Critical role of lysine 204 in switch I region of Galpha13 for regulation of p115RhoGEF and leukemia-associated RhoGEF.
Heterotrimeric G proteins of the G12 family regulate the Rho GTPase through RhoGEFs that contain an amino-terminal regulator of G protein signaling (RGS) domain (RGS-RhoGEFs). Direct regulation of the activity of RGS-RhoGEFs p115 or leukemia-associated RhoGEF (LARG) by Galpha13 has previously been demonstrated. However, the precise biochemical mechanism by which Galpha13 stimulates the RhoGEF activity of these proteins has not yet been well understood. Based on the crystal structure of Galphai1 in complex with RGS4, we mutated the Galpha13 residue lysine 204 to alanine (Galpha13K204A) and characterized the effect of this mutation in its regulation of RGS-RhoGEFs p115 or LARG. Compared with wild-type Galpha13, Galpha13K204A induced much less serum-response factor activation when expressed in HeLa cells. Recombinant Galpha13K204A exhibits normal function in terms of nucleotide binding, basal GTP hydrolysis, and formation of heterotrimer with betagamma. We found that lysine 204 of Galpha13 is important for interaction with the RGS domain of p115 or LARG and for the GTPase-activating protein activity of these proteins. In addition, the K204A mutation of Galpha13 impaired its regulation of the RhoGEF activity of p115 or LARG. We conclude that lysine 204 of Galpha13 is important for interaction with RGS-RhoGEFs and is critically involved in the regulation of their activity.


Personal exposure to particulate matter less than 2.5 microm in Mexico City: a pilot study.
This study was aimed to describe the personal exposure of permanent residents in Mexico City's Metropolitan Area (MCMA) to particulate matter of less than 2.5 microm diameter (PM(2.5)) during their daily activities. A total of 40 healthy volunteers (30 women and 10 men) with sedentary activities were included. All of them carried a PM(2.5) personal monitor during 13 h and registered their activities in a written diary that classified them in indoor and outdoor microenvironments in each 30 min period. All sample collections started at 0900 hours, and even though measurements were obtained during the rainy season (April-August 2002), the relative humidity was less than 70%. The data were categorized and evaluated under the following criteria: morning and afternoon exposure, indoor and outdoor activities, and geographical location. The descriptive analysis showed that the overall outdoor median concentration of PM(2.5) (89.50 microg/m(3)) was higher than the indoor one (67.55 microg/m(3)). PM(2.5) concentrations in the morning to early afternoon were more elevated than in the late afternoon, suggesting a circadian-like behavior. In the indoor microenvironment, the highest concentration occurred in the subway (106.2 microg/m(3)) followed by school (93.27 microg/m(3)), and the lowest at home (53.1 microg/m(3)). The outdoor microenvironment with the highest concentrations was the public transportation (bus) (99.95 microg/m(3)), while the automobile had the lowest (64.9 microg/m(3)). The geographical zone with the highest concentration was the Center city area (87.87 microg/m(3)), and the one with the lowest concentration was the northeast area of the city (50 microg/m(3)). All the differences were statistically significant (P<0.05). Multivariate analysis corroborated that PM(2.5) concentrations are mainly determined by geographical locations and hour of the day, but not by the type of microenvironment. The inclusion of covariables in the multivariable analysis ensures a more accurate estimation and prediction of the real PM(2.5) concentrations. In conclusion, PM(2.5) personal exposure of healthy adult permanent residents of MCMA is usually higher than recommended by the international standards in outdoor and even in indoor microenvironments. Particulate matter personal exposure varies in relation to hour of the day, daily activities and microenvironments.


Kids, Difficult Asthma and Fungus.
Fungi have many potential roles in paediatric asthma, predominantly by being a source of allergens (severe asthma with fungal sensitization, SAFS), and also directly damaging the epithelial barrier and underlying tissue by releasing proteolytic enzymes (fungal bronchitis). The umbrella term 'fungal asthma' is proposed for these manifestations. Allergic bronchopulmonary aspergillosis (ABPA) is not a feature of childhood asthma, for unclear reasons. Diagnostic criteria for SAFS are based on sensitivity to fungal allergen(s) demonstrated either by skin prick test or specific IgE. In children, there are no exclusion criteria on total IgE levels or IgG precipitins because of the rarity of ABPA. Diagnostic criteria for fungal bronchitis are much less well established. Data in adults and children suggest SAFS is associated with worse asthma control and greater susceptibility to asthma attacks than non-sensitized patients. The data on whether anti-fungal therapy is beneficial are conflicting. The pathophysiology of SAFS is unclear, but the epithelial alarmin interleukin-33 is implicated. However, whether individual fungi have different pathobiologies is unclear. There are many unanswered questions needing further research, including how fungi interact with other allergens, bacteria, and viruses, and what optimal therapy should be, including whether anti-neutrophilic strategies, such as macrolides, should be used. Considerable further research is needed to unravel the complex roles of different fungi in severe asthma.


Allelic forms of beta 2-microglobulin in the mouse.
Spleen cells from BALB/c and C57BL/6 mice were cultured separately or together, and the biosynthetically labeled supernates were examined by two-dimensional polyacrylamide gel electrophoresis. Although there were no major labeled proteins in the mixed group that were not present in the separate cultures, there was a major low-molecular-weight protein that differed in charge in the two strains. This protein was identified as beta 2-microglobulin; it could be labeled with 125I on the cell surface by using the lactoperoxidase technique, was noncovalently attached to the H-2K molecule, and had the expected size and charge when compared with human beta 2-microglobulin. Both acidic and basic forms were present in (BALB/c X C57BL/6) F1 hybrids, suggesting codominant expression, although allelic exclusion was not ruled out. Either parental form could combine with one parental form of the H-2K molecule. The beta 2-microglobulin gene does not appear to be closely linked to either the H-2 or th immunoglobulin heavy-chain complexes. It is proposed that beta 2-microglobulin is an "effector subunit" of histocompatibility antigens and that its physiological role is to interact with a specific killing structure on the surface of cytolytic T lymphocytes and thereby initiate cell destruction.


A link between parotid salivary Ig level and recurrent respiratory infections in young Down's syndrome patients.
The purpose of the present investigation was to assess the correlation between recurrent respiratory infections and the levels of salivary Ig in a group of young Down's syndrome (DS) individuals. Twenty-three DS and 10 age- and sex-matched healthy individuals were included. DS individuals who had experienced three or more upper respiratory tract infections (n = 10) in the previous 12 months were compared to DS individuals who had not experienced recurrent respiratory infections (n = 13) and to healthy controls (n = 10). A statistically significant reduction in the Ig salivary secretion rate was recorded in the subgroup with recurrent respiratory infections. No significant differences were seen between the subgroup without recurrent respiratory infections and controls. It is suggested that the secretory immune system provides local immune protection against pathogens in the respiratory tract. Detection of salivary Ig levels may serve as a predictor of the susceptibility of DS individuals to recurrent respiratory tract infections.


The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.
The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2',3,5',5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.


Long-term management of patients with hormone receptor-positive metastatic breast cancer: Concepts for sequential and combination endocrine-based therapies.
Treatment options for hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) continue to increase in parallel with expanding knowledge about the complex biology of breast cancer subtypes and resistance mechanisms to endocrine therapy. For patients with HR-positive MBC, there are now an unprecedented number of endocrine-based treatment options that can improve long-term outcomes, while preserving or optimizing quality of life, and that can be used before selecting more cytotoxic chemotherapeutic regimens. In addition to antiestrogens, steroidal and nonsteroidal aromatase inhibitors, the selective estrogen-receptor degrader, fulvestrant, and new endocrine-based combinations provide significant and clinically meaningful improvements in outcomes in the first line setting and beyond. Also, new clinical scenarios and indications for monotherapy endocrine and targeted therapies continue to be explored. Patients have several therapeutic options when their disease progresses or becomes resistant, although the optimal sequencing of these therapies remains unclear. Ongoing research in the resistant/refractory setting is anticipated to continue improving the outlook for these patients. This review will discuss current and investigational approaches to sequential single-agent endocrine and endocrine-based combination therapy for the long-term management of patients with HR-positive, human epidermal growth factor receptor 2-negative MBC.


