Drug related critical incidents.
Drug related incidents are a common form of reported medical errors. This paper reviews the critical incidents related to drug errors reported from the main operating theatre suite in a teaching hospital in a developing country from January 1997 to December 2002. Each report was evaluated individually by two reviewers using a structured process. During this period, 44 874 anaesthetics were administered; 768 critical incidents were reported, 165 (21%) of which were related to drug errors. Underdosage, side-effect/drug reaction and syringe swap were the most common. A total of 76% were classified as preventable; 56% due to human error and 19% due to system error. High risk incidents accounted for 10% of all drug errors and most of these were related to the use of neuromuscular blocking drugs. This analysis has been found useful in addressing some issues about priorities.


Time management governs climate resilience and productivity in the coupled rice-wheat cropping systems of eastern India.
India will need to produce 30% more wheat by 2050, and these gains must principally come from intensification in eastern India where low productivity is common. Through a dense network of on-farm surveys for the rice-wheat system in this region, we show that contemporary wheat sowing dates have a central influence on achieved and attainable yields, superseding all other crop management, soil and varietal factors. We estimate that untapped wheat production potential will increase by 69% with achievable adjustments to wheat sowing dates without incurring undesirable trade-offs with rice productivity, irrigation requirements or profitability. Our findings also indicate that transformative gains in wheat yields are only possible in eastern India if rice and wheat are managed as a coupled system. Steps taken to 'keep time' through better management of the annual cropping calendar will pay dividends for food security, profitability and climate resilience now and as a foundation for adaptation to progressive climate change.


Motor unit composition has little effect on the short-range stiffness of feline medial gastrocnemius muscle.
Studies on skinned fibers and single motor units have indicated that slow-twitch fibers are stiffer than fast-twitch fibers. This suggests that skeletal muscles with different motor unit compositions may have different short-range stiffness (SRS) properties. Furthermore, the natural recruitment of slow before fast motor units may result in an SRS-force profile that is different from electrical stimulation. However, muscle architecture and the mechanical properties of surrounding tissues also contribute to the net SRS of a muscle, and it remains unclear how these structural features each contribute to the SRS of a muscle. In this study, the SRS-force characteristics of cat medial gastrocnemius muscle were measured during natural activation using the crossed-extension reflex, which activates slow before fast motor units, and during electrical activation, in which all motor units are activated synchronously. Short, rapid, isovelocity stretches were applied using a linear puller to measure SRS across the range of muscle forces. Data were collected from eight animals. Although there was a trend toward greater stiffness during natural activation, this trend was small and not statistically significant across the population of animals tested. A simple model, in which the slow-twitch fibers were assumed to be 30% stiffer than the fast-twitch fibers, was used to simulate the experimental results. Experimental and simulated results show that motor unit composition or firing rate has little effect on the SRS property of the cat MG muscle, suggesting that architectural features may be the primary determinant of SRS.


A molecular and chemical perspective in defining melatonin receptor subtype selectivity.
Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT1 and MT2 transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules. Both MT1 and MT2 receptors are widely expressed in the central nervous system as well as many peripheral tissues, but each receptor subtype can be linked to specific functional responses at the target tissue. Given the broad therapeutic implications of melatonin receptors in chronobiology, immunomodulation, endocrine regulation, reproductive functions and cancer development, drug discovery and development programs have been directed at identifying chemical molecules that bind to the two melatonin receptor subtypes. However, all of the melatoninergics in the market act on both subtypes of melatonin receptors without significant selectivity. To facilitate the design and development of novel therapeutic agents, it is necessary to understand the intrinsic differences between MT1 and MT2 that determine ligand binding, functional efficacy, and signaling specificity. This review summarizes our current knowledge in differentiating MT1 and MT2 receptors and their signaling capacities. The use of homology modeling in the mapping of the ligand-binding pocket will be described. Identification of conserved and distinct residues will be tremendously useful in the design of highly selective ligands.


PHYSICAL EDUCATION CLASSES AND HEALTH OUTCOMES IN BRAZILIAN STUDENTS.
To analyze the association between participation and physical activity during Physical Education classes with health outcomes in Brazilian students. 681 Brazilian students (50.5% female) aged 10 to 17 years participated in this cross-sectional study. Independent variables analyzed were participation and physical activity during Physical Education classes, both assessed using a self-report questionnaire. The outcomes were: cardiorespiratory fitness (20-meter Shuttle Run test), muscle strength (Push-up test), overweight and obesity (body mass index) and high blood pressure. Statistical analysis was conducted by Poisson regression to estimate the prevalence ratio (PR) and 95% confidence intervals (95%CI) adjusted for confounding variables (age, sex, parental education, physical activity and sedentary behavior), considering the complex sample design. Participation in Physical Education classes was not associated with any of the studied variables. Being active during Physical Education classes was associated with achieving health related criteria for cardiorespiratory fitness (PR=1.34, 95%CI 1.16-1.55) and muscle strength (PR=1.36, 95%CI 1.09-1.71). The same did not occur for overweight (PR=1.04, 95%CI 0.95-1.14), obesity (PR=1.02, 95%CI 0.91-1.05), or high blood pressure (PR=0.98, 95%CI 0.90-1.06). Students who reported being active during classes presented a higher likelihood to achieve the health criteria for cardiorespiratory fitness and muscle strength. However, classes traditionally offered in Brazil do not protect students from overweight, obesity, or high blood pressure.


Evaluation of Multiple Embolic Agents for Embolization of the Superior Rectal Artery in an Animal Model.
To prospectively compare the safety of transcatheter embolization of superior rectal arteries in healthy pigs with multiple agents such as coils, spheres and liquids. Nine adult domestic pigs (three males, mean weight: 60 kg [50-70]) were randomly assigned to the embolization group: copolymer of ethylene vinyl alcohol (EVOH)-Onyx® (group 1, n = 3), microspheres 500 µ (group 2, n = 3), 2-mm micro-coils (group 3, n = 3). After a selective angiogram has been acquired, the embolic agent was infused at the distal part of rectal arteries. An angio-CT was performed before and after each embolization. After one week, angiography was repeated prior to euthanasia. At necropsy, the anorectal juncture was removed for histopathologic examination. At necropsy, 100% of animals embolized with Onyx developed a significant necrosis zone of the distal part of the rectum. Histological examination revealed a mural infarction. For the micro-coil and microsphere groups, gross examination of the intestines did not reveal any evidence of ischaemia. The coils were found in the distal arterial vasculature of the meso-rectum, allowing a downstream revascularization by collaterals. The microspheres and onyx in the rectal wall, more distally. Microspheres appear to induce fewer histologic complications than the liquid embolic agent and provide a more distal occlusion than micro-coils. These results suggest that, for superior rectal artery embolization, a super-selective embolization using spheres in human clinical conditions should be more effective and as safe as coil embolization. EVOH might be an unsafe embolization agent for haemorrhoids.


Linear-time general decoding algorithm for the surface code.
A quantum error correcting protocol can be substantially improved by taking into account features of the physical noise process. We present an efficient decoder for the surface code which can account for general noise features, including coherences and correlations. We demonstrate that the decoder significantly outperforms the conventional matching algorithm on a variety of noise models, including non-Pauli noise and spatially correlated noise. The algorithm is based on an approximate calculation of the logical channel using a tensor-network description of the noisy state.


Tedizolid vs Linezolid for the Treatment of Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients.
Treatment options for nontuberculous mycobacteria (NTM) infections are limited by the pathogen's intrinsic resistance profile and toxicities. Tedizolid and linezolid display in vitro activity against NTM species. However, safety data and treatment outcomes are limited in the solid organ transplant (SOT) population. This was a single-center retrospective cohort study of adult SOT recipients receiving linezolid or tedizolid for an NTM infection from January 1, 2010, to August 31, 2019. The primary outcome compared the hematologic safety profiles of tedizolid vs linezolid. We also described nonhematological adverse drug events (ADEs) and therapy discontinuation rates. In an exploratory analysis, we assessed symptomatic microbiologic and clinical outcomes in those receiving tedizolid or linezolid for at least 4 weeks. Twenty-four patients were included (15 tedizolid, 9 linezolid). No differences were identified comparing the effects of tedizolid vs linezolid on platelet counts, absolute neutrophil counts (ANCs), and hemoglobin over 7 weeks using mixed-effects analysis of variance models. ANC was significantly decreased in both groups after 7 weeks of therapy (P = .04). Approximately 20% of patients in each arm discontinued therapy due to an ADE. Seven of 12 (58%) and 2 of 3 (67%) patients were cured or clinically cured with tedizolid- and linezolid-containing regimens, respectively. This study suggests no significant safety benefit of tedizolid over linezolid for the treatment of NTM infections in SOT recipients. Tedizolid or linezolid-containing regimens demonstrated a potential benefit in symptomatic and microbiologic improvement. Larger cohorts are needed to further delineate the comparative role of linezolid and tedizolid for the treatment of NTM infections in SOT recipients.


Insights into the oral health beliefs and practices of mothers from a north London Orthodox Jewish community.
The objective of this study was to explore oral health knowledge and beliefs and access to dental care in a culturally distinct Orthodox Jewish community in North London, with a view to informing local health policy. A dual method qualitative approach to data collection was adopted in this study utilising semi-structured face to face interviews and focus groups with women from this North London orthodox Jewish community. In total nine interviews and four focus groups were conducted with a purposive sample of thirty three mothers from the community aged 21-58 years. The data were transcribed and analysed using Framework Methodology Cultural influences, competing pressures and perceptions of hereditary influences, together with a lack of contemporary oral health knowledge are the main factors affecting oral health knowledge and beliefs. This supported an overall perspective of disempowerment or a perceived lack of control over oral health behaviours, both for mothers and their children. Community signposting pointed mothers to dental services, whilst family pressures together with inadequate capacity and capability and generic barriers such as fear and cost acted as barriers. Mothers from this community welcomed community development initiatives from the NHS. The results of this study provide insight into the challenges of a culturally isolated community who would welcome community support through schools and expanded culturally appropriate opening hours to improve access to dental care.


