines have been developed that achieve trough concentrations of 10-15 mg/L earlier and more consistently than current guidelines.


Products for clotting factor replacement in developing countries.
Developing countries provide clotting factor replacement for hemophilia patients using one or more of the following strategies. (1) Production of domestic plasma and cryoprecipitate provides some self-sufficiency but depends heavily on the presence of an excellent blood transfusion service. The risk of transmitting donor infections is not completely obviated even with good serologic testing. (2) Domestic plasma fractionation has been achieved in a handful of emerging countries but can be expensive. Patients may distrust businessmen of their own country and may be dissatisfied with the style of product available from domestic plants. (3) Contract fractionation has been successful when the donor country is able to provide adequate amounts of well-tested plasma. Its cost is not always lower than that of imported concentrate but a degree of national self-sufficiency is retained. (4) Importation of concentrate allows a wide choice of products. The selection should focus not only on price but also on product safety, which depends upon well-validated donor testing and viral inactivation. High levels of purification are not of great importance. Successful national hemophilia programs also address organization of care, sensible dosing, and equitable distribution of resources to gain the maximum benefit from scarce resources.


FIFA Sudden Death Registry (FIFA-SDR): a prospective, observational study of sudden death in worldwide football from 2014 to 2018.
To investigate the underlying causes and regional patterns of sudden death in football (soccer) players worldwide to inform and improve existing screening and prevention measures. From 2014 to 2018 cases of sudden cardiac death (SCD), survived sudden cardiac arrest (SCA) and traumatic sudden death were recorded by media monitoring (Meltwater), a confidential web-based data platform and data synchronisation with existing national Sudden Death Registries (n=16). Inclusion criteria were met when sudden death occurred during football-specific activity or up to 1 hour afterwards. Death during other activities was excluded. A total of 617 players (mean age 34±16 years, 96% men) with sudden death were reported from 67 countries; 142 players (23%) survived. A diagnosis by autopsy or definite medical reports was established in 211 cases (34%). The leading cause in players >35 years was coronary artery disease (76%) and in players ≤35 years was sudden unexplained death (SUD, 22%). In players ≤35 years the leading cause of SCD varied by region: cardiomyopathy in South America (42%), coronary artery anomaly in North America (33%) and SUD in Europe (26%). Traumatic sudden death including commotio cordis occurred infrequently (6%). Cardiopulmonary resuscitation (CPR) resulted in a survival rate of 85% with the use of an automated external defibrillator (AED) compared with 35% without. Regional variation in SCD aetiology should be verified by expansion of national registries and uniform autopsy protocols. Immediate access to an AED at training and competition sites, as well as CPR training for players, coaches and staff members, is needed to improve survival from SCA.


Prevalence, distribution, and clinical characteristics of hemangiosarcoma-associated skeletal muscle metastases in 61 dogs: A whole body computed tomographic study.
Skeletal muscle metastases (SMMs) have been described sporadically in canine oncology. To determine the prevalence, localization, and clinical signs of SMMs associated with hemangiosarcoma (HSA) in a population of dogs presented for whole body computed tomography (CT). Dogs with a histologically confirmed HSA and a tissue core specimen or fine needle aspirate of suspected metastatic lesions were included in the study. Retrospective study. Dogs with a final diagnosis of visceral or muscular HSA that underwent whole body CT scan were enrolled in the study. Final diagnosis of primary tumor and SMMs was reached by histology, cytology, or both. Signalment, clinical signs, localization of the primary lesion, and metastases characteristics were reviewed. Sixty-one dogs met the inclusion criteria. Skeletal muscle metastases were detected in 15 dogs (24.6%) and all of these dogs had also metastases in ≥1 sites. Presence of SMMs was significantly higher in males but was not significantly related to age, neuter status, breed, localization, and dimensions of the primary tumor. Nine of 15 (60.0%) dogs with SMMs showed lameness or reluctance to move whereas these signs were not recorded in any of the 42 dogs without SMMs (P < .001). Prevalence of SMMs in our population of dogs with HSA was higher in comparison to previous studies in the human and veterinary medical literature. Whole body CT is recommended for staging of dogs with HSA, because SMMs could be missed by clinical examination and traditional diagnostic imaging modalities.