Breast cancer-associated pS2 protein: synthesis and secretion by normal stomach mucosa.
The human pS2 gene is specifically expressed under estrogen transcriptional control in a subclass of estrogen receptor-containing human breast cancer cells. The pS2 gene encodes an 84-amino acid protein that is secreted after signal peptide cleavage. The distribution of pS2 protein in normal human tissues was studied with antibodies to pS2; pS2 was specifically expressed and secreted by mucosa cells of the normal stomach antrum and body of both female and male individuals. Moreover, no estrogen receptor could be detected in these cells, indicating that pS2 gene expression is estrogen-independent in the stomach. The function of the pS2 protein in the gastrointestinal tract is unknown. However, the pS2 protein is similar in sequence to a porcine pancreatic protein that has been shown to inhibit gastrointestinal motility and gastric secretion.


Serum Ang and CysC Levels in Essential Hypertension Complicated by Hypertensive Emergencies.
To explore the value of serum angiotensin Ⅱ (Ang II) and cystatin C (CysC) levels in predicting hypertension emergency in patients with essential hypertension. Experimental study. Hangzhou Hospital of Zhejiang Medical and Health Group, from January 2018 to February 2020. One hundred and thirty seven patients with essential hypertension were divided into hypertension emergency group (Group A, 42 cases) and essential hypertension group without emergency (Group B, 95 cases). Ninety-five healthy subjects were selected as control group. Correlation between serum Ang and CysC and essential hypertension complicated with hypertension emergency was analysed. Diagnostic ability of Ang and CysC was analysed by ROC curve. Serum Ang and CysC levels in Group A and B were higher than those in control group (all p <0.001); serum Ang II and CysC levels in Group A were higher than those in Group B (both p <0.001). Serum Ang II and CysC levels were positively correlated with essential hypertension complicated with hypertension emergency (r=0.480, p <0.001; r=0.485,p <0.001, respectively). Area under ROC curve of serum Ang II combined with CysC for predicting hypertension emergency was 0.905 (95%CI: 0.854-0.955), which was larger than that of serum Ang II, CysC alone. Serum Ang II and CysC in patients with primary hyperemia complicated with hypertension emergency were higher. Combined detection of serum Ang II and CysC might be used as an effective reference index for predicting hypertension emergencies in patients with essential hypertension. Key Words: Serum, Angiotensin Ⅱ (Ang II), Cystatin C (CysC), Essential hypertension, Hypertension emergency.


Rotavirus vaccine impact and socioeconomic deprivation: an interrupted time-series analysis of gastrointestinal disease outcomes across primary and secondary care in the UK.
Rotavirus causes severe gastroenteritis in infants and young children worldwide. The UK introduced the monovalent rotavirus vaccine (Rotarix®) in July 2013. Vaccination is free of charge to parents, with two doses delivered at 8 and 12 weeks of age. We evaluated vaccine impact across a health system in relation to socioeconomic deprivation. We used interrupted time-series analyses to assess changes in monthly health-care attendances in Merseyside, UK, for all ages, from July 2013 to June 2016, compared to predicted counterfactual attendances without vaccination spanning 3-11 years pre-vaccine. Outcome measures included laboratory-confirmed rotavirus gastroenteritis (RVGE) hospitalisations, acute gastroenteritis (AGE) hospitalisations, emergency department (ED) attendances for gastrointestinal conditions and consultations for infectious gastroenteritis at community walk-in centres (WIC) and general practices (GP). All analyses were stratified by age. Hospitalisations were additionally stratified by vaccine uptake and small-area-level socioeconomic deprivation. The uptake of the first and second doses of rotavirus vaccine was 91.4% (29,108/31,836) and 86.7% (27,594/31,836), respectively. Among children aged < 5 years, the incidence of gastrointestinal disease decreased across all outcomes post-vaccine introduction: 80% (95% confidence interval [CI] 70-87%; p < 0.001) for RVGE hospitalisation, 44% (95% CI 35-53%; p < 0.001) for AGE hospitalisations, 23% (95% CI 11-33%; p < 0.001) for ED, 32% (95% CI 7-50%; p = 0.02) for WIC and 13% (95% CI -3-26%; p = 0.10) for GP. The impact was greatest during the rotavirus season and for vaccine-eligible age groups. In adults aged 65+ years, AGE hospitalisations fell by 25% (95% CI 19-30%; p < 0.001). The pre-vaccine risk of AGE hospitalisation was highest in the most socioeconomically deprived communities (adjusted incident rate ratio 1.57; 95% CI 1.51-1.64; p < 0.001), as was the risk for non-vaccination (adjusted risk ratio 1.54; 95% CI 1.34-1.75; p < 0.001). The rate of AGE hospitalisations averted per 1,000 first doses of vaccine was higher among infants in the most deprived communities compared to the least deprived in 2014/15 (28; 95% CI 25-31 vs. 15; 95% CI 12-17) and in 2015/16 (26; 95% CI 23-30 vs. 13; 95% CI 11-16). Following the introduction of rotavirus vaccination, incidence of gastrointestinal disease reduced across the health-care system. Vaccine impact was greatest among the most deprived populations, despite lower vaccine uptake. Prioritising vaccine uptake in socioeconomically deprived communities should give the greatest health benefit in terms of population disease burden.


Initial results in the assessment of multiple myeloma using 18F-FDG PET.
This prospective study was undertaken to investigate the appearance of multiple myeloma on fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET). Furthermore, the accuracy of FDG-PET in detecting myeloma lesions and its influence on patient management were evaluated. Forty-three patients with known multiple myeloma (n=28) or solitary plasmacytoma (n=15) underwent FDG-PET. The results of routinely performed radiographs and of scans obtained using all available imaging modalities (MRI, CT), as well as the clinical course, were used for verification of detected lesions. Focally increased tracer uptake was observed in 38 of 41 known osteolytic bone lesions (sensitivity 92.7%) in 23 patients. In addition, 71 further bone lesions which were negative on radiographs were detected in 14 patients. Twenty-six (36.6%) of these lesions could be confirmed in ten patients. As a result of FDG-PET imaging, clinical management was influenced in five (14.0%) patients. The positive predictive value for active disease was 100% in patients with focal or mixed focal/diffuse skeletal FDG uptake and 75% in patients with diffuse bone marrow uptake. Depending on the interpretation of the PET scans in patients with diffuse bone marrow uptake, the sensitivity ranged from 83.8% to 91.9% and the specificity from 83.3% to 100%. FDG-PET thus proved highly accurate in detecting multiple myeloma, and revealed a greater extent of disease than routine radiographs in 14 of 23 (60.9%) patients who had osteolytic bone lesions. FDG-PET might contribute to the initial staging of solitary plasmacytoma.


Preconception paternal alcohol exposure exerts sex-specific effects on offspring growth and long-term metabolic programming.
Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-β signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm.


The effect of pore size and porosity on mechanical properties and biological response of porous titanium scaffolds.
The effect of pore size and porosity on elastic modulus, strength, cell attachment and cell proliferation was studied for Ti porous scaffolds manufactured via powder metallurgy and sintering. Porous scaffolds were prepared in two ranges of porosities so that their mechanical properties could mimic those of cortical and trabecular bone respectively. Space-holder engineered pore size distributions were carefully determined to study the impact that small changes in pore size may have on mechanical and biological behaviour. The Young's moduli and compressive strengths were correlated with the relative porosity. Linear, power and exponential regressions were studied to confirm the predictability in the characterisation of the manufactured scaffolds and therefore establish them as a design tool for customisation of devices to suit patients' needs. The correlations were stronger for the linear and the power law regressions and poor for the exponential regressions. The optimal pore microarchitecture (i.e. pore size and porosity) for scaffolds to be used in bone grafting for cortical bone was set to <212μm with volumetric porosity values of 27-37%, and for trabecular tissues to 300-500μm with volumetric porosity values of 54-58%. The pore size range 212-300μm with volumetric porosity values of 38-56% was reported as the least favourable to cell proliferation in the longitudinal study of 12days of incubation.


Smoothed Bootstrap Aggregation for Assessing Selection Pressure at Amino Acid Sites.
To detect positive selection at individual amino acid sites, most methods use an empirical Bayes approach. After parameters of a Markov process of codon evolution are estimated via maximum likelihood, they are passed to Bayes formula to compute the posterior probability that a site evolved under positive selection. A difficulty with this approach is that parameter estimates with large errors can negatively impact Bayesian classification. By assigning priors to some parameters, Bayes Empirical Bayes (BEB) mitigates this problem. However, as implemented, it imposes uniform priors, which causes it to be overly conservative in some cases. When standard regularity conditions are not met and parameter estimates are unstable, inference, even under BEB, can be negatively impacted. We present an alternative to BEB called smoothed bootstrap aggregation (SBA), which bootstraps site patterns from an alignment of protein coding DNA sequences to accommodate the uncertainty in the parameter estimates. We show that deriving the correction for parameter uncertainty from the data in hand, in combination with kernel smoothing techniques, improves site specific inference of positive selection. We compare BEB to SBA by simulation and real data analysis. Simulation results show that SBA balances accuracy and power at least as well as BEB, and when parameter estimates are unstable, the performance gap between BEB and SBA can widen in favor of SBA. SBA is applicable to a wide variety of other inference problems in molecular evolution.