Emergence and diversification of fly pigmentation through evolution of a gene regulatory module.
The typical pattern of morphological evolution associated with the radiation of a group of related species is the emergence of a novel trait and its subsequent diversification. Yet the genetic mechanisms associated with these two evolutionary steps are poorly characterized. Here, we show that a spot of dark pigment on fly wings emerged from the assembly of a novel gene regulatory module in which a set of pigmentation genes evolved to respond to a common transcriptional regulator determining their spatial distribution. The primitive wing spot pattern subsequently diversified through changes in the expression pattern of this regulator. These results suggest that the genetic changes underlying the emergence and diversification of wing pigmentation patterns are partitioned within genetic networks.


Can asthma treatment in sports be doping? The effect of the rapid onset, long-acting inhaled beta2-agonist formoterol upon endurance performance in healthy well-trained athletes.
Inhaled beta2-agonists have been subject to restrictions in relationship to sports due to fear of possible improvement in endurance performance. According to the international doping regulations only inhaled salbutamol, terbutaline and salmeterol are allowed for use in sports. Formoterol is a recently introduced rapid onset-long-acting inhaled beta2-agonist. The main aim of the present randomized, double-blind placebo-controlled study was to investigate possible improvement in endurance performance of inhaled formoterol in 24 healthy well-trained competitive male athletes, 21-29 years old. Lung function (flow-volume loops) was measured before, 15 min after each inhaled study drug and before and repeatedly after exercise. On day 1, maximum oxygen uptake (VO2max), peak ventilation (VEpeak) and running time till exhaustion were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3 the subjects inhaled the study drugs, rested for 1 h, then exercised, and VO2max, VEpeak and running time until exhaustion were determined. Inhaled formoterol did not improve any parameter of endurance performance. On the other hand a statistically significant, although not clinically significant (0.05 ml(-1) min kg(-1)), change was found in estimated difference of VO2max between formoterol and placebo in favour of placebo. Lung function increased significantly after inhaled formoterol, and after exercise also for placebo, but without differences between the beta2-agonist and placebo after exercise. In conclusion, inhaled formoterol did not improve endurance performance compared to placebo.


Rate and prognosis of patients under conscious sedation requiring emergent intubation during neuroendovascular procedures.
Neuroendovascular procedures are performed with the patient under conscious sedation (local anesthesia) in varying numbers of patients in different institutions, though the risk of unplanned conversion to general anesthesia is poorly characterized. Our aim was to ascertain the rate of failure of conscious sedation in patients undergoing neuroendovascular procedures and compare the in-hospital outcomes of patients who were converted from conscious sedation to general anesthesia with those whose procedures were initiated with general anesthesia. All patients who had an endovascular procedure initiated under general anesthesia or conscious sedation were identified through a prospective data base maintained at 2 comprehensive stroke centers. Patient clinical and procedural characteristics, in-hospital deaths, and favorable outcomes (modified Rankin Scale score, 0-2) at discharge were ascertained. Nine hundred seven endovascular procedures were identified, of which 387 were performed with the patient under general anesthesia, while 520 procedures were initiated with conscious sedation. Among procedures initiated with intent to be performed under conscious sedation, 9 (1.7%) procedures required emergent conversion to general anesthesia. Favorable clinical outcome and in-hospital mortality in patients requiring emergent conversion from conscious sedation to general anesthesia and in those with procedures initiated with general anesthesia were not statistically different (42% versus 50%, P = .73 and 17% versus 13%, P = 1.00, respectively). In our study, there was a very low rate of conscious sedation failure and associated adverse outcomes among patients undergoing neuroendovascular procedures. Proper patient selection is important if procedures are to be performed with the patient under conscious sedation. Limitations of the methodology used in our study preclude us from offering specific recommendations regarding when to use a specific anesthetic protocol.


The role of innate immune signals in antitumor immunity.
Innate immunity serves as a first line of defense against infectious agents, and germ-line-encoded pattern recognition receptors detect stressed and infected cells and elicit potent effector activities that accomplish efficient microbe containment. Recent evidence demonstrates that these pattern-sensing systems are also applicable to the recognition of tumor-derived stress-related factors. In particular, toll-like receptors and cytosolic sensors for DNA and RNA recognition utilize endogenous host elements containing microbial components, danger-associated molecules, and/or nucleic acids to stimulate innate signaling pathways and generate protective immune responses against nascent tumors in animal models and humans. In this review, we describe recent advances and perspectives about antitumor mechanisms and clinical application of innate immune signals and pathways.


Need for and Steps Toward a Clinical Guideline for the Telemental Healthcare of Children and Adolescents.
This article identifies and describes key considerations toward the development of a clinical guideline intended to optimize telemental healthcare (TMH) of children and adolescents. The literature was searched with key terms and title words. Of 2824 articles that met primary or secondary key word search criteria, 326 met both criteria, and 118 thematically related directly to child and adolescent TMH. Only 44 studies met levels of evidence I-III and expert recommendation criteria used in clinical guidelines; review of their references found 8 additional studies (52 total). Data from adult, child, and adolescent in-person psychiatric care and adult TMH were applied to provide context in developing the key considerations. TMH guidelines for adults are well delineated, and TMH guidelines for children and adolescents are likely to closely overlap in terms of general clinical, technical, and administrative issues. However, for a child and adolescent focus, modifications of existing general guidelines appear necessary; for example, based on developmental status, family involvement, and patient-site modifications for space and sound. Additional clinical issues include specify who, exactly, is the "patient" (i.e., the patient, family, and /or other stakeholders), modalities of care (i.e., age-related psychotherapies such as play therapy or behavior management), and psychopharmacology. Specific clinical, administrative, and technical issues are key considerations - based on the nuances of established child and adolescent mental healthcare - and must be considered in developing a clinical guideline for TMH of these patients. Developing such guidance should proceed from a careful review of the growing evidence base, and through expert consensus processes.


Evolution of time coding systems.
The auditory and electrosensory systems contain circuits that are specialized for the encoding and processing of microsecond time differences. Analysis of these circuits in two specialists, weakly electric fish and barn owls, has uncovered common design principles and illuminated some aspects of their evolution.


Characterization of Constituents and Anthelmintic Properties of Hagenia abyssinica.
The dried female flowers of Hagenia abyssinica (Bruce) J. F. Gmel. (Rosaceae) are traditionally used as an anthelmintic remedy in Ethiopia and formerly were incorporated into the European Pharmacopoeia. One-, two- and tricyclic phloroglucinol derivatives (kosins) were suggested to be the active principles. However, polar constituents may also contribute to the activity. Therefore, we investigated for the first time the polar constituents. We isolated typical Rosaceae constituents such as quercetin 3-O-β-glucuronide, quercetin 3-O-β-glucoside and rutin. Polar kosin glycosides or derivatives could not be detected.The anthelmintic activity of fractions of different polarity were tested against the blood fluke Schistosoma mansoni, the liver flukes Clonorchis sinensis and Fasciola hepatica and the intestinal fluke Echinostoma caproni. The anthelmintic activity decreased with increasing polarity of the tested fractions. ESI-MS investigations indicated the predominant occurrence of kosins in the active fractions.Using the anthelmintic active extracts of Hagenia abyssinica we developed a simple, inexpensive bioassay against the non-parasitic nematode Caenorhabditis elegans, which can be used as an initial screening procedure for anthelmintic properties of crude extracts of plants or fungi. The anthelmintic activity of test extracts against the model organism was determined in a microtiter plate assay by enumeration of living and dead nematodes under a microscope.


Pathogens in space: Advancing understanding of pathogen dynamics and disease ecology through landscape genetics.
Landscape genetics has provided many insights into how heterogeneous landscape features drive processes influencing spatial genetic variation in free-living organisms. This rapidly developing field has focused heavily on vertebrates, and expansion of this scope to the study of infectious diseases holds great potential for landscape geneticists and disease ecologists alike. The potential application of landscape genetics to infectious agents has garnered attention at formative stages in the development of landscape genetics, but systematic examination is lacking. We comprehensively review how landscape genetics is being used to better understand pathogen dynamics. We characterize the field and evaluate the types of questions addressed, approaches used and systems studied. We also review the now established landscape genetic methods and their realized and potential applications to disease ecology. Lastly, we identify emerging frontiers in the landscape genetic study of infectious agents, including recent phylogeographic approaches and frameworks for studying complex multihost and host-vector systems. Our review emphasizes the expanding utility of landscape genetic methods available for elucidating key pathogen dynamics (particularly transmission and spread) and also how landscape genetic studies of pathogens can provide insight into host population dynamics. Through this review, we convey how increasing awareness of the complementarity of landscape genetics and disease ecology among practitioners of each field promises to drive important cross-disciplinary advances.