The deliberation-without-attention effect: evidence for an artifactual interpretation.
Proponents of unconscious-thought theory assert that letting the unconscious "mull it over" can enhance decisions. In a series of recent studies, researchers demonstrated that participants whose attention was focused on solving a complex problem (i.e., those using conscious thought) made poorer choices, decisions, and judgments than participants whose attention was distracted from the problem (i.e., those purportedly using unconscious thought). We argue that this finding, rather than establishing the existence of a deliberation-without-attention effect, is explained more compellingly in terms of the well-established distinction between on-line and memory-based judgments. In Experiment 1, we reversed the recent finding by simply changing participants' on-line processing goal from impression formation to memorization. Experiment 2 provided a replication and further established that some cognitive effort appears necessary to produce both the original pattern of results and its reversal, suggesting that such judgments are ultimately a product of conscious, rather than unconscious, thinking.


Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.
Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = β = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.


Effects of SQ 20881 and captopril on mesenteric, renal, and iliac vasculatures.
The ability of two kininase II inhibitors, SQ 20881 and captopril, to inhibit conversion of angiotensin I to angiotensin II and to potentiate the vascular responsiveness to exogenous bradykinin were compared in the mesenteric, renal, and external iliac vasculatures of the dog. Basal rate of angiotensin I-to-angiotensin II conversion was found to be lower in the renal vasculature, average conversion being 4.7%, than in the mesenteric and iliac vasculatures, in which the average conversion was 30.7 and 26.3%, respectively. Inhibition of angiotensin I conversion by both kininase II inhibitors was independent of the basal angiotensin I conversion rate; however, SQ 20881 was a more potent inhibitor of angiotensin I conversion than captopril in all vascular beds tested. In the presence of equal molar doses of SQ 20881 and captopril, only 20-30% of the control bradykinin doses was needed to produce the same vascular effects in the mesenteric and iliac vasculatures. In the kidney, 70% of the control bradykinin doses was needed to produce the same vascular effects in the presence of SQ 20881; in contrast to SQ 20881, neither an equimolar nor 20 times an equimolar dose of captopril produced any change in the renal vascular responsiveness to bradykinin. In conclusion, 1) SQ 20881 is a more potent inhibitor of angiotensin conversion than captopril, and 2) captopril, unlike SQ 20881, does not alter renal vascular responsiveness to bradykinin.


Brain MR perfusion image segmentation using independent component analysis and hierarchical clustering.
Extraction of various perfusion components from dynamic-susceptibility-contrast (DSC) MR brain images is critical for the analysis of brain perfusion. According to the variation of temporal signal on different brain tissues, one can segment whole brain area into distinct blood supply patterns which are vital for the profound analysis of cerebral hemodynamics. In this study, independent component analysis (ICA) is used to project the perfusion image data into independent components from which each elucidated tissue cluster can be automatically segment out by using the hierarchical clustering (HC). Five normal subjects and a case of internal carotid artery stenosis subjects were analyzed. The results demonstrated that ICA-HC is effective in multi-tissue hemodynamic classification which improves differentiation of pathological and physiological hemodynamics.


A network-based approach reveals the dysregulated transcriptional regulation in non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. We performed network analysis to investigate the dysregulated biological processes in the disease progression and revealed the molecular mechanism underlying NAFLD. Based on network analysis, we identified a highly conserved disease-associated gene module across three different NAFLD cohorts and highlighted the predominant role of key transcriptional regulators associated with lipid and cholesterol metabolism. In addition, we revealed the detailed metabolic differences between heterogeneous NAFLD patients through integrative systems analysis of transcriptomic data and liver-specific genome-scale metabolic model. Furthermore, we identified transcription factors (TFs), including SREBF2, HNF4A, SREBF1, YY1, and KLF13, showing regulation of hepatic expression of genes in the NAFLD-associated modules and validated the TFs using data generated from a mouse NAFLD model. In conclusion, our integrative analysis facilitates the understanding of the regulatory mechanism of these perturbed TFs and their associated biological processes.