Image-Driven Modeling of Nanoscopic Cardiac Function: Where Have We Come From, and Where Are We Going?
Complementary developments in microscopy and mathematical modeling have been critical to our understanding of cardiac excitation-contraction coupling. Historically, limitations imposed by the spatial or temporal resolution of imaging methods have been addressed through careful mathematical interrogation. Similarly, limitations imposed by computational power have been addressed by imaging macroscopic function in large subcellular domains or in whole myocytes. As both imaging resolution and computational tractability have improved, the two approaches have nearly merged in terms of the scales that they can each be used to interrogate. With this review we will provide an overview of these advances and their contribution to understanding ventricular myocyte function, including exciting developments over the last decade. We specifically focus on experimental methods that have pushed back limits of either spatial or temporal resolution of nanoscale imaging (e.g., DNA-PAINT), or have permitted high resolution imaging on large cellular volumes (e.g., serial scanning electron microscopy). We also review the progression of computational approaches used to integrate and interrogate these new experimental data sources, and comment on near-term advances that may unify understanding of the underlying biology. Finally, we comment on several outstanding questions in cardiac physiology that stand to benefit from a concerted and complementary application of these new experimental and computational methods.


Enabling student nurses to use the information superhighway.
Nursing graduates must be sophisticated in the use of information technologies and understand how these technologies interface with various health care systems. The purpose of this project was to evaluate the impact of a newly developed Internet course, focusing on current information technologies, on 20 RN-to-MSN students. Author-developed instruments were used to measure weekly computer use, perceived computer skill, and knowledge related to the information superhighway. The Stronge & Brodt Nurses Attitudes Toward Computerization Questionnaire was used to assess attitudes toward computerization. Qualitative data was elicited using weekly evaluation forms. When compared to 23 students at a similar stage of their nursing program, quantitative findings indicated that, at the end of the semester, students in the pilot course had more computer knowledge, reported greater computer skill, and used computers more. Qualitative findings suggested that pilot students: * Were connected with nursing networks and expressed their intent to maintain these networks. * Were able to use current health information found on the Internet in their nursing practices. * Used skills learned in the pilot class to complete projects in other classes. * Communicated with classmates via the Internet, thus forming a potentially valuable professional support system. * Used the library and librarians early in their programs. * Understood the relevancy of telemedicine and the Internet to the future survival of nursing in a changing health care arena. While the authors caution that an adequate infrastructure must be available to support such an endeavor, they emphasize that knowledge of the relevancy and use of the information superhighway is crucial to the future survival of nursing in a rapidly changing health care arena.


Thrombin activatable fibrinolysis inhibitor: a putative target to enhance fibrinolysis.
Thrombin activatable fibrinolysis inhibitor (TAFI) was discovered two decades ago consequent to the identification of an unstable carboxypeptidase (CPU) formed upon thrombin activation of its proenzyme. The antifibrinolytic effects of the activated form (TAFIa, CPU) are linked with its capacity to remove C-terminal lysines from the surface of the fibrin clot. A distinctive characteristic of TAFIa is its temperature-dependent conformational instability: TAFIa activity spontaneously decays with an apparent half-life of 8 to 15 minutes at 37°C. A variety of studies has demonstrated a role for TAFI/TAFIa in venous and arterial diseases. In addition, a role for TAFI/TAFIa in inflammation and cell migration has also been shown. Because TAFI/TAFIa is a potential risk factor for thrombotic disorders, many inhibitors, both at the level of activation or at the level of activity, have been developed and were proven to exhibit a profibrinolytic effect in animal models. Pharmacologically active inhibitors of the TAFI/TAFIa system may open new ways for the prevention of thrombotic diseases or for the establishment of adjunctive treatments during thrombolytic therapy.


Implicit and self-attributed motives to achieve: two separate but interacting needs.
This research examined how implicit and self-attributed needs to achieve (labeled as n Ach and san Ach, respectively) combine with self-referenced and norm-referenced feedback to predict effort-related (task performance) and choice-related (task continuation) indexes of students' engagement in a mental concentration task. In Experiment 1 the authors found that in a task-focused setting, task performance was predicted by the joint effect of self-referenced feedback and n Ach, whereas task continuation was predicted by the joint effect of norm-referenced feedback and san Ach. In Experiment 2 the authors found that in an ego-focused setting, n Ach and san Ach interacted in the prediction of task performance but not of task continuation. In Experiment 3 the authors found that the effects of n Ach and san Ach on students' performance were mediated by the anticipated affective value of achievement outcomes. These findings are discussed in relation to a 2-system approach to achievement motivation.


Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection.
HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-β, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear.


Dorsal bunion after clubfoot surgery: outcome of reverse Jones procedure.
The dorsal bunion deformity consists of the elevation of first metatarsal head, plantar flexion contracture at the first metatarsophalangeal joint, and dorsiflexion contracture of the tarsometatarsal joint. A reverse Jones procedure with transfer of the flexor hallucis longus to the metatarsal head has been an effective method in correcting this deformity. This is a retrospective review of 27 patients with 33 feet who had reverse Jones procedure with or without metatarsal osteotomy between 1983 and 2002. All patients had previous soft tissue releases for clubfoot deformity. Clinical reviews included muscle function test and radiographic evaluation before and after procedures. We used the American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal-interphalangeal scale for functional outcome results. The average follow-up was 4.96 years. There were 21 boys and 6 girls. Average age at time of procedure was 13.7 years. With the reverse Jones procedure, there were 18 first metatarsal osteotomies and 12 split anterior tibial tendon transfers. Before surgery, decreased muscle strength in triceps surae (73%), tibialis posterior (76%), peroneus longus (67%), and extensor hallucis longus (76%) was noted. Patients (84.9%) had normal tibialis anterior and flexor hallucis longus power. In radiographic evaluations, the operation resulted in decreased elevation of the first metatarsal by measuring the metatarsal-horizontal angle. The lateral metatarsophalangeal angle improved from 23 degrees plantar flexion to 1 degree in dorsiflexion. The average global American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal-interphalangeal score was 70 preoperatively and 92 postoperatively with improvement of subscores in pain, activity, footwear, range of motion, callus, and alignment. Dorsal bunion is a recognized long-term complication after clubfoot surgery. The causes of the deformity are weakness of Achilles tendon, overpowering of flexor hallucis longus, and strong anterior tibial tendon with weakness of peroneus longus. The reverse Jones procedure improved the condition in this series and provided a long-lasting and effective correction of the dorsal bunion deformity. Level 4.


Copper-Catalyzed, Stereoselective Bis-trifluoromethylthiolation of Propiolic Acid Derivatives with AgSCF3.
A copper-catalyzed chemo- and stereoselective oxidative bis-trifluoromethylthiolation of propiolic acid derivatives was achieved by using carboxylic acid as the activating group and formic acid as a cosolvent. The reaction of propiolic acid derivatives and AgSCF3 in the presence of (NH4)2S2O8 and catalytic Cu(OAc)2 in MeCN/HCO2H afforded bis-trifluoromethylthiolated acrylic acids in moderate to excellent yields with E selectivity. Further derivatization of the resultant products gave a series of polysubstituted SCF3-containing alkenes.


Update on the role of pharmaceutical-grade chondroitin sulfate in the symptomatic management of knee osteoarthritis.
Osteoarthritis (OA) is the most prevalent musculoskeletal disease and a major cause of negative relevant outcomes, associated with an ever-increasing societal burden. Pharmaceutical-grade chondroitin sulfate (CS) was repeatedly reported to reduce pain and improve function in patients with knee OA. This treatment was also shown to be cost-effective, compared to placebo, up to 24 months. However, controversies still persist regarding the usefulness of CS for patients with knee OA, mainly due to inconsistent reports from various clinical trials. In this literature review, we aimed to summarize the main most recent findings on the efficacy and safety of CS in OA. Based on the results of studies presenting a low risk of bias, the most recent meta-analysis shows that only the pharmaceutical-grade CS may be considered as an appropriate background treatment for the management of knee OA. Evidence from another recent meta-analysis, using data from full safety reports, confirms the good safety profile of CS in OA. This new evidence on efficacy and safety suggests that recommendations for the use of CS in patients with knee OA cannot be extrapolated to other low-grade preparations as generics, nutraceutical-grade or over-the-counter preparations.