Economic Impact of the Introduction of Outpatient Medical Specialist Care (ASV) of Gastrointestinal Cancer Patients from a German Hospital Management Perspective.
The treatment of cancer patients in Germany is characterized by sectoral separation of the in- and outpatient care accompanied by 2 separate reimbursement systems. By introducing the Guideline of Outpatient Medical Specialist Care in accordance with §116b SGB V (ASV) in 2014, the German legislation empowers office-based physicians and hospitals to jointly provide medical care in the ambulatory setting. A 1-year period each before and after the introduction of ASV was compared by means of data from the Center for Integrated Oncology Cologne at the University Hospital of Cologne. Only adults with a reliable diagnosis of gastrointestinal tumor (GIT) were considered. Overall, 1,872 cases were considered in the analysis showing significant (p < 0.001) higher median values of revenues across ICD-subgroups for ASV (EUR 427.46) compared to Ambulatory Treatments in Hospitals (EUR 234.21). The exemplary analysis of revenues in neoplasms of the pancreas shows EUR 173.69 on average which are only invoiceable through ASV: flat rate incl. surcharges (EUR 117.79; 68%), structure lump sum (EUR 29.49; 17%), positron-emission tomography (PET)/CT (EUR 13.53; 18%), and ASV consultation hour (EUR 12.89; 7%). ASV leads to significant higher revenues across different ICD-subgroups for patients suffering from severe GIT. The collaboration of hospital and office-based physicians ensures patient-centered care with accumulated expertise and avoidance of double examinations. Thus, the inclusion of additional services in the Uniform Value Scale (invoiceable for ASV) is legitimated and enables cost-covering care for the involved parties.


Glycolysis and the Hexosamine Biosynthetic Pathway as Novel Targets for Upper and Lower Airway Inflammation.
Glycolysis is a process that rapidly converts glucose to lactate to produce adenosine triphosphate (ATP) under anaerobic conditions and occurs in all eukaryotic and prokaryotic cells. On the other hand, the hexosamine biosynthetic pathway (HBP) converts glucose to intermediate products like UDP-N-acetylglucosamine, which is critical for post-translational modifications of proteins, such as protein glycosylation. These 2 pathways are well known to contribute to glucose metabolism, but recent studies indicate modulation of these pathways can alter immune system function. In this review article, the authors present results suggesting how cellular metabolism, including glycolysis and the HBP, occurs in immune cells, and the immunologic significances of such activities. In addition, they provide a review of the literature on the effects of glycolysis and the HBP on various autoimmune, immunologic, and allergic diseases. Finally, the authors briefly introduce the results of their research on the immunologic effects of HBP supplementation (glucosamine) in animal models of allergic disease.


The Affordable Care Act In The Heart Of The Opioid Crisis: Evidence From West Virginia.
West Virginia is at the epicenter of a national opioid crisis, with a 2016 fatal opioid overdose rate of 43.4 per 100,000 population-more than triple the US average. We used claims data for 2014-16 to examine trends in treatment for opioid use disorder (OUD) among people enrolled in the West Virginia Medicaid expansion program under the Affordable Care Act. Expanding Medicaid could provide services to populations that may previously have had limited access to OUD treatment. We thus sought to understand trends over time in OUD diagnosis and treatment, especially with medications. About 5.5 percent of all enrollees were diagnosed with OUD per year, and the monthly prevalence of OUD diagnoses nearly tripled during this three-year period. The ratio of people filling buprenorphine to the number diagnosed with OUD was around one-third in early 2014, increasing to more than 75 percent by late 2016. Mean annual duration of filled buprenorphine increased from 161 days in 2014 to 185 days in 2016, and most people filling buprenorphine also received counseling and drug testing during the study period. The growing use of medication treatment for OUD in the West Virginia Medicaid expansion population provides an opportunity to reduce overdose deaths.


[An important concomitancy: interstitial lung diseases and sleep related breathing disorders].
Interstitial lung diseases (ILD), are a group of diseases which can involve pulmonary interstitium, small airways, and vessels, and diffusely affect pulmonary parenchyma as a consequence development of inflammation, and fibrosis leading to respiratory failure, and finally death. Obstructive sleep apnea syndrome (OSAS) is a disorder which courses with its systemic outcomes, and increasing morbidity, and mortality when accompanied with other respiratory system diseases. Concomitancy of OSAS with other lung diseases including chronic obstructive pulmonary disease, asthma, ILD, cystic fibrosis is termed as ''overlap syndrome''. Because of characteristic feature of OSAS ie. recurrent oxygen desaturations during night hours, ILD-OSAS concomitancy accelerates progression of underlying lung disease. Therefore, in cases with ILD, early diagnosis, and treatment of comorbid OSAS conveys vital importance in that this approach improves quality of life of the patients, and slows down progression of the disease. In this review ILD-OSAS concomitancy will be analyzed from its various aspects.


Negative evaluation of role transitions is associated with perceived stress and alcohol consequences: Examination of the Transitions Overload Model in young adulthood using two years of monthly data.
Young adulthood is characterized by transitions into and out of social roles in multiple domains. Consistent with self-medication models of alcohol use, the Transitions Overload Model (J Stud Alcohol Suppl, 14, 2002, 54) hypothesizes that one cause of increased alcohol use during young adulthood may be the stress of navigating simultaneous role transitions. This study examined the simultaneous occurrence of major developmental role transitions in the domains of education, employment, romantic relationships, and residential status and their associations with perceived stress, heavy episodic drinking (HED), and negative alcohol-related consequences. Further, we extended the Transitions Overload Model to explore whether the number of transitions rated as having a negative impact on one's life was related to perceived stress, HED, and alcohol-related consequences. A community sample of young adult drinkers (N = 767, 57% women, ages 18 to 25 years) in the Pacific Northwest provided monthly data across 2 years. Multilevel models were used to assess the average (between-person) and month-to-month (within-person) associations of role transitions with perceived stress, HED, and negative alcohol-related consequences. Although having more role transitions was positively associated with HED frequency and alcohol-related consequences at both the between- and within-person (monthly) levels, it was not associated with increased stress. The number of transitions rated as having a negative impact on one's life, however, was positively associated with stress. Thus, rather than the total number of transitions, it is the number of negatively perceived major developmental role transitions that is associated with perceived stress and increased risk for negative alcohol-related consequences. Contrary to Transitions Overload Model assumptions, more transitions were not a significant predictor of more perceived stress; rather, the evaluation of the transition as negative was associated with stress and negative alcohol-related outcomes. This distinction may help elucidate the etiology of stress and subsequent alcohol consequences and identify individuals at-risk of these effects.


The control of airway mucus secretion.
Airway mucus is essential for the effectiveness of cough and mucociliary transport. Even the resting airway produces some mucus but, under a great variety of threats to airway function, this production increases. A number of mechanisms may be responsible for augmenting secretion; these include reflexes, initiated by nervous receptors in the airways, and with their efferent limbs in the autonomic nerves to the airways. Cigarette smoke short circuits this reflex pathway; nicotine absorbed from the smoke stimulates ganglion cells directly and so drives secretion. Secretomotor nerves which control the output from submucosal glands include cholinergic, adrenergic and NANC fibres. A number of mediators of the sort released during inflammation and antigen challenge, including prostaglandins and leukotrienes, can also elicit secretion into the airway lumen. Other stimuli act at least partly on unknown mechanisms to release mucus from the surface epithelium into the airway lumen. For example inhalation of dust, which stimulates cough receptors and so acts partly by driving mucus secretion reflexly, also initiates secretion into the denervated airway. Similarly, during the inhalation of cool dry air, the airway lining secretes more mucus, probably by a non-nervous mechanism which responds to drying of the airway surface. More needs to be learned about such apparently direct mechanisms. Different control systems appear to stimulate the production of a variety of mucins from distinct cell types. We do not yet know the physiological and pathological importance of these differences.


Oncogenic viruses associated with vulva cancer in HIV-1 patients in Botswana.
Oncoviruses such as HPV, KSHV, and EBV have been reported in patients with HIV infection and AIDS. How oncovirus-associated cancers rise in AIDS patients has not been fully established. The purpose of our study was to identify the viral agents in vulvar cancer and to assess their contribution to pathogenesis. We retrospectively identified a total of 13 vulva tissue samples from HIV-1 positive and 9 vulvar samples from HIV-1 negative patients from the Botswana National Health Laboratory in Gaborone, Botswana, a Southern African country with a high incidence of HIV. We utilized PCR and IHC to identify HPV, EBV, KSHV, and JC virus in FFPE preserved tissue samples. Using the GP5(+)/GP6(+) primer set we detected several HPV types in tissue samples. EBV was detected in all of the positive cases (100%) and in most of the negative cases (89%). KSHV was detected in 39% of the HIV-1 positive samples and in 11% of the negative samples, and no JC virus was detected in any of the samples. Using IHC we demonstrated that LANA was expressed in 61% of the positive samples and in 44% of the negative samples. The ubiquitous EBV was more consistently expressed in negative cases (100%) than in positive cases (69%). Interestingly, the HPV-16 E6 transcript was detected in 56% of the negative samples compared to 31% of the positive samples. However, the cell cycle protein P21 used as a surrogate marker for HPV was detected in 77% of the positive samples and in 44% of the negative samples, while VEGF signals were similar in both positive (92%) and negative samples (89%). Our study, suggests that in Botswana, vulvar squamous cell carcinoma (VSCC) is associated with oncogenic viruses present in the niche but the contribution and progression may be regulated by HPV and other immunosuppressive infections that include HIV-1.


Modelling phagosomal lipid networks that regulate actin assembly.
When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel. We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds.In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP. By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.