Sex-Dependent Expression and Fitness Consequences of Sunlight-Derived Color Phenotypes.
To understand whether early phenotypes are adaptive, knowledge of the environmental factors involved in their variation and the derived benefits from their expression is needed. Temperature and sunlight are considered two major selective forces influencing phenotypic coloration of birds at a global scale. However, within-population color adaptations in response to sunlight temperature variation have been scarcely investigated, and their acclimatization capacity is currently unknown. In addition, the sexes differ in their sensitivity to environmental factors during growth. This study evaluates how melanin plumage coloration varies in relation to sex and sunlight exposure in developing griffon vultures Gyps fulvus and how this correlates with survival. The results show that individuals grown in nests more exposed to sunlight developed paler plumages, as predicted by the thermal melanism hypothesis. In addition, paler males-but not females-have lower survival probability. Finally, a significant sexual dichromatism in fledgling plumage was observed, with females being paler than males. These results reveal within-population color variation related to sunlight temperature conditions, probably as a capacity for local acclimatization through color plasticity, and also provide evidence of sex differences in fitness optima for this trait under ecological pressures.


Metronomic palliative chemotherapy in locally advanced, recurrent and metastatic head-and-neck cancer: A single-arm, retrospective study of a regional cancer center of North India (Asia).
Head-and-neck cancer is the most common cancer in developing countries of Southeast Asia. Most of the patients present to the hospital in advanced stage and have a poor prognosis. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of methotrexate and celecoxib in locally advanced, recurrent and metastatic head-and-neck cancers. This was a single-arm retrospective observational study that included posttreatment patients with locally advanced, recurrent and metastatic disease in the year 2016 (January 1, to December 31, 2016). A total of 84 patients warranting palliative chemotherapy but not willing to take intravenous chemotherapy were included in the study. The oral MCT schedule consisted of oral celecoxib (200 mg twice daily) and oral methotrexate (15 mg/m2/week). Response evaluation was done using the Response Evaluation Criteria in Solid Tumors criteria version 1.1, and toxicity profile was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Descriptive statistics and Kaplan-Meier analysis were performed. Eighty-four patients, 68 males and 16 females, with a median age of 62 years (range: 35-80 years), were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group performance status was 0-1 in 62 patients and 2-3 in 22 patients. The primary sites of disease were buccal mucosa (18), tongue (22), tonsil (24), lower alveolus (7), hypopharynx (10), and soft palate (3). The best clinical response rate in post oral MCT was seen in the first 4 months (120 days). Objective response was observed in 67% of patients in the form of stable disease (56%) and partial response (11%). Disease progression was observed in 27% of patients. The median follow-up was 192 (6.4 months) days. The median estimated overall survival was 195 (6.5 months) days. The median estimated progression-free survival was 110 (3.6 months) days. Symptomatic relief with respect to pain was reported in about 75% of patients. Eighteen (21%) patients had Grade I-II mucosal reactions. Grade III-IV mucosal reactions were observed in five (6%) patients. Seventy-eight (93%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (18%) patients. Oral MCT using celecoxib and methotrexate is an effective, economical, and well-tolerated regimen with good pain control and low toxicity profile in patients with locally advanced, recurrent and metastatic head-and-neck cancer.