Clinical Significance of Hepatocyte Growth Factor and Transforming Growth Factor-Beta-1 Levels in Assessing Disease Activity in Inflammatory Bowel Disease.
Background. Transforming growth factor-beta (TGF-β) and hepatocyte growth factor (HGF) are inflammatory cytokines which function as key regulators of immunological homeostasis and inflammatory responses. They have been linked to inflammatory bowel diseases (IBD). In this study, we aim to assess the levels of TGF-β and HGF and other inflammatory markers in patients with IBD and correlate them with the disease activity. Study Design. A cross-sectional study involving 100 patients with ulcerative colitis (UC) and 100 patients with Crohn's disease (CD) and 50 control subjects. TGF-β and HGF levels were measured and correlated with disease activity. Results and Conclusion. Serum levels of TGF-β and HGF were significantly higher in IBD patients compared with the control group. In the UC group, the levels of HGF and TGF-β were significantly higher than in the CD group. Levels of TGF-β and HGF correlate with the activity of IBD.


[Regional anesthesias in children--the concept, advantages and general principles].
Validates the concept and discusses the advantages of central and peripheral regional anesthesias in children in combination with superficial narcosis during the stage of analgesia in surgical interventions of any severity. Emphasizes the efficacy of regional blocking, including prolonged ones, for postoperative analgesia. Presents the fundamentals of regional anesthesias in children.


Toward youth self-report of health and quality of life in population monitoring.
This paper addresses population monitoring of youth health and quality of life, including the concepts used, methodological and practical criteria for indicators, and existing surveys and measures. Current population surveys of youth generally focus on poor health, such as disability or health-risk behaviors. Although these are important end points, indicators of illness or risk do not reflect the health or life perspective of the majority of youth who do not experience health problems. The measures used to monitor youth health should be appropriate and sensitive to future needs and capture the perspectives of youths. Two potential concepts for this "scorecard" are self-perceived health and quality of life, which have been shown to be useful in adults. For youth, the quality of life framework seems particularly relevant as it incorporates both positive and negative aspects of health and well-being and also captures salient aspects of health other than physical health, such as sense of self, social relationships, environment and culture, and life satisfaction.


The connection between QT dispersion and autonomic neuropathy in patients with type 2 diabetes.
It is controversial whether an increase in the QT dispersion (QTd) on the electrocardiogram (ECG) reflects cardiac autonomic neuropathy in diabetic patients. In the current study, the QTd was compared in 60 type 2 diabetic patients and in 30 healthy subjects, and its association with autonomic neuropathy in diabetic patients was investigated. An increased QTd was found in diabetic patients, compared to healthy subjects. The QTd had significant negative associations with the log of the low and high frequency power (log LF and HF, respectively) of the power spectral analyses (PSA) of heart rate variations and the systolic blood response during standing (Delta BP). There was no significant difference in the QTd between patients with and without sympathetic skin response (SSR), reflecting peripheral sympathetic function. A significant positive correlation was also found between QTd and the systolic blood pressure (SBP). On the other hand, there was no correlation between QTd and serum total cholesterol (TC), triglycerides (TG), fasting plasma glucose (FPG), hemoglobin (Hb) A (1C) concentrations or body mass index (BMI). By multiple regression analysis, the log HF, which reflects cardiac parasympathetic function, and the SBP alone were significantly associated with QTd as the dependent variable. The Delta BP and log LF, which partially reflect sympathetic nerve function, had no significant associations with QTd. These findings suggest that QTd reflects cardiac autonomic neuropathy (relative parasympathetic neuropathy) and that the QTd is also influenced by SBP, independent of autonomic neuro-function.


(S)-2-(1-Methyl-indolin-2-yl)-1,3-diphenyl-propan-2-ol.
The five-membered ring in the the title mol-ecule, C(24)H(25)NO, fused with the phenyl-ene ring, is almost planar (r.m.s. deviation = 0.023 Å), with the methyl-ene C atom deviating most from this mean plane [0.031 (1) Å]. The tertiary N atom shows a flattened pyramidal configuration [Σ(angles at N) = 350.3 (6)°].


[Omics molecular subtyping, prognostic prediction and individualized treatment of prostate cancer: Advances in studies].
Prostate cancer (PCa) is a most common malignancy in males. It has a greater heterogeneity than other cancers, which poses a real challenge to the clinical diagnosis, classification and prognostic monitoring. At present, high-, medium- and low-risk PCa patients are classified mainly by Gleason scores and the PSA level, which, however, fail to reveal the diverse molecular heterogeneity and precisely distinguish the molecular subtypes of PCa. With the development of high-throughput sequencing, more and more studies on the molecular classification of the malignancy have paved the theoretical ground for the early diagnosis, efficacy prediction and individualized treatment of PCa. This study reviews the molecular classification, prognosis prediction and individualized treatment of PCa to date, hoping to contribute to the development of the precise treatment of PCa.


Metrizamide in experimental urography. V. Renal excretion mechanism of a non-ionic contrast medium in rabbit and cat.
The excretion mechanisms of the non-ionic contrast medium, metrizamide, and the ionic, sodium diatrizoate, are compared to investigate the potential usefulness of metrizamide in clinical urography. A mixture of 125I-labeled metrizamide and 131I-labeled diatrizoate was injected intravenously to rabbits or cats. Urine, bile and blood were analyzed for their concentration of iodine. From these concentrations the renal and total clearance was calculated. In the rabbit the excretion of metrizamide was also compared with that of 3H-inulin with or without influence of p-aminohippurate or probenecid. The earlier reported relatively low urinary iodine concentrations after intravenous injection to rabbits of low doses were explained by the following findings: In the rabbit the volume of distribution, the renal clearance and the total clearance of metrizamide were smaller than those measured for diatrizoate and inulin. The biological half-life in serum measured 30-150 min after injection was the same for all three compounds. No indication of tubular secretion was found. The excretion mechanism of the contrast media exhibits species differences as no differences between metrizamide and diatrizoate in the parameters mentioned above could be measured in the cat.


Cellular Automata Modeling of Ostwald Ripening and Rayleigh Instability.
A cellular automata (CA) approach to modeling both Ostwald ripening and Rayleigh instability was developed. Curvature-driven phase interface migration was implemented to CA model, and novel CA rules were introduced to ensure the conservation of phase volume fraction of nearly equilibrium two-phase system. For transient Ostwald ripening, it is shown that the temporal growth exponent m is evolving with time and non-integer temporal exponents between 2 and 3 are predicted. The varying temporal growth exponent m is related to the particle size distributions (PSDs) evolution. With an initial wide PSD, it becomes narrowed toward steady state. With an initial narrow PSD, it becomes widened at first and then narrowed toward steady state. For Rayleigh instability, two cases (one with sinusoidal perturbation on the surface of the long cylinder, and the other with grain boundaries in the interior of the long cylinder) were simulated, and the breakup of the long cylinder was shown for both cases. In the end, a system containing long cylinders with interior grain boundaries was simulated, which demonstrated the integration of Rayleigh instability and Ostwald ripening relating to the spheroidization of the lamellar structure.


Three-dimensional transcranial Doppler blood flow mapping in patients with cerebrovascular disorders.
We investigated 60 patients with cerebrovascular disorders using a three-dimensional transcranial Doppler blood flow mapping system. A composite display of the circle of Willis is created with computer assistance, allowing accurate vessel identification and optimal data documentation of blood flow velocity and direction in the basal cerebral arteries. The basilar artery was insonated in every patient; the middle cerebral artery and the most distal internal carotid artery were found in 95% of the patients, the anterior cerebral artery in 85%, and the posterior cerebral artery in 84%. Insonation problems occurred predominantly in elderly women. Transcranial Doppler blood flow mapping showed an abnormal result in 23 of 60 patients (38%). An intracranial stenosis with greater than 50% diameter reduction or occlusion was found in 10 of 31 patients (32%) with completed stroke, reversible ischemic neurologic deficit, or transient ischemic attack. Collateral blood flow mechanisms could be demonstrated in patients with extracranial carotid artery occlusions. Intra-arterial cerebral angiography performed in 21 patients confirmed the transcranial Doppler blood flow mapping diagnosis in 19 (90.5%). In one patient an arteriovenous malformation diagnosed by transcranial Doppler blood flow mapping was confirmed by magnetic resonance imaging.