Relationship Between Preoperative NT-proBNP and Postoperative Adverse Events in Patients with Left Ventricular Assist Device.
The aim of this study is to investigate the relationship of preoperative NT-proBNP values with postoperative adverse events in patient left ventricular assist device (LVAD) implantation. Forty-six patients (35 males; mean age 49.4 ± 12.9 years) who underwent LVAD implantation between 2016 and 2018 were evaluated in this study. The analysis was made on the relationship between preoperative NT-proBNP and mortality, postoperative right ventricular failure (RVF), postoperative drainage, duration of intubation, and intensive care unit stay, was examined. The optimal NT-proBNP cut-off values for predicting mortality were determined using Receiver Operator Characteristic (ROC) curve analysis and the patients were divided into two groups according to the specified cut-off point. Median NT-proBNP was higher in patients who died, had postoperative extracorporeal membrane oxygenation, and early RVF. The median NT-proBNP was 11,103 pg/ml in patients with IABP, and 2943 pg/ml in patients without IABP, and the difference was statistically significant (p = 0.002). The cut-off point for NT-proBNP was found to be 1725.5 pg/ml (Sensitivity:0.929, Specificity:0.688). Accordingly, when the patients were divided into two groups and analyzed, no statistically significant difference was found between preoperative NT-proBNP below or above 1725.5 and postoperative adverse events. There was no statistically significant correlation between preoperative NT-proBNP and postoperative drainage, duration of intubation time, and duration of ICU stay (p > 0.05). Routine monitoring of preoperative NT-proBNP and comparison with postoperative values are important in terms of patient selection, the timing of surgery, follow-up of postoperative adverse events, and improving outcomes in VAD patients.


Variants in IL23R-C1orf141 and ADO-ZNF365-EGR2 are associated with susceptibility to Vogt-Koyanagi-Harada disease in Japanese population.
Vogt-Koyanagi-Harada (VKH) disease is a systemic inflammatory disorder that affects pigment cell-containing organs such as the eye (e.g., chronic and/or recurrent granulomatous panuveitis). While the exact etiology and pathogenic mechanism of VKH disease are unclear, HLA-DR4 alleles have been documented to be strongly associated with VKH disease in various ethnic groups. Recently, a genome-wide association study (GWAS) found two new genetic risk factors (IL23R-C1orf141 and ADO-ZNF365-EGR2) in a non-HLA region from a Han Chinese population. In this study, we replicated these GWAS findings in a Japanese population. A total of 1,643 Japanese samples (380 cases with VKH disease and 1,263 healthy controls) were recruited. We assessed four single nucleotide polymorphisms (SNPs) shown in previous GWAS: rs78377598 and rs117633859 in IL23R-C1orf141, and rs442309 and rs224058 in ADO-ZNF365-EGR2. A significant allelic association with VKH disease was observed for all of the four SNPs (rs78377598: pc = 0.0057; rs117633859: pc = 0.0017; rs442309: pc = 0.021; rs224058: pc = 0.035). In genotypic association analysis, the minor alleles of IL23R-C1orf141 rs78377598 and rs117633859 had the strongest association with disease susceptibility under the additive model (pc = 0.0075 and pc = 0.0026, respectively). The minor alleles of ADO-ZNF365-EGR2 rs442309 and rs224058 were most strongly associated with disease susceptibility under the dominant model (pc = 0.00099 and pc = 0.0023, respectively). The meta-analysis of the current and previous studies found that all of the four SNPs exhibited a significantly strong association with VKH disease (meta-p < 0.00001: rs78377598, meta-odds ratio (OR) = 1.69; rs1176338, meta-OR = 1.82; rs442309, meta-OR = 1.34; rs224058, meta-OR = 1.33). In summary, our study replicated significant associations with VKH disease susceptibility reported in a previous GWAS. Thus, the IL23R-C1orf141 and ADO-ZNF365-EGR2 loci may play important roles in the development of VKH disease through genetic polymorphisms.


[Study on the occupational exposure limit of glyphosate in the air of workplace].
Objective: To establish occupational exposure limits for glyphosate in workplace air. Methods: In November 2014, by searching the documents of the United States Environmental Protection Agency (EPA) on glyphosate toxicity, the toxicity data and clinical symptoms of glyphosate toxicity were collected through various literature databases, and the target organs of glyphosate toxicity were determined. A total of 5 representative production enterprises in Jiangsu Province and Shandong Province were selected for field investigation. A total of 968 people were selected as the study subjects, including 526 workers exposed to glyphosate as the contact group, and 442 off-site (such as financial, administrative, etc.) workers with enterprises as the control group. Health examination was carried out in the exposure group and the control group to observe the damage of target organs of workers with different exposure concentrations and determine the occupational exposure limit. Results: The main target organs of glyphosate are liver and kidney and its effect on cholinesterase activity. The time-weighted average concentration (TWA) of glyphosate exposure in the exposure group was <0.03~48.91 mg/m(3), and there were statistically significant differences in liver and renal function between the exposure group and the control group (P<0.05). When the concentration of glyphosate in the air was higher than 5 mg/m3, there was a statistically significant difference in the abnormal rate of renal function between the exposure group and the control group (P<0.05) . Conclusion: The study sets the occupational exposure limit of glyphosate as 5 mg/m(3). The safety of this standard conforms to the relevant requirements of toxicology and occupational disease epidemiology, and also conforms to the existing economic and technological level in my country, and is highly feasible.


Refining the genetic structure and relationships of European cattle breeds through meta-analysis of worldwide genomic SNP data, focusing on Italian cattle.
The availability of genotyping assays has allowed the detailed evaluation of cattle genetic diversity worldwide. However, these comprehensive studies did not include some local European populations, including autochthonous Italian cattle. In this study, we assembled a large-scale, genome-wide dataset of single nucleotide polymorphisms scored in 3,283 individuals from 205 cattle populations worldwide to assess genome-wide autozygosity and understand better the genetic relationships among these populations. We prioritized European cattle, with a special focus on Italian breeds. Moderate differences in estimates of molecular inbreeding calculated from runs of homozygosity (FROH) were observed among domesticated bovid populations from different geographic areas, except for Bali cattle. Our findings indicated that some Italian breeds show the highest estimates of levels of molecular inbreeding among the cattle populations assessed in this study. Patterns of genetic differentiation, shared ancestry, and phylogenetic analysis all suggested the occurrence of gene flow, particularly among populations originating from the same geographical area. For European cattle, we observed a distribution along three main directions, reflecting the known history and formation of the analyzed breeds. The Italian breeds are split into two main groups, based on their historical origin and degree of conservation of ancestral genomic components. The results pinpointed that also Sicilian breeds, much alike Podolian derived-breeds, in the past experienced a similar non-European influence, with African and indicine introgression.


Pneumomediastinum as a complication of cocaine abuse.
A 26-year-old male presented with a 24-hour history of pleuritic chest pain following intranasal cocaine insufflation. He was a smoker, cannabis and alcohol user. Cardiovascular and respiratory examinations were unremarkable.His admission blood tests were within normal limits. The admission electrocardiogram (ECG) showed sinus rhythm, with ST-segment elevation in an inferolateral distribution. This appeared to be an early repolarisation abnormality, with no evolving changes.His chest radiogram showed a double outline at the left heart border with subcutaneous gas collection over the left supraclavicular fossa but no evidence of pneumothorax. A computed tomography (CT) showed prominent mediastinum with gas tracking into the neck but no connection to the oesophagus or pneumothorax.He was managed conservatively and a repeat chest radiogram after 48 hours showed improvement.


Implications of the Patient Protection and Affordable Care Act on Insurance Coverage and Rehabilitation Use Among Young Adult Trauma Patients.
Trauma is the leading cause of death and disability among young adults, who are also among the most likely to be uninsured. Efforts to increase insurance coverage, including passage of the Patient Protection and Affordable Care Act (ACA), were intended to improve access to care and promote improvements in outcomes. However, despite reported gains in coverage, the ACA's success in promoting use of high-quality care and enacting changes in clinical end points remains unclear. To assess for observed changes in insurance coverage and rehabilitation use among young adult trauma patients associated with the ACA, including the Dependent Coverage Provision (DCP) and Medicaid expansion/open enrollment, and to consider possible insurance and rehabilitation differences between DCP-eligible vs -ineligible patients and among stratified demographic and community subgroups. A longitudinal assessment of DCP implementation and Medicaid expansion/open enrollment using risk-adjusted before-and-after, difference-in-difference, and interrupted time-series analyses was conducted. Eleven years (January 1, 2005, to September 31, 2015) of Maryland Health Services Cost Review Commission data, representing complete patient records from all payers within the state, were used to identify all hospitalized young adult (aged 18-34 years) trauma patients in Maryland during the study period. Of the 69 507 hospitalized patients included, 50 548 (72.7%) were male, and the mean (SD) age was 25 (5) years. Before implementation of the DCP, 1 of 4 patients was uninsured. After ACA implementation, the number fell to less than 1 of 10, with similar patterns emerging in emergency department and outpatient settings. The change was primarily driven by Medicaid expansion/open enrollment, which corresponded to a 20.1 percentage-point increase in Medicaid (95% CI, 18.9-21.3) and an 18.2 percentage-point decrease in uninsured (95% CI, -19.3 to -17.2). No changes were detected among privately insured patients. Rehabilitation use increased by 5.4 percentage points (95% CI, 4.5-6.2)-a 60% relative increase from a baseline of 9%. Mortality (-0.5; 95% CI, -0.9 to -0.1) and failure-to-rescue rates (-4.5; 95% CI, -7.4 to -1.6) also significantly declined. Stratified changes point to significant differences in the percentage of uninsured patients and rehabilitation access across the board, mitigating or even eradicating disparities in certain cases. For patients who are injured, young, and uninsured, Medicaid expansion/open enrollment in Maryland changed insurance coverage and altered patient outcomes in ways that the DCP alone was never intended to do. Implementation of Medicaid expansion/open enrollment transformed the landscape of trauma coverage, directly affecting the health of one of the country's most vulnerable at-risk groups.