Molecular cloning and characterization of the cys-3 regulatory gene of Neurospora crassa.
The regulatory gene cys-3+ controls the synthesis of a number of enzymes involved in sulfur metabolism. cys-3 mutants show a multiple loss of enzymes in different pathways of sulfur metabolism. The cys-3+ gene was isolated by transformation of an aro-9 qa-2 cys-3 inl strain with a clone bank followed by screening with the "sib selection" method. The library used (pRAL1) contained inserts of Sau3a partial digest fragments of about 9 kilobases as well as the Neurospora qa-2+ gene. Double selection for qa-2+ and cys-3+ function was carried out. The transformants obtained with the isolated cys-3+ clone show recovery of the enzyme activities associated with the cys-3 mutation (e.g., arylsulfatase and sulfate permease). Restriction fragment length polymorphism experiments confirmed the identity of the clone, mRNA studies with Northern blots show that the expression of the cys-3+ gene is inducible. In contrast to cys-3+, the cys-3 (P22) mutant gene was not expressed at a higher level under sulfur-derepressed conditions.


eDNA Inactivation and Biofilm Inhibition by the PolymericBiocide Polyhexamethylene Guanidine Hydrochloride (PHMG-Cl).
The choice of effective biocides used for routine hospital practice should consider the role of disinfectants in the maintenance and development of local resistome and how they might affect antibiotic resistance gene transfer within the hospital microbial population. Currently, there is little understanding of how different biocides contribute to eDNA release that may contribute to gene transfer and subsequent environmental retention. Here, we investigated how different biocides affect the release of eDNA from mature biofilms of two opportunistic model strains Pseudomonas aeruginosa ATCC 27853 (PA) and Staphylococcus aureus ATCC 25923 (SA) and contribute to the hospital resistome in the form of surface and water contaminants and dust particles. The effect of four groups of biocides, alcohols, hydrogen peroxide, quaternary ammonium compounds, and the polymeric biocide polyhexamethylene guanidine hydrochloride (PHMG-Cl), was evaluated using PA and SA biofilms. Most biocides, except for PHMG-Cl and 70% ethanol, caused substantial eDNA release, and PHMG-Cl was found to block biofilm development when used at concentrations of 0.5% and 0.1%. This might be associated with the formation of DNA-PHMG-Cl complexes as PHMG-Cl is predicted to bind to AT base pairs by molecular docking assays. PHMG-Cl was found to bind high-molecular DNA and plasmid DNA and continued to inactivate DNA on surfaces even after 4 weeks. PHMG-Cl also effectively inactivated biofilm-associated antibiotic resistance gene eDNA released by a pan-drug-resistant Klebsiella strain, which demonstrates the potential of a polymeric biocide as a new surface-active agent to combat the spread of antibiotic resistance in hospital settings.


The selection of aptamers specific for membrane molecular targets.
A growing number of RNA aptamers have been selected experimentally using the SELEX combinatorial approach, and these aptamers have several advantages over monoclonal protein antibodies or peptides with respect to their applications in medicine and nanobiotechnology. Relatively few successful selections have been reported for membrane molecular targets, in contrast to the situation with non-membrane molecular targets. This review compares the procedures and techniques used in selections against membrane proteins and membrane lipids. In the case of membrane proteins, the selections were performed against soluble protein fragments, detergent-membrane protein mixed micelles, whole cells, vesicles derived from cellular membranes, and enveloped viruses. Liposomes were used as an experimental system for the selection of aptamers against membrane lipids. RNA structure-dependent aptamer binding for rafts in lipid vesicles was reported. Based on the selected aptamers against DOPC and the amino acid tryptophan, a specific passive membrane transporter composed of RNA was constructed. The determination of the selectivity of aptamers appears to be a crucial step in a selection, but has rarely been fully investigated. The selections, which use whole cells or vesicles derived from membranes, can yield aptamers not only against proteins but also against membrane lipids.