Significance of C4d expression in peritubular capillaries concurrent with microvascular inflammation in for-cause biopsies of ABO-incompatible renal allografts.
Pathologic diagnosis of antibody-mediated rejection (ABMR) in ABO-incompatible (ABOi) transplantation patients is often challenging because patients without ABMR are frequently immunopositive for C4d. The aim of this study was to determine whether C4d positivity with microvascular inflammation (MVI), in the absence of any detectable donor-specific antibodies (DSAs) in ABOi patients, could be considered as ABMR. A retrospective study of 214 for-cause biopsies from 126 ABOi kidney transplantation patients was performed. Patients with MVI score of ≥2 and glomerulitis score of ≥1 (n = 62) were divided into three groups: the absolute ABMR group (DSA-positive, C4d-positive or C4d-negative; n = 36), the C4d-positive group (DSA-negative, C4d-positive; n = 22), and the C4d-negative group (DSA-negative, C4d-negative; n = 4). The Banff scores, estimated glomerular filtration rates (eGFRs), and graft failure rates were compared among groups. C4d-positive biopsies showed higher glomerulitis, peritubular capillaritis, and MVI scores compared with C4d-negative specimens. The C4d-positive group did not show significant differences in eGFRs and graft survival compared with the absolute ABMR group. The results indicate that C4d positivity, MVI score of ≥2, and glomerulitis score of ≥1 in ABOi allograft biopsies may be categorized and treated as ABMR cases.


Catecholamine-induced cardiovascular disease in the spontaneously hypertensive and atherosclerotic turkey.
The interest evoked by the Broad Breasted White Turkey (BBWT) as an animal model for studying the cardiovascular damages produced by hypertension and catecholamines is mainly due to the fact that hypertension is spontaneous and tissue and circulating catecholamines, especially norepinephrine, are extremely high. In this paper we focused our attention on three characteristic pathophysiological features displayed by these animals which are strictly related, as well as in humans, to the elevated blood pressure values and to catecholamine action. We also described the possibility of modifying the development of some of these lesions with pharmacological interventions liable to antagonize the peripheral effects of norepinephrine and epinephrine. The dissecting aneurysm of the aorta accounts for 5-10% of sudden deaths in this animal strain. It can be prevented by lowering blood pressure, especially with beta-blockers, and facilitated by MAO-inhibitors. The degree of cardiac hypertrophy is remarkably high and unexpectedly characterized by the synthesis of a "fast" V1-like isomyosin with high Ca++ activated ATPase activity, oxygen consumption and speed of muscle shortening. Neither the reduction of the degree of cardiac hypertrophy, nor treatment with labetalol alone were able to modify this peculiar pattern. In spite of having very high levels of high-density-lipoproteins, which are known to be protective against atherosclerosis, this animal develops a severe atheromatous disease especially in the abdominal aorta, where the cellular growth has also been proven to be in vitro more pronounced than in the thoracic tract. Treatment with beta-blockers reduced the severity and extent of the lesion even in absence of a significant reduction in blood pressure.


Limited and digestive proteolysis: crosstalk between evolutionary conserved pathways.
Contents 958 I. 958 II. 959 III. 960 IV. 962 V. 962 962 References 963 SUMMARY: Proteases can either digest target proteins or perform the so-called 'limited proteolysis' by cleaving polypeptide chains at specific site(s). Autophagy and the ubiquitin-proteasome system (UPS) are two main mechanisms carrying out digestive proteolysis. While the net outcome of digestive proteolysis is the loss of function of protein substrates, limited proteolysis can additionally lead to gain or switch of function. Recent evidence of crosstalk between autophagy, UPS and limited proteolysis indicates that these pathways are parts of the same proteolytic nexus. Here, we focus on three emerging themes within this area: limited proteolysis as a mechanism modulating autophagy; interplay between autophagy and UPS, including autophagic degradation of proteasomes (proteophagy); and specificity of protein degradation during bulk autophagy.


[Feline leukemia virus (FeLV) and FeLV-associated diseases in cats: a review].
Feline leukaemia virus (FeLV) usually occurs in its natural species, the domestic cat. FeLV is also important to human individuals as a comparative model, as FeLV may cause a variety of diseases which are partly malignant and partly benign, such as immunosuppression which bears a resemblance to AIDS (acquired immune deficiency syndrome) in man. Although FeLV is a common infective agent, the incidence of disease due to FeLV is much higher in cats kept in closed households in which several of them are present than it is in free-range cats. Consequently, diseases caused by FeLV are frequently diagnosed in pedigree cats which are often maintained in relatively large numbers. FeLV is transmitted among cats by contagion. The main sources of infection are persistantly infected FeLV carrier cats which continuously excrete virus from the mouth and in other secretions. The majority of cats infected with FeLV will produce neutralising antibodies. Cats which are unable to do so, will become permanently infected. The prognosis is bad in these cats: 90 per cent will die within five years. Various techniques are used to detect FeLV. The most common method, the indirect immunofluorescence (IFA) test, is performed on air-dried blood smears. The results of the IFA agree with that are almost completely identical to those of the virus isolation test. Another test is ELISA (enzyme-linked immunosorbent assay), which produces approximately 10 per cent more positive results which are probably due to circulating FeLV antigens. Dissemination of FeLV among cats may be prevented by identifying infected carrier cats and removing them from contact with non-infected cats. Removal programmes using indirect immunofluorescent antibody (IFA) tests were used successfully in the Netherlands. The proportion of FeLV-positive cats decreased from 9 per cent in 1974 to approximately 3 per cent in 1985 during such a removal programme. During the above period, the removal programme was carried out in the society of Dutch cat breeders 'Felikat', the programme being made compulsory on all members of the society. The incidence of cats positive for FeLV decreased from over 11 per cent in 1974 to less than 2 per cent within four years. None of the cats tested in this society was found to be positive for FeLV in 1984 and 1985. Besides removal programmes, other methods of control, such as vaccination, were developed to prevent the spread of FeLV. The FeLV-immunostimulating complex vaccine (FeLV-ISCOM vaccine) a subunit vaccine in which FeLV-gp70 is presented in a particular manner, seems to be promising.


Order statistics of Rosenstock's trapping problem in disordered media.
The distribution of times t(j,N) elapsed until the first j independent random walkers from a set of N>>1, all starting from the same site, are trapped by a quenched configuration of traps randomly placed on a disordered lattice is investigated. In doing so, the cumulants of the distribution of the territory explored by N independent random walkers S(N)(t), and the probability Phi(N)(t) that no particle of an initial set of N is trapped by time t are considered. Simulation results for the two-dimensional incipient percolation aggregate show that the ratio between the nth cumulant and the nth moment of S(N)(t) is, for large N, (i) very large in comparison with the same ratio in Euclidean media, and (ii) almost constant. The first property implies that, in contrast with Euclidean media, approximations of the order higher than the standard zeroth-order Rosenstock approximation are required to provide a reasonable description of the trapping order statistics. Fortunately, the second property (which has a geometric origin) can be exploited to build these higher-order Rosenstock approximations. Simulation results for the two-dimensional incipient percolation aggregate confirm the predictions of our approach.


Alternaphenol B2, a new IDH1 inhibitor from the coral-derived fungus Parengyodontium album SCSIO SX7W11.
A new aromatic polyketide, alternaphenol B2 (1), and four known compounds (2-5) were isolated from the coral-derived fungus Parengyodontium album SCSIO SX7W11. Their structures were elucidated by high-resolution mass spectrometry, 1D and 2D NMR spectroscopy and comparison with reported literatures. Compounds 1 and 2 exhibited selective inhibitory activity against isocitrate dehydrogenase mutant R132H (IDH1m), with IC50 values of 41.9 and 27.7 μM, respectively. Our findings thus provide a fresh incentive for investigation on IDH1m inhibitors as lead compounds for cancer treatment.


Tactile stimulation facilitates functional recovery and dendritic change following neonatal hemidecortication in rats.
After large neocortical lesions, such as hemidecortication, children can show significant motor and cognitive impairments. It thus is of considerable interest to identify treatments that might enhance long-term functional outcome. We have previously shown that tactile stimulation enhances recovery from perinatal focal cortical lesions in rats, so the goal of the present experiment was to explore the effectiveness of postlesion tactile stimulation in reducing functional deficits associated with neonatal hemidecortication. Rats were given hemidecortications on postnatal day 10 (P10). Half of the group was then exposed to a daily tactile stimulation treatment for 15 min, three times a day for eleven days following the surgery. All groups were then tested on a number of behavioural tasks (Morris water task, skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were two main findings in this experiment: 1) Tactile stimulation improved cognitive ability and some motor performance after P 10 hemidecortication; and, 2) Tactile stimulation altered cortical organization after P10 hemidecortication. Tactile stimulation may provide an important noninvasive therapy after hemispherectomy in children.