Analysis of the floral transcriptome uncovers new regulators of organ determination and gene families related to flower organ differentiation in Gerbera hybrida (Asteraceae).
Development of composite inflorescences in the plant family Asteraceae has features that cannot be studied in the traditional model plants for flower development. In Gerbera hybrida, inflorescences are composed of morphologically different types of flowers tightly packed into a flower head (capitulum). Individual floral organs such as pappus bristles (sepals) are developmentally specialized, stamens are aborted in marginal flowers, petals and anthers are fused structures, and ovaries are located inferior to other floral organs. These specific features have made gerbera a rewarding target of comparative studies. Here we report the analysis of a gerbera EST database containing 16,994 cDNA sequences. Comparison of the sequences with all plant peptide sequences revealed 1656 unique sequences for gerbera not identified elsewhere within the plant kingdom. Based on the EST database, we constructed a cDNA microarray containing 9000 probes and have utilized it in identification of flower-specific genes and abundantly expressed marker genes for flower scape, pappus, stamen, and petal development. Our analysis revealed several regulatory genes with putative functions in flower-organ development. We were also able to associate a number of abundantly and specifically expressed genes with flower-organ differentiation. Gerbera is an outcrossing species, for which genetic approaches to gene discovery are not readily amenable. However, reverse genetics with the help of gene transfer has been very informative. We demonstrate here the usability of the gerbera microarray as a reliable new tool for identifying novel genes related to specific biological questions and for large-scale gene expression analysis.


The application of metabolomics toward pulmonary tuberculosis research.
In the quest to identify novel biomarkers for pulmonary tuberculosis (TB), high-throughput systems biology approaches such as metabolomics has become increasingly widespread. Such biomarkers have not only successfully been used for better disease characterization, but have also provided new insights toward the future development of improved diagnostic and therapeutic approaches. In this review, we give a summary of the metabolomics studies done to date, with a specific focus on those investigating various aspects of pulmonary TB, and the infectious agent responsible, Mycobacterium tuberculosis. These studies, done on a variety of sample matrices, including bacteriological culture, sputum, blood, urine, tissue, and breath, are discussed in terms of their intended research outcomes or future clinical applications. Additionally, a summary of the research model, sample cohort, analytical apparatus and statistical methods used for biomarker identification in each of these studies, is provided.


A prospective, randomized study of open vs laparoscopic inguinal hernia repair. An assessment of postoperative pain.
To compare postoperative pain after laparoscopic hernia repair and conventional open hernia repair. Prospective, randomized study. Veterans Affairs Medical Center. Sixty-two patients scheduled for elective inguinal hernia repair. Patients were randomized in the operating room to have a laparoscopic hernia repair (30 patients) or a conventional open hernia repair (32 patients). All operations were performed while the patient was under general anesthesia to avoid anesthesia as a confounding variable. Postoperative pain following laparoscopic hernia repair and open hernia repair were compared using the McGill Pain Score, the McGill Visual Analogue Pain Scale score, and the number of acetaminophen with 30-mg codeine sulfate (Tylenol 3) tablets needed for pain during the first and second 24-hour periods postoperatively. All of the patients were interviewed and the postoperative pain was evaluated by a special study nurse (P.M.L.) who was blinded to the repair technique. At 24 hours, the patients with laparoscopic hernia repair had 26% less pain by the McGill Pain Score (P = .02) and 31% less pain by the McGill Visual Analogue Scale (P = .006) than those who underwent an open hernia repair. At 48 hours the patients who underwent laparoscopic hernia repair had 28% less pain by the McGill Pain Score (P = .03), 42% less pain by the McGill Visual Analogue Scale (P = .002), and used 42% fewer analgesic tablets (P = .004). Patients with a laparoscopic hernia repair had significantly less pain postoperatively than those with standard open hernia repairs.


Pulmonary endocrine cells in plexogenic pulmonary arteriopathy associated with cirrhosis.
A clear association has been described between numbers of pulmonary endocrine cells and the migration and/or proliferation of myofibroblasts which is thought to underlie the vascular changes seen in plexogenic pulmonary arteriopathy due to cardiac shunts and primary pulmonary hypertension. In contrast, the pulmonary endocrine system in a subject with florid pulmonary plexogenic arteriopathy associated with cirrhosis was entirely normal, suggesting possible differences in its pathogenesis.


Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome.
The dual-specificity tyrosine-phosphorylation-regulated kinase, DYRK1B, is expressed de novo during myogenesis, amplified or mutated in certain cancers and mutated in familial cases of metabolic syndrome. DYRK1B is activated by cis auto-phosphorylation on tyrosine-273 (Y273) within the activation loop during translation but few other DYRK1B phosphorylation sites have been characterised to date. Here, we demonstrate that DYRK1B also undergoes trans-autophosphorylation on serine-421 (S421) in vitro and in cells and that this site contributes to DYRK1B kinase activity. Whilst a DYRK1B(S421A) mutant was completely defective for p-S421 in cells, DYRK1B inhibitors caused only a partial loss of p-S421 suggesting the existence of an additional kinase that could also phosphorylate DYRK1B S421. Indeed, a catalytically inactive DYRK1B(D239A) mutant exhibited very low levels of p-S421 in cells but this was increased by KRAS(G12V). In addition, selective activation of the RAF-MEK1/2-ERK1/2 signalling pathway rapidly increased p-S421 in cells whereas activation of the stress kinases JNK or p38 could not. S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro. Our results show that DYRK1B is a novel ERK2 substrate, uncovering new links between two kinases involved in cell fate decisions. Finally, we show that DYRK1B mutants that have recently been described in cancer and metabolic syndrome exhibit normal or reduced intrinsic kinase activity.


Randomized, double-blind, and placebo-controlled trial of clenbuterol in denervated muscle atrophy.
Objectives. β(2)-adrenergic agonists, such as clenbuterol, have been shown to promote the hypertrophy of healthy skeletal muscles and to ameliorate muscle wasting in a few pathological conditions in both animals and humans. We intended to investigate the clinical efficacy of clenbuterol on attenuating denervation-induced muscle atrophy. Methods. A double-blind, placebo-controlled, parallel, and randomized trial was employed. 71 patients, suffering from brachial plexus injuries, were given either clenbuterol (60 μg, bid) or placebo for 3 months. Before and at the end of the study, patients were given physical examinations, biopsies of biceps brachii, electromyograms (EMGs), and other laboratory tests. Results. Compared with placebo treatment, clenbuterol significantly mitigated the decreases in cross-sectional areas of type I and II muscle fibers and alleviated the reduction in fibrillation potential amplitudes, without any adverse effects. Conclusions. Clenbuterol safely ameliorated denervated muscle atrophy in this cohort; thus larger clinical studies are encouraged for this or other β(2) agonists on denervation-induced muscle atrophy.


Meeting public health needs in emergencies-World Health Organization guidelines.
The World Health Organization (WHO) is a leading source of trustworthy guidelines in public health, including in emergencies. In addition to standard guidelines produced in preparation for emergency response, WHO has processes and methods for issuing guidelines in the context of urgent public health need, including rapid advice guidelines (production time 2 to 3 months) and health emergency interim guidelines (days to weeks). There are numerous challenges to producing guidelines in response to an emergency in addition to the compressed timeline which necessitates truncating or modifying standard processes. There is frequently a lack of scientific data on the disease or situation at hand, especially early in the event timeline. Resources are limited, particularly the availability of WHO staff and external experts, and disease and emergency response experts may lack knowledge and experience in developing guidelines. Finally, the rapid production of new information and the resultant short shelf-life of recommendations pose a significant challenge to keeping guidelines up to date. In order to better meet end-users' needs, WHO must anticipate areas of uncertainty in emergency response and proactively develop relevant guidelines, explore optimal ways of communicating gaps in knowledge in the field to guideline developers, and promote and participate in research on the sources of bias in guideline development within compressed timeframes.


Transforming growth factor beta decreases the rate of proliferation of rat vascular smooth muscle cells by extending the G2 phase of the cell cycle and delays the rise in cyclic AMP before entry into M phase.
Transforming growth factor beta 1 (TGF-beta 1) decreased the rate of proliferation of rat aortic vascular smooth muscle cells (VSMCs) stimulated with serum showing a maximal effect at > 5 ng/ml (200 pM). However, it did not reduce the proportion of cells which passed through S phase (> 90%) and entry into S phase was delayed by less than 3 h. The proportion of cells passing through M phase (> 90%) was also unaffected, but entry into mitosis was delayed by approx. 24 h. This increase in cell cycle time was therefore due mainly to an increase in the G2 to mitotic metaphase period. Addition of TGF-beta 1 late in G1 or late in S phase failed to delay the onset of mitosis, but the presence of TGF-beta 1 between 0 and 12 h after the addition of serum to quiescent cells was sufficient to cause the maximal delay in mitosis of approx. 24 h. The role of cyclic AMP in the mechanism of the TGF-beta 1 effects on the cell cycle was examined. Entry into mitosis was preceded by a transient 2-fold increase in cyclic AMP concentration and TGF-beta 1 delayed both this increase in cyclic AMP and entry into mitosis to the same extent. Addition of forskolin or 8-(4-chlorophenylthio)-cyclic AMP to cells 30 h after stimulation with serum completely reversed the increase in duration of G2 in the presence of TGF-beta 1, suggesting that the rise in cyclic AMP levels which precedes mitosis might trigger entry of the VSMCs into M phase. Addition of forskolin late in S phase (26 h after stimulation with serum) advanced the entry of the cells into M phase and they divided prematurely. This effect was unaffected by the addition of cycloheximide with the forskolin; however, the effect of forskolin on cell division was completely inhibited when cycloheximide was added late in G1. TGF-beta 1 prevented the loss of smooth-muscle-specific myosin heavy chain (SM-MHC), which occurs in primary VSMC cultures in the presence or absence of serum, and the cells proliferated while maintaining a differentiated phenotype. However, TGF-beta 1 did not cause re-differentiation of subcultured VSMCs which contained very low amounts of SM-MHC and the effect of TGF-beta 1 in extending the G2 phase of the cell cycle is exerted independently of its effect on differentiation.