The Effect of Peer Instruction Lectures on Learning Attitudes in Epidemiology Education.
Research suggests that the fundamental concepts of epidemiology cannot be sufficiently learned in traditional lectures, and interactive learning is necessary. However, few studies have investigated interactive epidemiology education in general, or peer instruction (PI) in particular. This study investigated the effect of PI. Study par-ticipants were fourth-year medical students. The attitude of participants in regard to PI learning was examined in a non-PI and a PI group. The Survey of Attitudes Toward Statistics (SATS) (containing six sub-categories) was conducted as a learning-attitudes index. The pre- and post-lecture scores were compared between the non-PI and PI groups using double robust (DR) estimation. The non-PI and PI groups consisted of 20 and 121 student participants, respectively. In DR estimation, affect exhibited the lowest SATS score changes, at -0.51 (95% confidence interval -0.78 to -0.24; p-value < 0.001), whereas effort exhibited the highest score changes of 0.01 (95% confidence interval -0.30 to 0.32; p-value = 0.952). The epidemiology lecture with PI did not increase the SATS scores. This might be due to issues related to the experimental design. Further research investigating the effects of interactive epidemiology education, it will be necessary to develop tools for assessing the learning of epidemiological concepts and to improve the research design.


Catalytic synthesis of enantiopure mixed diacylglycerols – synthesis of a major M. tuberculosis phospholipid and platelet activating factor.
An efficient catalytic one-pot synthesis of TBDMS-protected diacylglycerols has been developed, starting from enantiopure glycidol. Subsequent migration-free deprotection leads to stereo- and regiochemically pure diacylglycerols. This novel strategy has been applied to the synthesis of a major Mycobacterium tuberculosis phospholipid, its desmethyl analogue, and platelet activating factor.


SENSITIVE TO FREEZING2 Aides in Resilience to Salt and Drought in Freezing-Sensitive Tomato.
SENSITIVE TO FREEZING2 (SFR2) is crucial for protecting chloroplast membranes following freezing in Arabidopsis (Arabidopsis thaliana). It has been shown that SFR2 homologs are present in all land plants, including freezing-sensitive species, raising the question of SFR2 function beyond freezing tolerance. Similar to freezing, salt and drought can cause dehydration. Thus, it is hypothesized that in freezing-sensitive plants SFR2 may play roles in their resilience to salt or drought. To test this hypothesis, SlSFR2 RNAi lines were generated in the cold/freezing-sensitive species tomato (Solanum lycopersicum [M82 cv]). Hypersensitivity to salt and drought of SlSFR2-RNAi lines was observed. Higher tolerance of wild-type tomatoes was correlated with the production of trigalactosyldiacylglycerol, a product of SFR2 activity. Tomato SFR2 in vitro activity is Mg2+-dependent and its optimal pH is 7.5, similar to that of Arabidopsis SFR2, but the specific activity of tomato SFR2 in vitro is almost double that of Arabidopsis SFR2. When salt and drought stress were applied to Arabidopsis, no conditions could be identified at which SFR2 was induced prior to irreversibly impacting plant growth, suggesting that SFR2 protects Arabidopsis primarily against freezing. Discovery of tomato SFR2 function in drought and salt resilience provides further insights into general membrane lipid remodeling-based stress tolerance mechanisms and together with protection against freezing in freezing-resistant plants such as Arabidopsis, it adds lipid remodeling as a possible target for the engineering of abiotic stress-resilient crops.


Lycopene inhibits LPS-induced proinflammatory mediator inducible nitric oxide synthase in mouse macrophage cells.
Lycopene is a fat-soluble red-orange carotenoid found primarily in tomatoes and tomato-derived products, including tomato sauce, tomato paste, and ketchup, and other dietary sources, including dried apricots, guava, watermelon, papaya, and pink grapefruit. In this study, we have demonstrated the molecular mechanism underlying the anti-inflammatory properties of lycopene using a mouse macrophage cell line (RAW 264.7). Treatment with lycopene (10 microM) inhibited lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production (40% compared with the control). Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that lycopene treatment decreased LPS-induced inducible nitric oxide synthase (iNOS) protein and mRNA expression in RAW 264.7 cells, respectively. These results suggest that lycopene has anti-inflammatory activity by inhibiting iNOS proteins and mRNA expressions in mouse macrophage cell lines. Furthermore, cyclooxygenase-2 (COX-2) protein and mRNA expression were not affected by treatment with lycopene.