Acidosis, local anesthetics, and the newborn.
Four newborn infants were studied following maternal epidural block with lidocaine or mepivacaine. Each of these neonates, born with a pH of 7.23 or below in the umbilical vein blood, showed an elevated fetal-to-maternal concentration ratio, a possible manifestation of ion trapping of a weak base.


Metal ion substrate inhibition of ferrochelatase.
Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. Robust kinetic analyses of the reaction mechanism are complicated by the instability of ferrous iron in aqueous solution, particularly at alkaline pH values. At pH 7.00 the half-life for spontaneous oxidation of ferrous ion is approximately 2 min in the absence of metal complexing additives, which is sufficient for direct comparisons of alternative metal ion substrates with iron. These analyses reveal that purified recombinant ferrochelatase from both murine and yeast sources inserts not only ferrous iron but also divalent cobalt, zinc, nickel, and copper into protoporphyrin IX to form the corresponding metalloporphyrins but with considerable mechanistic variability. Ferrous iron is the preferred metal ion substrate in terms of apparent k(cat) and is also the only metal ion substrate not subject to severe substrate inhibition. Substrate inhibition occurs in the order Cu(2+) > Zn(2+) > Co(2+) > Ni(2+) and can be alleviated by the addition of metal complexing agents such as beta-mercaptoethanol or imidazole to the reaction buffer. These data indicate the presence of two catalytically significant metal ion binding sites that may coordinately regulate a selective processivity for the various potential metal ion substrates.


Inflammation and viral infection as disease modifiers in schizophrenia.
Numerous studies have now implicated a role for inflammation in schizophrenia. However, many aspects surrounding this aspect of the disease are still controversial. This controversy has been driven by conflicting evidence on the role of both pro-and anti-inflammatory factors and by often contentious findings concerning cytokine and immune cell profiles in the central nervous system and periphery. Current evidence supports the point that interleukin-6 is elevated in CSF, but does not support activation of microglia, resident macrophage-like cells in the brain. Furthermore, the mechanisms involving transit of the peripheral immune system factors across the blood brain barrier to central parenchyma have still not been completely elucidated. This process appears to involve perivascular macrophages and accompanying dendritic cells retained in the parenchyma by the chemokine and cytokine composition of the surrounding milieu. In addition, a number of studies have shown that this can be modulated by infection with viruses such as herpes simplex virus type I which may disrupt antigen presentation in the perivascular space, with long-lasting consequences. In this review article, we discuss the role of inflammation and viral infection as potential disease modifiers in schizophrenia. The primary viral hit may occur in the fetus in utero, transforming the immune response regulatory T-cells or the virus may secondarily remain latent in immune cells or neurons and modify further immune responses in the developing individual. It is hoped that unraveling this pathway further and solidifying our understanding of the pathophysiological mechanisms involved will pave the way for future studies aimed at identification and implementation of new biomarkers and drug targets. This may facilitate the development of more effective personalized therapies for individuals suffering with schizophrenia.


Bordetella hinzii Meningitis in Patient with History of Kidney Transplant, Virginia, USA.
A patient in Virginia, USA, who had previously undergone multiple kidney transplantations showed signs of Bordetella hinzii bacteremia and meningitis. This emerging pathogen has been increasingly identified as a clinically significant pathogen in immunosuppressed and, less frequently, immunocompetent patients. This patient was treated and recovered without further issue.


A PKC that controls polyphosphate levels, pinocytosis and exocytosis, regulates stationary phase onset in Dictyostelium.
Many cells can pause their growth cycle, a topic much enriched by studies of the stationary phase (SP) of model microorganisms. Although several kinases are implicated in SP onset, whether protein kinase C has a role remains unknown. We show that Dictyostelium discoideum cells lacking pkcA entered SP at a reduced cell density, but only in shaking conditions. Precocious SP entry occurs because levels of extracellular polyphosphate (polyP) reach the threshold needed to induce the SP onset at a lower cell density than seen in wild-type cells; adding exopolyphosphatase to pkcA- cells reverses the effect and mimics wild-type growth. PkcA-mediated regulation of polyP depended on inositol hexakisphosphate kinase and phospholipase D. PkcA- mutants also had higher F-actin levels, higher rates of exocytosis and lower pinocytosis rates. Postlysosomes were smaller and present in fewer pkcA- cells compared to the wild type. Overall, the results suggest that a reduced PkcA level triggers SP primarily because cells do not acquire or retain nutrients as efficiently, thus mimicking, or amplifying, the conditions of actual starvation. This article has an associated First Person interview with the first author of the paper.


[Physiological and biochemical properties of a Pseudomonas methanolica culture under chemostat cultivation].
The effect of different concentrations of methanol on Pseudomonas methanolica BKM B-1131 was studied. The limitation of growth by methanol in chemostat was found at a concentration of the substrate below 0.1--0.23 per cent; higher concentrations resulted in the appearance of residual methanol in the medium and in a decrease of the economic coefficient. A declining chemostat curve has been obtained when the growth was limited by a deficiency of methanol. If the growth rate increased, the content of RNA remained the same, the content of protein decreased from 50 to 39 per cent, and the content of POBA increased. Changes in the specific activity of some key enzymes of the Krebs and Embden-Meyerhof cycles and of methanol dehydrogenase suggest an increase in the activity of the Krebs cycle enzymes with the growth rate because at this time the substances between acetate and pyruvate are accumulated which are favourable substrates for the synthesis of POBA.


Repeat scintigraphy of the internal mammary lymph nodes in rabbits.
Rabbits were subjected to different combinations of scintigraphy of the internal mammary lymph nodes, fractionated irradiation, and surgical trauma to the chest wall. No influence could be demonstrated on the image at repeat scintigraphy of the internal mammary nodes. Microscopic changes in the lymph nodes and vessels were relatively slight and inconstant.


Scoping a perforated bleeding peptic ulcer: learning points.
Peptic ulcer perforation and haemorrhage is not unusual as a complication of peptic ulcer disease. In the older patientspresentation can be dramatic and atypical. The authors are presenting a case of duodenal ulcer perforation and haemorrhage which was misdiagnosed as a gastric malignancy and thus failure to have Helicobacter pylori eradication, recurrence with complication and hesitancy in surgical intervention due to initial label of malignancy.


Final-Year Students' and Clinical instructors' Experience of Workplace-Based Assessments Used in a Small-Animal Primary-Veterinary-Care Clinical Rotation.
Final-year veterinary students must meet baseline clinical competency upon completion of their training for entry to practice. Workplace-based assessments (WBAs), widely used in human medical training to assess post-graduate students' professionalism and clinical performance, have recently been adopted in undergraduate veterinary clinical teaching environments. WBAs should support veterinary trainees' learning in a clinical teaching environment, though utility of WBAs within veterinary education may differ from that in medical training due to differences in context and in learners' stage of clinical development. We conducted focus groups with final-year veterinary students and clinical instructors following the implementation of three WBAs (Direct Observation of Procedural Skills [DOPS], the Mini-Clinical evaluation exercise [Mini-CEX], and the In-Training Evaluation Report [ITER]) during a small-animal primary-veterinary-care rotation. Students and clinical instructors viewed the DOPS and Mini-CEX as feasible and valuable learning and assessment tools that offered an overall opportunity for timely in-the-moment feedback. Instructors viewed the ITER as less feasible in the context of a service-oriented veterinary clinical teaching environment. Students believed the ITER had potential to be informative, although in its existing application the ITER had limited utility due to time constraints on instructors that prevented them from providing students with individualized and specific feedback. In service-oriented veterinary clinical teaching environments, successful implementation of WBAs requires balancing provision of feedback to students, time demands on clinical instructors, and flexibility of assessment tools.


Argpyrimidine-tagged rutin-encapsulated biocompatible (ethylene glycol dimers) nanoparticles: Application for targeted drug delivery in experimental diabetes (Part 2).
Diabetes mellitus is characterized by hyperglycemia and associated complications. However, long-term diabetes control is not often sustained by currently available therapeutic approaches. Research on nanoparticle-mediated drug delivery systems is in progress. Here we have tested a ligand (argpyrimidine)-tagged drug (rutin)-encapsulated biocompatible (ethylene glycol dimers) nanoparticle for targeted drug delivery in streptozotocin-induced diabetic rats. Argpyrimidine, being an advanced glycation end product (AGE), directs the nanoparticles to interact with cell surface receptors of AGEs (RAGE) and delivers the drug into the cells. The bioflavonoid rutin possesses antihyperglycemic property, and has been used for nanocapsulation. Two doses of nanoparticles containing 20mg rutin/kg body weight were administered (i.v. at 7days interval) into streptozotocin-induced diabetic rats. Compared to free rutin, nanoparticle treatment appears to be significantly more effective in controlling the diabetogenic effects - hyperglycemia, hyperlipidemia, oxidative stress etc, including heart-associated complications. This approach may thus be explored for drug delivery in the treatment of diabetes mellitus.