The importance of perfusion index monitoring in evaluating the efficacy of stellate ganglion blockage treatment in Raynaud's disease.
Stellate ganglion blockage (SGB) is a method used for treating Raynaud's phenomenon (RP). This study primarily aimed to determine whether the perfusion index (PI) can be used an alternative to Horner's signs in evaluating the efficacy of SGB in patients diagnosed with RP. In a total of 40 patients, aged 18-65 years and diagnosed with primary RP, SGB was applied for 5 days on the same side with the 2-finger method, using 6 mL of 5% levobupivacaine at the 7th cervical vertebra level. The PI values were recorded from the distal end of the 2nd finger of the upper extremity on the side applied with the block at baseline and at 5, 15, 30, 60 and 120 min. The onset time of Horner findings was recorded. The PI values and visual analogue scale (VAS) pain scores were recorded pre-treatment and after 2 weeks.When the PI values of the 40 patients were examined, a 62.7% increase was observed from baseline to the first session at 5 min (p < 0.05). When all sessions were evaluated, a statistically significant increase was determined in the PI values measured at 5, 15, 30, 60 and 120 min compared with the baseline PI values. There was a statistically significant decrease in the post-treatment VAS pain scores and a statistically significant increase in the post-treatment PI values (p < 0.05). By eliminating peripheral vasospasm with the application of SGB in patients with RP, the distal artery blood flow and PI are increased. PI measurement is a more objective method and therefore could be used as an alternative to Horner findings in evaluating the success of SGB. PI is a non-invasive and simple measurement and also an earlier indicator in evaluating the success of SGB than Horner's signs.


The Gastrointestinal Tract Is an Alternative Route for SARS-CoV-2 Infection in a Nonhuman Primate Model.
Gastrointestinal (GI) manifestations have been increasingly reported in patients with coronavirus disease 2019 (COVID-19). However, the roles of the GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We investigated how the GI tract is involved in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19. Our previously established nonhuman primate (NHP) model of COVID-19 was modified in this study to test our hypothesis. Rhesus monkeys were infected with an intragastric or intranasal challenge with SARS-CoV-2. Clinical signs were recorded after infection. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction. Host responses to SARS-CoV-2 infection were evaluated by examining inflammatory cytokines, macrophages, histopathology, and mucin barrier integrity. Intranasal inoculation with SARS-CoV-2 led to infections and pathologic changes not only in respiratory tissues but also in digestive tissues. Expectedly, intragastric inoculation with SARS-CoV-2 resulted in the productive infection of digestive tissues and inflammation in both the lung and digestive tissues. Inflammatory cytokines were induced by both types of inoculation with SARS-CoV-2, consistent with the increased expression of CD68. Immunohistochemistry and Alcian blue/periodic acid-Schiff staining showed decreased Ki67, increased cleaved caspase 3, and decreased numbers of mucin-containing goblet cells, suggesting that the inflammation induced by these 2 types of inoculation with SARS-CoV-2 impaired the GI barrier and caused severe infections. Both intranasal and intragastric inoculation with SARS-CoV-2 caused pneumonia and GI dysfunction in our rhesus monkey model. Inflammatory cytokines are possible connections for the pathogenesis of SARS-CoV-2 between the respiratory and digestive systems.


Signal pathway of GnRH-III inhibiting FSH-induced steroidogenesis in granulosa cells.
Gonadotrophin-releasing hormone type 1 and type 2 have been demonstrated to inhibit follicle-stimulating hormone (FSH)-induced granulosa cell (GC) steroidogenesis. A third type of GnRH (GnRH-III) was also purified from salmon, its action on the FSH-regulated GC function, however is not clear. In the present study we demonstrated that the FSH-induced estrogen and progesterone production in cultured DES-treated GCs was significantly inhibited by GnRH-III. Furthermore, the FSH-stimulated steroidogenic acute regulatory protein and the enzymes for steroidigenesis, such as HSD3B2,aromatase and cytochrome P450 side-chain cleavage were also significantly suppressed by this peptide. The inhibitory action of GnRH-III on the FSH-induced steroidogenenisis was demonstrated via Akt and p38 mitogen-activated protein kinase signaling pathways through suppressing its own receptor expression. Further studies indicated that FSH could stimulate NR5A2 and upstream stimulatory factor (USF) activation, and their induction was significantly suppressed by the GnRH-III. Therefore, it is suggested that GnRH-III inhibiting FSH-induced steroidogenenisis in GCs might be by suppressing FSH-induced its own receptor expression via NR5A2 and USF transcriptional factors.


Familial melanopathy with gigantic melanocytes.
Familial melanopathy with giant melanocytes is a unique pigmentary disorder that to the best of the author's knowledge has not been described before. The clinical and pathological features of this disorder, herein described in four patients, are very characteristic and can be easily discerned both grossly and histologically. More patients with this disorder will probably now be recognized, particularly in the Far and Middle East.


Paratenonitis of the foot and ankle in young female dancers.
In their pursuit of excellence, dancers continually face the risk of injuries, such as paratenonitis. This attests to the strong need for preventive action, which is possible only if major risk factors are identified. The aim of the present descriptive study was to determine the association between risk factors and paratenonitis in young recreational female dancers. One thousand eighty-two non-professional female dancers, aged 8 to 16 years, were screened. The risk factors considered for paratenonitis were: joint range of motion (ROM), body structure, anatomic anomalies, dance technique, and dance discipline. All dancers were clinically examined for current ankle/foot paratenonitis. Ninety-three dancers (8.6%) manifested a paratenonitis at the ankle or foot joints. ROM such as hyper ankle plantarflexion and hyper hip external rotation, false dance technique, and hours of practice per week were found to be associated with increased rate of injury. Regression analysis indicated that dancers with paratenonitis had greater hip external rotation ROM compared to dancers without paratenonitis. No association with injury was found with age of onset of menarche, body structure, and anatomic anomalies such as scoliosis. Precautionary steps, such as screening for joint ROM and dance technique, may reduce the risk of dance injury. Furthermore, our results led to a very significant justification of the dance maxim ``don't force your natural joint ROM and especially your `turnout' position,'' as it could increase your chance to develop paratenonitis.


Two-dimensional growth mode of thiolate-protected gold nanoclusters Au28+4n(SR)20+2n (n = 0-8): compared with their one-dimensional growth mode.
In this paper, six new atomic structures of thiolate-protected gold nanoclusters, i.e. Au32(SR)20, Au40(SR)26, Au48(SR)30, two Au56(SR)34, and Au60(SR)36, are predicted. Considering these six newly predicted structures and six previously predicted or crystallized Au28(SR)20, Au36(SR)24, Au44(SR)28, Au52(SR)32, and Au60(SR)36 altogether, the two-dimensional (2D) growth mode of Au28+4n(SR)20+2n (n = 0-8) nanoclusters is completely presented to compare with their one-dimensional (1D) growth mode. In Au28+4n(SR)20+2n (n = 0-8) nanoclusters with both 1D and 2D growth modes, the same number of gold-core atoms with different morphologies can be seen. Furthermore, the growth of the gold cores occurs via sequential fusion of one tetrahedral Au4 unit by sharing one gold atom. In addition, density functional theory calculations show that these six newly predicted gold nanoclusters following the 2D growth mode have relative energies very close to those of their isomeric structures following the 1D growth mode, large highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gaps, and all-positive harmonic vibration frequencies, indicating their high stabilities. Therefore, the complete presentation of the 2D growth mode of Au28+4n(SR)20+2n (n = 0-8) is beneficial not only for a better understanding of the structural growth of gold nanoclusters, but also for a theoretical guidance on the prediction of new stable structures for experimental confirmation.


Nailfold capillaroscopy.
Nailfold capillaroscopy is a safe and well-established method for the assessment of structural alterations of the microcirculation. It is a crucial tool in the investigation and monitoring of patients presenting with Raynaud's phenomenon. Detection of the characteristic "scleroderma pattern" on capillaroscopy may indicate an underlying rheumatic disease, particularly systemic sclerosis (SSc). Herein, we highlight the practical aspects of videocapillaroscopy, including image acquisition and analysis, with mention of dermoscopy. Special emphasis is placed on standardized use of terminology to describe capillary characteristics. Systematic evaluation of images in discerning the normal from the abnormal using the validated European Alliance of Associations for Rheumatology (EULAR) Study Group consensus reporting framework is paramount. In addition to the relevance of capillaroscopy in the (very) early diagnosis of SSc, its emerging predictive value (especially capillary loss) for new organ involvement and disease progression is underscored. We further provide capillaroscopic findings in selected other rheumatic diseases.