Esthetic implant restorations.
The success achieved with osseointegrated implants in the treatment of edentulous patients created a demand for their use in partially edentulous patients as well. New challenges confronted restorative clinicians with this group of patients, particularly esthetic challenges. New components and techniques had to be developed to improve the esthetic results. The "UCLA" abutment allows the restoration to connect directly to the implant fixture, emerging through the mucosa with a natural appearance. Esthetic titanium abutments can now also be used for a subgingival restorative design that creates a natural and gradual emergence profile similar to the UCLA abutment while maintaining more of the time-tested biomechanical principles of the older cylindrical titanium abutments.


Human plasma alpha 2-macroglobulin and von Willebrand factor possess covalently linked ABO(H) blood group antigens in subjects with corresponding ABO phenotype.
We recently identified ABO(H) blood group structures in Asn-linked sugar chains of human von Willebrand factor (vWF) purified from factor VIII concentrates (J Biol Chem 267:8723, 1992). We surveyed plasma glycoproteins carrying ABO(H) blood group antigens by Western blotting analysis and sandwich enzyme-linked immunosorbent assay using blood group-specific monoclonal antibodies (MoAbs) and a lectin. Two major plasma proteins showing apparent molecular weight of about 180 Kd and 270 Kd by sodium dodecyl sulfate polyacrylamide gel electrophoresis reacted with blood group-specific MoAbs and Ulex europaeus lectin I in accordance with donor blood group. Direct sequence analysis of the protein bands showed their identity with the N-terminal sequences of alpha 2-macroglobulin (alpha 2M) and vWF, respectively. The two bands also reacted with anti-alpha 2M and anti-vWF antibodies. The alpha 2M and vWF prepared from plasma by immunoprecipitation showed the appropriate blood group antigenicity. After incubation with endoglycosidase F, both alpha 2M and vWF lost almost all reactivity with anti-blood group reagents. About 90% of plasma vWF, but only approximately 10% of alpha 2M, was immunoprecipitated with anti-blood group antibody. These results indicate that at least two plasma glycoproteins, vWF and alpha 2M, possess Asn-linked ABO(H) blood group antigens in normal individuals with corresponding ABO phenotype. Therefore, ABO(H) blood group antigens in plasma glycoproteins should be considered during preparation of plasma materials for therapeutic use.


Limited contribution of mucosal IgA to Simian immunodeficiency virus (SIV)-specific neutralizing antibody response and virus envelope evolution in breast milk of SIV-infected, lactating rhesus monkeys.
Breast milk transmission of human immunodeficiency virus (HIV) remains an important mode of infant HIV acquisition. Interestingly, the majority of infants remain uninfected during prolonged virus exposure via breastfeeding, raising the possibility that immune components in milk prevent mucosal virus transmission. HIV-specific antibody responses are detectable in the milk of HIV-infected women and simian immunodeficiency virus (SIV)-infected monkeys; however, the role of these humoral responses in virus neutralization and local virus quasispecies evolution has not been characterized. In this study, four lactating rhesus monkeys were inoculated with SIVmac251 and monitored for SIV envelope-specific humoral responses and virus evolution in milk and plasma throughout infection. While the kinetics and breadth of the SIV-specific IgG and IgA responses in milk were similar to those in plasma, the magnitude of the milk responses was considerably lower than that of the plasma responses. Furthermore, a neutralizing antibody response against the inoculation virus was not detected in milk samples at 1 year after infection, despite a measurable autologous neutralizing antibody response in plasma samples obtained from three of four monkeys. Interestingly, while IgA is the predominant immunoglobulin in milk, the milk SIV envelope-specific IgA response was lower in magnitude and demonstrated more limited neutralizing capacity against a T-cell line-adapted SIV compared to those of the milk IgG response. Finally, amino acid mutations in the envelope gene product of SIV variants in milk and plasma samples occurred in similar numbers and at similar positions, indicating that the humoral immune pressure in milk does not drive distinct virus evolution in the breast milk compartment.