Framingham Risk Score and the Risk of Progression from Mild Cognitive Impairment to Dementia.
Mild cognitive impairment (MCI) often represents the clinical manifestation of cognitive deterioration preceding Alzheimer's disease (AD). Currently, there are no reliable approaches for an objective evaluation of the risk of developing AD in MCI patients. The aim of this study was to verify whether the Framingham cardiovascular risk profile (FCRP) could be useful to identify patients at the highest risk of conversion from MCI to AD. Patients with amnestic MCI (aMCI) were carefully investigated to assess their vascular risk profile. They were also submitted to a comprehensive neuropsychological evaluation. The FCRP was calculated for each patient and the apolipoprotein E (ApoE) genotype was determined from peripheral blood cells. The main outcome was defined as a conversion to AD within 24 months after inclusion. 385 consecutive aMCI subjects were included. Age, FCRP, and vascular age showed a fairly predictive value on conversion to AD. Selecting the subpopulation of ApoE ɛ4 carriers, we observed that FCRP had an increased performance in predicting the conversion. The rate of conversion increased from 12.5% in the FCRP low-risk group to 43.2% in the high-risk group (p < 0.0001). ApoE ɛ4 carriers had a 3.7-times increased probability of conversion with respect to the other subjects (p < 0.0001). FCRP assessment could be considered a reliable approach to predict conversion to AD in aMCI subjects. The presence of ApoE ɛ4 increases significantly the risk of conversion. These data confirm the narrow relationship between genetic and vascular risk factors in influencing the evolution of cognitive impairment.


Long-term outcomes of Botulinum toxin in the treatment of chronic anal fissure: 5 years of follow-up.
Chronic anal fissure is a frequent and disabling disease, often affecting young adults. Botulinum toxin and lateral internal sphincterotomy are the main therapeutic options for refractory cases. Botulinum toxin is minimally invasive and safer compared with surgery, which carries a difficult post-operative recovery and fecal incontinence risk. The long-term efficacy of Botulinum toxin is not well known. The aim of this study was to evaluate the long-term efficacy and safety of Botulinum toxin in the treatment of chronic anal fissure. This was a retrospective study at a single center, including patients treated with Botulinum toxin from 2005 to 2010, followed over at least a period of 5 years. All patients were treated with injection of 25U of Botulinum toxin in the intersphincteric groove. The response was registered as complete, partial, refractory and relapse. Botulinum toxin was administered to 126 patients, 69.8% (n = 88) were followed over a period of 5 years. After 3 months, 46.6% (n = 41) had complete response, 23.9% (n = 21) had partial response and 29.5% (n = 26) were refractory. Relapse was observed in 1.2% (n = 1) at 6 months, 11.4% (n = 10) at 1 year, 2.3% (n = 2) at 3 years; no relapse at 5 years. The overall success rate was 64.8% at 5 years of follow-up. Botulinum toxin was well tolerated by all patients and there were no complications. The use of Botulinum toxin to treat patients with chronic anal fissure was safe and effective in long-term follow-up.


Transcriptional interference by RNA polymerase III affects expression of the Polr3e gene.
Overlapping gene arrangements can potentially contribute to gene expression regulation. A mammalian interspersed repeat (MIR) nested in antisense orientation within the first intron of the Polr3e gene, encoding an RNA polymerase III (Pol III) subunit, is conserved in mammals and highly occupied by Pol III. Using a fluorescence assay, CRISPR/Cas9-mediated deletion of the MIR in mouse embryonic stem cells, and chromatin immunoprecipitation assays, we show that the MIR affects Polr3e expression through transcriptional interference. Our study reveals a mechanism by which a Pol II gene can be regulated at the transcription elongation level by transcription of an embedded antisense Pol III gene.


Penile rehabilitation after radical prostatectomy: important therapy or wishful thinking?
On the basis of data accumulated thus far, it is reasonable to discuss the implementation of a "penile rehabilitation" program with patients undergoing radical prostatectomy. Central to discussions of penile rehabilitation after radical prostatectomy is evidence demonstrating significant fibrotic changes in the corpus cavernosum that occur postoperatively. Several studies have been published evaluating the efficacy of various pro-erectogenic agents. The limited data regarding intracavernous injections and vacuum constriction devices suggest that an increased percentage of treated patients experienced a return of natural erections compared with patients who received no treatment. Longer, prospective, randomized, placebo-controlled studies will be needed to confirm the utility of these treatments. Data from contemporary studies evaluating the chronic use of oral phosphodiesterase type 5 inhibitors suggest a beneficial effect on endothelial cell function among men suffering from erectile dysfunction due to a variety of causes. Limited data suggest that this effect might be seen among post-prostatectomy patients, implying a possible role for these agents in enhancing the return of sexual function in such individuals.


BL-MOL-AR Project, Preliminary Results about Liquid Biopsy: Molecular Approach Experience and Research Activity in Oncological Settings.
Background Liquid biopsy is mainly used to identify tumor cells in pulmonary neoplasms. It is more often used in research than in clinical practice. The BL-MOL-AR study aims to investigate the efficacy of next-generation sequencing (NGS) and clinical interpretation of the circulating free DNA (cfDNA) levels. This study reports the preliminary results from the first samples analyzed from patients affected by various neoplasms: lung, intestinal, mammary, gastric, biliary, and cutaneous. Methods The Biopsia Liquida-Molecolare-Arezzo study aims to enroll cancer patients affected by various malignancies, including pulmonary, intestinal, advanced urothelial, biliary, breast, cutaneous, and gastric malignancies. Thirty-nine patients were included in this preliminary report. At time zero, a liquid biopsy is executed, and two types of NGS panels are performed, comprising 17 genes in panel 1, which is already used in the routine tissue setting, and 52 genes in panel 2. From the 7th month after enrollment, 10 sequential liquid biopsies are performed up to the 17th month. The variant allele frequency (%) and cfDNA levels (ng/mL) are measured in every plasmatic sample. Results The NGS results obtained by different panels are similar even though the number of mutations is more concordant for lung pathologies. There are no significant differences in the actionability levels of the identified variants. Most of the molecular profiles of liquid biopsies reflect tissue data. Conclusions Preliminary data from this study confirm the need to clarify the limitations and potential of liquid biopsy beyond the lung setting. Overall, parameters related to cfDNA levels and variant allele frequency could provide important indications for prognosis and disease monitoring.


Effect of COVID-19 on Musculoskeletal Performance in Gait and the Timed-Up and Go Test.
The total number of confirmed cases of COVID-19 caused by the SARS-CoV-2 virus infection is over 621 million in the world. In approximately 63% of cases, the patient still experiences persistent symptoms 30 days after the onset of symptoms or hospitalisation, and 45.9% of patients have experienced or will experience symptoms for at least three months. Despite the prevalence of chronic symptoms and pathological changes that may affect gait and functional mobility in people with a history of COVID-19, there are few publications investigating the impact of these abnormalities. This study aims to determine the long-term effects of COVID-19 on gait and the Timed-Up and Go Task. A total of 30 individuals took part in the experiment. The subjects in the study group were infected with the COVID-19 virus and required hospital treatment. Prior to the study, the subjects had no chronic diseases or other conditions affecting the musculoskeletal system. The non-infected by COVID-19 group was a healthy population with no history of COVID-19 disease. The study used the inertial system wireless motion analysis system based on 15 inertial sensors (inertial measurement units, IMUs). IMU sensors were placed on the following body segments: head, sternum, middle and lower spine, shoulder, arm, forearm, hand, shank, for the left and right limb. Movement task reports generated from the recording were created using myoRESEARCH 3.10. The subjects in the study group were asked to perform a movement task test-the Timed-Up and Go Test (TUG): sit-to-stand, walk (3 m) without change in direction, walk termination, and stand-to-sit. It took 46% longer for those infected by COVID-19 (participants) to complete the entire movement task compared to those in the not-infected by COVID-19 group. Sit-to-Stand Time [s] was greater in the infected by COVID-19 group and was 2.1 ± 0.7. Mean Walking Speed [m/s] was lower than in the not-infected by COVID-19 group and was 0.26 ± 0.07. Walking cadence [steps/min] was lower and was 21.2 ± 1.2. Infected by COVID-19 participants achieved a smaller anterior pelvic tilt angle (p < 0.001) and a smaller hip flexion angle (p = 0.025), with an increase in knee (p < 0.001) and ankle (p < 0.001) flexion angles. Individuals in the infected by COVID-19 group present changes in the ranges of motion and the time to complete the TUG task, despite the fact that at least eight weeks passed after hospital discharge.