Motion adaptation reveals that the motion vector is represented in multiple coordinate frames.
Accurately perceiving the velocity of an object during smooth pursuit is a complex challenge: although the object is moving in the world, it is almost still on the retina. Yet we can perceive the veridical motion of a visual stimulus in such conditions, suggesting a nonretinal representation of the motion vector. To explore this issue, we studied the frames of representation of the motion vector by evoking the well known motion aftereffect during smooth-pursuit eye movements (SPEM). In the retinotopic configuration, due to an accompanying smooth pursuit, a stationary adapting random-dot stimulus was actually moving on the retina. Motion adaptation could therefore only result from motion in retinal coordinates. In contrast, in the spatiotopic configuration, the adapting stimulus moved on the screen but was practically stationary on the retina due to a matched SPEM. Hence, adaptation here would suggest a representation of the motion vector in spatiotopic coordinates. We found that exposure to spatiotopic motion led to significant adaptation. Moreover, the degree of adaptation in that condition was greater than the adaptation induced by viewing a random-dot stimulus that moved only on the retina. Finally, pursuit of the same target, without a random-dot array background, yielded no adaptation. Thus, in our experimental conditions, adaptation is not induced by the SPEM per se. Our results suggest that motion computation is likely to occur in parallel in two distinct representations: a low-level, retinal-motion dependent mechanism and a high-level representation, in which the veridical motion is computed through integration of information from other sources.


Enhanced expression of type 1 procollagen and transforming growth factor-beta in tuberculin induced delayed type hypersensitivity.
Tissue fibrosis is a common and serious consequence of chronic inflammation. The mechanism linking these two processes is poorly understood. The present study has utilised a human in vivo model of a delayed type hypersensitivity (DTH) reaction, the tuberculin Heaf reaction, induced by intradermal tuberculin in BCG immunised subjects, to dissect the relation between these two processes. Punch skin biopsy specimens were obtained on day 5, day 13 and six to 16 weeks following the tuberculin Heaf test in 18 subjects with grade 3 or 4 responses. Skin biopsy specimens from six subjects served as controls. The specimens were examined using immunohistochemical staining for type 1 procollagen and transforming growth factor-beta (TGF-beta), as well as in situ hybridisation for type 1 procollagen messenger RNA (mRNA). Immunohistochemical analysis revealed increased deposition of TGF-beta in tissue matrix in the biopsy specimens obtained on day 5 following the tuberculin Heaf test. There was also extensive type 1 procollagen staining in the biopsy specimens obtained as early as day 5. Procollagen-1 staining was maximal on day 13, and was present in biopsy specimens from tuberculin Heaf test sites up to eight weeks after the tuberculin inoculation. The type 1 procollagen was localised within cells surrounding areas of inflammatory infiltrate and in perivascular tissues. The presence of new collagen formation was confirmed by in situ hybridisation using oligonucleotide probes for type 1 procollagen mRNA in cells in sections from biopsy specimens obtained on day 13. These data from a human in vivo model of a DTH response indicate that the immune response is intimately associated with an increase in the production of growth factors and the initiation of a fibrotic response.


Multiple factors are required for poly(A) addition to a mRNA 3' end.
Polyadenylation of pre-mRNAs in the nucleus involves a specific endonucleolytic cleavage, followed by the addition of approximately 200 adenylic acid residues. We have assayed HeLa nuclear extracts for the activity that catalyzes the poly(A) addition reaction. The authenticity of the in vitro assay was indicated by the observation that the poly(A) tract added in vitro is approximately 200 nucleotides in length. We have fractionated nuclear extracts in order to define components involved in specific poly(A) addition. No single fraction from DEAE-Sephacel chromatography of a HeLa nuclear extract possessed the specific poly(A) addition activity. However, if the various fractions were recombined, activity was restored, indicating the presence of multiple components. Further fractionation revealed the presence of at least two factors necessary for the poly(A) addition reaction. The reconstituted system retains the characteristics and specificity seen in the crude extract. Additional purification of one of the factors strongly suggests it to be a previously characterized poly(A) polymerase which, when assayed in the absence of the other factor, can add AMP to an RNA terminus but without specificity. Thus, the other component of the reaction may provide specificity to the process. In contrast to the 3' cleavage reaction, the poly(A) addition machinery does not possess an essential RNA component, as assayed by micrococcal nuclease digestion, nor do anti-Sm sera inhibit the reaction. Thus, the total process of formation of a polyadenylated mRNA 3' end is complex and requires the concerted action of distinct nuclear components.


Management of disc herniations with bi-radicular symptoms via combined lateral and interlaminar approach.
Large lumbosacral disc herniations causing bi-radicular symptoms are very rare clinical entities and may present a surgical challenge. This study was undertaken to evaluate the effectiveness of the simply modified combined lateral and interlaminar approach for the treatment of these unique disc herniations. Between 2000 and 2005, 18 patients with bi-radicular symptoms secondary to large disc herniations of the lumbar spine underwent surgery. There were 13 men and five women, ranging in age between 25 and 64 years (mean 54.3 years). In this three-step operation, the osseous areas that are not essential for the facet joint were removed and both upper and lower nerve roots were decompressed. There were no intraoperative or postoperative complications, except transient dysesthesia in one (5.5%) patient. The mean follow-up period was 62.6 months (range 36-96 months). At the latest follow-up examination, outcomes using the Macnab classification were excellent in 13 patients (72.2 %), good in four (22.2%) and fair in one (5.5%). Recurrent disc herniations and/or instability, either symptomatic or radiographic, have not occurred as a result of the procedure during the follow-up period. The combined approach described here is a safe and effective procedure in the surgical treatment of this subtype of disc herniations with bi-radicular involvement. It permits optimum decompression of both nerve roots, avoiding the risk of secondary spinal instability.


[Osteosarcoma cell immunophenotype and heterogeneity].
48 cases of osteosarcoma, including 18 cases of osteoblastic type, 16 of fibroblastic type and 14 of chondroblastic type, were studied in accordance with Dahlin's classification. All specimens were stained with 11 specific markers using immunohistochemical ABC methods. Positive immunostaining for BMP was found in all of these cases. The results showed 48 vimentin positive cases, 46 actin positive cases, 5 keratin positive cases and 4 desmin positive cases. Neither cytokeratin nor EMA was identified in any of the cases. Positive reactions to S-100 protein, collagen type IV, UEA-1 and factor XIII were observed in 26, 20, 36 and 13 of the cases respectively. The results of this study confirm that osteosarcoma possesses the unique multidirectional differentiation potential toward osteoblastic, chondroblastic, myofibroblastic, fibrohistiocytic and epithelial cells, and also indicate that immunophenotypic analysis is useful for the diagnosis, differential diagnosis and classification of the tumor cells of osteosarcoma.


Cordyceps cicadae Prevents Renal Tubular Epithelial Cell Apoptosis by Regulating the SIRT1/p53 Pathway in Hypertensive Renal Injury.
Hypertensive renal injury is a primary etiology of end-stage renal disease, and satisfactory therapeutic strategies are urgently required. Cordyceps cicadae, a traditional Chinese herb, has potential renoprotective benefits and is widely used in the treatment of many kidney diseases. To investigate the mechanisms underlying the renoprotective effect of C. cicadae on hypertensive renal injury, we studied the effect of C. cicadae on tubular epithelial cells (TECs) in a spontaneously hypertensive rat (SHR) model and angiotensin II- (AngII-) cultured primary TECs. Our study showed that C. cicadae treatment could decrease 24-hour urine albumin, albumin-to-creatinine ratio (ACR), β2-MG level, and kidney injury molecule-1 (kim-1) level in SHR urine, alleviate interstitial fibrosis, and reduce α-smooth muscle actin (α-SMA) expression in SHR kidney. In primary TECs, medicated serum containing C. cicadae (CSM) might significantly reduce the AngII-induced production of kim-1 and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, C. cicadae treatment could decrease TEC apoptosis in SHRs as assessed by the terminal transferase-mediated biotin dUTP nick-end labeling (TUNEL) assay. CSM could inhibit caspase-3 activity and enhance cellular viability as measured by methyl thiazolyl tetrazolium in AngII-cultured TECs, suggesting that CSM might reduce the apoptosis level in TECs induced by AngII. We found that the SIRT1 expression level was markedly lowered, while the protein level of acetylated-p53 was elevated in the TECs of patients with hypertensive renal injury and SHRs. C. cicadae presented the effect of regulating the SIRT1/p53 pathway. Further SIRT1 inhibition with EX527 reversed the effect of C. cicadae on AngII-induced apoptosis. Taken together, our results indicate that C. cicadae offers a protective effect on TECs under hypertensive conditions, which may be related to its antiapoptotic effect through regulation of the SIRT1/p53 pathway.


A summary-statistic representation in peripheral vision explains visual crowding.
Peripheral vision provides a less faithful representation of the visual input than foveal vision. Nonetheless, we can gain a lot of information about the world from our peripheral vision, for example in order to plan eye movements. The phenomenon of crowding shows that the reduction of information available in the periphery is not merely the result of reduced resolution. Crowding refers to visual phenomena in which identification of a target stimulus is significantly impaired by the presence of nearby stimuli, or flankers. What information is available in the periphery? We propose that the visual system locally represents peripheral stimuli by the joint statistics of responses of cells sensitive to different position, phase, orientation, and scale. This "textural" representation by summary statistics predicts the subjective "jumble" of features often associated with crowding. We show that the difficulty of performing an identification task within a single pooling region using this representation of the stimuli is correlated with peripheral identification performance under conditions of crowding. Furthermore, for a simple stimulus with no flankers, this representation can be adequate to specify the stimulus with some position invariance. This provides evidence that a unified neuronal mechanism may underlie peripheral vision, ordinary pattern recognition in central vision, and texture perception. A key component of our methodology involves creating visualizations of the information available in the summary statistics of a stimulus. We call these visualizations "mongrels" and show that they are highly useful in examining how the early visual system represents the visual input. Mongrels enable one to study the "equivalence classes" of our model, i.e., the sets of stimuli that map to the same representation according to the model.