Molecular biomarker analyses using circulating tumor cells.
Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard. Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs. We report similar performance for the various platforms tested in capturing CTCs, and find that capture efficiency is dependent on the level of EpCAM expression. We demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, qRT-PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence (IF). We quantify cell surface expression of EGFR in metastatic lung cancer patient samples. In addition, we determined HER2 status by IF and FISH in CTCs from metastatic breast cancer patients. In the majority of patients (89%) we found concordance with HER2 status from patient tumor tissue, though in a subset of patients (11%), HER2 status in CTCs differed from that observed in the primary tumor. Surprisingly, we found CTC counts to be higher in ER+ patients in comparison to HER2+ and triple negative patients, which could be explained by low EpCAM expression and a more mesenchymal phenotype of tumors belonging to the basal-like molecular subtype of breast cancer. Our data suggests that molecular characterization from captured CTCs is possible and can potentially provide real-time information on biomarker status. In this regard, CTCs hold significant promise as a source of tumor material to facilitate clinical biomarker evaluation. However, limitations exist from a purely EpCAM based capture system and addition of antibodies to mesenchymal markers could further improve CTC capture efficiency to enable routine biomarker analysis from CTCs.


Profile of congenital rubella syndrome in Soetomo General Hospital Surabaya, Indonesia.
Definition of Congenital Ruben Syndrome (CRS): a disease caused by rubella virus infection. Routine surveillance of CRS is part of a government program in documenting the incidence of CRS so that infants with CRS are diagnosed promptly and receive appropriate care. This study aims to report the profile of CRS patients 2015 in Audiology Outpatient General Hospital Dr. Soetomo Surabaya. A descriptive study from CRS surveillance data for the period from January 1st until December 31rd, 2015. Data was from Infants who came to the Audiology Outpatient General Hospital Dr. Soetomo Surabaya and did hearing and serological examination. A total of 65 infants were involved in surveillance. The highest number of patients was the age group 1- <3 years (21 patients, 31.2%). A total of 36 patients (55.4%) were male, 45 babies (69.2%) were suspected of suffering from CRS with 2 infants (3.1%) classified as a laboratory-confirmed CRS. Hearing abnormalities were found in 36 infants (55.4%). Bilateral hearing loss was found in 23 infants (35.4%) and unilateral in 13 infants (20%). This study shows that hearing impairment is the most common clinical symptom with most bilateral hearing loss. The supervision still needs to be continued to capture more CRS cases in the community and effective supervision to detect hearing impairment early.


Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish.
Regulation of intestinal dietary fat absorption is critical to maintaining energy balance. While intestinal microbiota clearly impact the host's energy balance, their role in intestinal absorption and extraintestinal metabolism of dietary fat is less clear. Using in vivo imaging of fluorescent fatty acid (FA) analogs delivered to gnotobiotic zebrafish hosts, we reveal that microbiota stimulate FA uptake and lipid droplet (LD) formation in the intestinal epithelium and liver. Microbiota increase epithelial LD number in a diet-dependent manner. The presence of food led to the intestinal enrichment of bacteria from the phylum Firmicutes. Diet-enriched Firmicutes and their products were sufficient to increase epithelial LD number, whereas LD size was increased by other bacterial types. Thus, different members of the intestinal microbiota promote FA absorption via distinct mechanisms. Diet-induced alterations in microbiota composition might influence fat absorption, providing mechanistic insight into how microbiota-diet interactions regulate host energy balance.


Irreversible inactivation of beta-lactamase I from Bacillus cereus by chlorinated 6-spiroepoxypenicillins.
On incubation of the chlorinated 6-spiroepoxypenicillin anilides (I) and (II) [formula: see text] with beta-lactamase 1 from Bacillus cereus, three distinct processes are observed. The inhibitors act as (a) substrates, the turnover of which respectively results in a single product, namely 6-substituted 2(H)-3,4-dihydro-1,4-thiazine, (b) a transiently inhibited enzyme complex, and finally (c) an irreversibly inactivated enzyme complex. Although differing only in their stereochemistry at one centre, the anilide (K) is a more potent irreversible inactivator of beta-lactamase I than is compound (II). Analysis of irreversibly inactivated beta-lactamase I by isoelectric focusing and inspection of peptide fragmentation maps indicated that irreversible inactivation appears to be accompanied by covalent modification. These studies reveal that the chlorinated 6-spiroepoxypenicillin anilide (I) is a mechanism-based beta-lactamase inhibitor.


Dysautonomia in Parkinson disease.
Dysautonomias are conditions in which altered function of one or more components of the autonomic nervous system (ANS) adversely affects health. This review updates knowledge about dysautonomia in Parkinson disease (PD). Most PD patients have symptoms or signs of dysautonomia; occasionally, the abnormalities dominate the clinical picture. Components of the ANS include the sympathetic noradrenergic system (SNS), the parasympathetic nervous system (PNS), the sympathetic cholinergic system (SCS), the sympathetic adrenomedullary system (SAS), and the enteric nervous system (ENS). Dysfunction of each component system produces characteristic manifestations. In PD, it is cardiovascular dysautonomia that is best understood scientifically, mainly because of the variety of clinical laboratory tools available to assess functions of catecholamine systems. Most of this review focuses on this aspect of autonomic involvement in PD. PD features cardiac sympathetic denervation, which can precede the movement disorder. Loss of cardiac SNS innervation occurs independently of the loss of striatal dopaminergic innervation underlying the motor signs of PD and is associated with other nonmotor manifestations, including anosmia, REM behavior disorder, orthostatic hypotension (OH), and dementia. Autonomic dysfunction in PD is important not only in clinical management and in providing potential biomarkers but also for understanding disease mechanisms (e.g., autotoxicity exerted by catecholamine metabolites). Since Lewy bodies and Lewy neurites containing alpha-synuclein constitute neuropathologic hallmarks of the disease, and catecholamine depletion in the striatum and heart are characteristic neurochemical features, a key goal of future research is to understand better the link between alpha-synucleinopathy and loss of catecholamine neurons in PD.


Survey of blindness and visual impairment in Bioko, Equatorial Guinea.
This study was designed to estimate the prevalence of blindness and its main aetiologies in Bioko, an onchocerciasis endemic zone of Equatorial Guinea. Random sampling was applied, proportionally to population distribution into urban or rural areas. All the subjects underwent a basic eye examination by trained nurses. In the presence of any ocular affection or a visual acuity of less than 0.3, the subject was visited by the ophthalmologist. This visit included direct and indirect ophthalmoscopy, anterior segment examination with a slit lamp, and intraocular pressure recording. Blindness and visual impairment were defined by using the WHO criteria. 3218 subjects were screened, with a mean age of 34.1 (SD 21.6) years, ranging from 1 month to 102 years (median 34 years). The overall prevalence of blindness was 3.2% (95% CI: 2.6% to 3.9%). Unilateral blindness was present in 4.2%. Visual impairment was diagnosed in 200 patients (6.8%). More than 20% of the acuities inferior to 0.7 improved when explored with a pinhole. The main causes of blindness were cataracts (61.3%); macular affection (25.3%), optic atrophy (16%), and glaucoma (13.3%). Ocular onchocerciasis was detected in 12 cases (0.4%). Ocular onchocerciasis was very uncommon in an area of high endemicity. Results also pointed at the lack of basic ophthalmologist eye care and optician resources in the island.