Association between hospitalisation for ambulatory care-sensitive conditions and primary health care physician specialisation: a cross-sectional ecological study in Curitiba (Brazil).
Hospitalisation for ambulatory care-sensitive conditions (HACSCs) is frequently used as an indicator of the quality and effectiveness of primary healthcare (PHC) services around the world. The aim of the present study was to evaluate whether the PHC model (family health strategy (FHS) x conventional) and the availability of specialised PHC physicians is associated or not with total hospitalisation or HACSCs in the National Health System (SUS) of the municipality of Curitiba, Paraná state (PR), Brazil. This is a cross-sectional ecological study using multiple linear regression with socioeconomic and professional data from municipal health units (MHUs) between 1 April 2014 and 31 March 2015. After adjustment for age and sex and control of socioeconomic variables, the FHS model was associated with six fewer HACSCs a year per 10 000 inhabitants in relation to the conventional model and the availability of one family physician at each FHS model MHU per 10 000 inhabitants was associated with 1.1 fewer HACSCs for heart failure a year per 10 000 inhabitants. Basic specialists (clinicians, paediatricians and obstetrician/gynaecologists) and subspecialists showed no significant association with HACSC rates. These results obtained in a major Brazilian city reinforce the role of FHS as a priority PHC model in the country and indicate the potentially significant impact of specialising in family medicine on improving the health conditions of the population.


Molecular characteristic of antibodies in the blood serum and in the lymph nodes during fractional immunization with small doses of bacterial vaccines.
An experiment on 58 rabbits demonstrated that only macromolecular agglutinins 19S are present in extracts from the lymph nodes after fractional immunization with small doses of typhoid vaccine or some dysentery vaccine. At the same time, antibodies in the blood serum are distributed in fractions of different molecular weight, starting from the 14th day of experiment. It is very probable that this distribution of antibodies is associated with the occurrence in the blood of an inhibitor of the activity of macromolecular antibodies.


Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps.
Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-kappaB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-kappaB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.


Ability to distinguish whisky (uisge beatha) from brandy (cognac).
To assess ability to distinguish between first rate malt whisky and brandy and between different brands of each. Crossover with two sessions of 12 blindfold tastings of two whiskies and two brandies before and after supper, repeated not more than seven days later. Dundas, Ontario. 4 volunteers aged 50-68 years, all moderate drinkers of alcohol and members of a wine club. Proportion of samples correctly identified (whisky v brandy) and, of those, the proportion of brands correctly identified. Only one participant produced irrefutable statistical evidence (P < 0.0001) of being able to distinguish between whisky and brandy, correctly identifying 50/51 (98%) samples. Two participants achieved some success in identification (72%, P = 0.0031 and 65% P = 0.031). The fourth participant's responses reflected pure guesswork. Brandy was no easier to identify than whisky (P = 0.84). The participant who was best able to distinguish between whisky and brandy was also best able to identify correctly the brand of whisky (100%, P < 0.0001). Despite the fact that not all participants completed the full number of tastings the results show that some participants could distinguish neither between malt whisky and brandy nor between different brands of whisky and brandy. However, the success of one participant shows that "it can be done" and that his whisky specific ability is acquired not innate.


Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells.
Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c(+) DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction of regulatory T cells. Our results show that a reduction of DCs interferes with tolerance, resulting in a stronger inflammatory response, and that other APC populations could compensate for the loss of immunogenic APC function in DC-depleted mice.


Enteritis associated with Campylobacter laridis.
Campylobacter laridis has occasionally been isolated from patients with diarrhea, but its clinical significance in this setting has yet to be established. We report a patient with a self-limited diarrheal illness whose stool cultures yielded C. laridis. The patient also developed a specific serum bactericidal antibody response to this strain of C. laridis, suggesting that the organism was causally related to the enteric illness.


Deducing drop size and impact velocity from circular bloodstains.
An experimental study was done to determine the diameter and velocity of blood drops falling on a surface by measuring the size of bloodstains they produced and counting the number of radial spines projecting from them. Bloodstains were formed by releasing drops of pig blood with a range of diameters (3.0-4.3 mm) and impact velocities (2.4-4.9 m/s), onto four different flat surfaces (glass, steel, plastic, paper) with varying roughness (0.03-2.9 microm). High-speed photography was used to record drop impact dynamics. Bloodstain diameters and the number of spines formed around the rim of stains increased with impact velocity and drop diameter. Increasing surface roughness reduced stain diameter and promoted merging of spines, diminishing their number. Equations are presented that explicitly relate drop diameter and impact velocity to measurements of stain diameter and number of spines.


Intramolecular substitution uncages fluorogenic probes for detection of metallo-carbapenemase-expressing bacteria.
This work reports a novel caging strategy for designing fluorogenic probes to detect the activity of β-lactamases. The caging strategy uses a thiophenyl linker connected to a fluorophore caged by a good leaving group-dinitrophenyl. The uncaging proceeds in two steps through the sulfa-releasing and subsequent intramolecular substitution. The length of the linker has been examined and optimized to maximize the rate of intramolecular reaction and thus the rate of fluorescence activation. Finally based on this strategy, we prepared a green fluorogenic probe CAT-7 and validated its selectivity for detecting metallo-carbapenemases (VIM-27, IMP-1, NDM-1) in carbapenem-resistant Enterobacteriaceae (CRE) lysates.


Comprehensive Analysis of Serum microRNAs in Autoimmune Pancreatitis.
Autoimmune pancreatitis (AIP) is a rare disease that has recently emerged as a unique type of pancreatitis with a presumed autoimmune etiology. MicroRNA (miRNA) is a small non-coding RNA that targets multiple mRNAs. miRNAs might exist in serum in a stabilized form, suggesting its potential application as a biomarker. We here examined the miRNA expression profile in the serum of patients with AIP. miRNAs were prepared from serum samples of patients with various pancreatic diseases (AIP (n = 3, each before and after the steroid therapy), chronic pancreatitis (n = 5), pancreatic cancer (n = 5)) or healthy controls (n = 5). A human miRNA Oligo chip containing approximately 2,000 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. Microarray analysis identified miRNAs highly expressed in the serum of patients with AIP: 13 miRNAs vs. CP, 204 miRNAs vs. pancreatic cancer, and 19 miRNAs vs. healthy controls. miR-150-5p was commonly upregulated in AIP compared to the other samples. IPA revealed the most biological processes affected by the steroid therapy including cellular development, cellular growth, and cell movement. Our results identified that miRNAs were differentially expressed in the serum of AIP patients.


The thioredoxin reductase system of mycoplasmas.
Representative species of the Mollicutes possess a thioredoxin reductase system (NTS) composed of a low-molecular-mass thioredoxin (TRX) and NADPH-binding thioredoxin reductase (NTR). The TRXs of Mycoplasma pneumoniae and M. capricolum have molecular masses of 11-2 and 12 kDa, respectively, and are stable at 90 degree C for 10 min. Both TRXs reacted with monospecific polyclonal antibodies generated against the Bacillus subtilis TRX, but not with anti-Escherichia coli TRX antisera. The M. capricolum and M. pneumoniae NTRs were partially purified and were found to be active with the homologous TRX, but not with the TRX of B. subtilis or E. coli. The NTS activity had an optimal pH of 6.5-7.5 and was dependent on NADPH as an election donor, a requirement which could not be fulfilled by NADH. The genes encoding the TRX and NTR (trxA and trxB) or M. pneumoniae were cloned and sequenced. The comparative analysis of the predicted amino acid sequence of trxA showed that the 11.2 kDa protein (102 aa) shared 26-68% sequence similarity with products of other known trxA genes and contained the conserved active site Cys-Gly-Pro-Cys. The predicted amino acid sequence of trxB contained 315 residues with a conserved NADPH binding domain and FAD binding domains I and II. The cysteine dithiol redox active region had isoleucine rather than threonine at the active site, as compared with other NTRs. The high activity of the NTS in mycoplasmas suggests that mycoplasmas may have evolved the NTS to protect themselves from the consequences of their self-generated oxidative challenge.


Statistical research on marine natural products based on data obtained between 1985 and 2008.
Since the 1960s, more than 20,000 compounds were discovered from marine organisms. In this paper we performed a quantitative analysis for the novel marine natural products reported between 1985 and 2008. The data was extracted mainly from the reviews of Faulkner and Blunt [1-26]. The organisms producing these marine natural products are divided into three major biological classes: marine microorganisms (including phytoplankton), marine algae and marine invertebrate. The marine natural products are divided into seven classes based on their chemical structure: terpenoids, steroids (including steroidal saponins), alkaloids, ethers (including ketals), phenols (including quinones), strigolactones, and peptides. The distribution and the temporal trend of these classes (biological classes and chemical structure classes) were investigated. We hope this article provides a comprehensive perspective on the research of marine natural products.


Chemotherapy for head and neck cancer.
This overview of the role of chemotherapy in head and neck cancer is based on clinical trials conducted at The Princess Margaret Hospital and on a critical review of the literature. For recurrent or metastatic squamous cell carcinoma, no drug or combination has been found superior to methotrexate, which in large series gives transient responses in about 25% of patients. Reports of higher rates of response have not correlated with increased survival, and response rates from many series have been inflated by the use of poor and variable criteria of response or by inappropriate exclusion of patients. Chemotherapy may lead to high rates of response when used initially as part of combined modality treatment with radiation and/or surgery, but longterm benefit has not yet been demonstrated. Chemotherapy should not be considered part of standard management for recurrent or metastatic head and neck cancer, and should be used as part of primary treatment for loco-regional disease only in the context of large, well designed clinical trials.