Sleep apnea, alertness, and motor vehicle crashes.
Sleep apnea causes impairment in performance and is associated with an increased risk of motor vehicle crashes compared with the general population of drivers. Despite this increased risk, the actual number of accidents is still quite low, although the implications are significant in commercial vehicle drivers. It is difficult for physicians to assess risk and ability to drive in many patients with sleep apnea, yet physicians are often mandated to make these assessments with obvious implications for patients. Because many patients may never have a crash, it is not practical or feasible to restrict all untreated patients from driving, unless they operate commercial vehicles. Thresholds of disease severity that prompt driving restriction need to be established for sleep apnea much like they have been for alcohol. Until more data emerge, continued educational efforts about sleep apnea are needed to convince government and insurance organizations to provide appropriate resources for diagnosis and treatment of sleep apnea, because apnea risk is minimized with successful apnea treatment.


Genome-wide transcriptional profiling of the purple sulfur bacterium Allochromatium vinosum DSM 180T during growth on different reduced sulfur compounds.
The purple sulfur bacterium Allochromatium vinosum DSM 180(T) is one of the best-studied sulfur-oxidizing anoxygenic phototrophic bacteria, and it has been developed into a model organism for laboratory-based studies of oxidative sulfur metabolism. Here, we took advantage of the organism's high metabolic versatility and performed whole-genome transcriptional profiling to investigate the response of A. vinosum cells upon exposure to sulfide, thiosulfate, elemental sulfur, or sulfite compared to photoorganoheterotrophic growth on malate. Differential expression of 1,178 genes was observed, corresponding to 30% of the A. vinosum genome. Relative transcription of 551 genes increased significantly during growth on one of the different sulfur sources, while the relative transcript abundance of 627 genes decreased. A significant number of genes that revealed strongly enhanced relative transcription levels have documented sulfur metabolism-related functions. Among these are the dsr genes, including dsrAB for dissimilatory sulfite reductase, and the sgp genes for the proteins of the sulfur globule envelope, thus confirming former results. In addition, we identified new genes encoding proteins with appropriate subcellular localization and properties to participate in oxidative dissimilatory sulfur metabolism. Those four genes for hypothetical proteins that exhibited the strongest increases of mRNA levels on sulfide and elemental sulfur, respectively, were chosen for inactivation and phenotypic analyses of the respective mutant strains. This approach verified the importance of the encoded proteins for sulfur globule formation during the oxidation of sulfide and thiosulfate and thereby also documented the suitability of comparative transcriptomics for the identification of new sulfur-related genes in anoxygenic phototrophic sulfur bacteria.


Air pollution and percent emphysema identified by computed tomography in the Multi-Ethnic study of Atherosclerosis.
Air pollution is linked to low lung function and to respiratory events, yet little is known of associations with lung structure. We examined associations of particulate matter (PM2.5, PM10) and nitrogen oxides (NOx) with percent emphysema-like lung on computed tomography (CT). The Multi-Ethnic Study of Atherosclerosis (MESA) recruited participants (45-84 years of age) in six U.S. states. Percent emphysema was defined as lung regions < -910 Hounsfield Units on cardiac CT scans acquired following a highly standardized protocol. Spirometry was also conducted on a subset. Individual-level 1- and 20-year average air pollution exposures were estimated using spatiotemporal models that included cohort-specific measurements. Multivariable regression was conducted to adjust for traditional risk factors and study location. Among 6,515 participants, we found evidence of an association between percent emphysema and long-term pollution concentrations in an analysis leveraging between-city exposure contrasts. Higher concentrations of PM2.5 (5 μg/m3) and NOx (25 ppb) over the previous year were associated with 0.6 (95% CI: 0.1, 1.2%) and 0.5 (95% CI: 0.1, 0.9%) higher average percent emphysema, respectively. However, after adjustment for study site the associations were -0.6% (95% CI: -1.5, 0.3%) for PM2.5 and -0.5% (95% CI: -1.1, 0.02%) for NOx. Lower lung function measures (FEV1 and FVC) were associated with higher PM2.5 and NOx levels in 3,791 participants before and after adjustment for study site, though most associations were not statistically significant. Associations between ambient air pollution and percentage of emphysema-like lung were inconclusive in this cross-sectional study, thus longitudinal analyses may better clarify these associations with percent emphysema.


Chemiluminescence resulting from an interaction between imipramine and human polymorphonuclear leukocytes.
The addition of imipramine to a suspension of resting polymorphonuclear leukocytes (PMNs) resulted in the generation of chemiluminescence (CL) (100,000 cpm with 1 X 10(-4)M imipramine). In the presence of a particle (zymosan) capable of activating the PMNs to generate reactive oxygen species, the magnitude of CL observed with 1 X 10(4)M imipramine was greatly enhanced (greater than 1,000,000 cpm). No CL was detected upon the addition of imipramine to PMNs isolated from a chronic granulomatous child or to alveolar macrophages isolated from rats. Another tricyclic antidepressant, amitriptyline, failed to generate CL with PMNs either alone or in the presence of zymosan; however, both imipramine and amitriptyline generated CL upon addition to the xanthine oxidase-purine superoxide generating system. Although the mechanism by which this drug-cell interaction results in the generation of CL is not known, the observations are suggestive that the CL may originate, in part, from the activation of imipramine by some reactive oxygen state(s).


Integral phase modulation properties of a single-mode optical fiber subjected to controlled vibration.
Dynamic measurements of optical phase modulation in a single-mode fiber subjected to controlled mechanical vibrations are reported. An accurate analysis of the fiber strain state explains the observed phase vs frequency characteristic behavior. The integration properties of the single-mode fiber are evaluated quantitatively for the vibrations applied. The experimental results emphasize the excellent capabilities of optical fibers to sense mechanical vibrations.


Inhibition of complement and CD14 attenuates the Escherichia coli-induced inflammatory response in porcine whole blood.
The innate immune response is a double-edged sword in systemic inflammation and sepsis. Uncontrolled or inappropriate activation can damage and be lethal to the host. Several studies have investigated inhibition of downstream mediators, including tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Emerging evidence indicates that upstream inhibition is a better therapeutic approach for attenuating damaging immune activation. Therefore, we investigated inhibition of two central innate immune pathways, those of complement and CD14/Toll-like receptor 4 (TLR4)/myeloid differentiation protein 2 (MD-2), in a porcine in vitro model of Escherichia coli-induced inflammation. Porcine whole blood anticoagulated with lepuridin, which did not interfere with the complement system, was incubated with E. coli lipopolysaccharide (LPS) or whole bacteria. Inhibitors of complement and CD14 and thus the LPS CD14/TLR4/MD-2 receptor complex were tested to investigate the effect on the inflammatory response. A broad range of inflammatory readouts were used to monitor the effect. Anti-CD14 was found to saturate the CD14 molecule on granulocytes and completely inhibited LPS-induced proinflammatory cytokines in a dose-dependent manner. Anti-CD14 significantly reduced the levels of the E. coli-induced proinflammatory cytokines TNF-alpha and IL-1beta, but not IL-8, in a dose-dependent manner. No effect on bacterial clearance was seen. Vaccinia complement control protein and smallpox inhibitor of complement enzymes, two Orthopoxvirus-encoded complement inhibitors, completely inhibited complement activation. Furthermore, these agents almost completely inhibited the expression of wCD11R3, which is associated with CD18 as a beta2 integrin, on porcine granulocytes and decreased IL-8 levels significantly in a dose-dependent manner. As expected, complement inhibition reduced bacterial clearance. We conclude that inhibition of complement and CD14 attenuates E. coli-induced inflammation and might be used as a therapeutic regimen in gram-negative sepsis along with appropriate treatment with antibiotics.


A literature review on the levels of automation during the years. What are the different taxonomies that have been proposed?
In this paper we present a literature review of the evolution of the levels of autonomy from the end of the 1950s up until now. The motivation of this study was primarily to gather and to compare the literature that exists, on taxonomies on levels of automation. Technical developments within both computer hardware and software have made it possible to introduce autonomy into virtually all aspects of human-machine systems. The current study, is focusing on how different authors treat the problem of different levels of automation. The outcome of this study is to present the differences between the proposed levels of automation and the various taxonomies, giving the potential users a number of choices in order to decide which taxonomy satisfies their needs better. In addition, this paper surveys deals with the term adaptive automation, which seems to be a new trend in the literature on autonomy.


A field-expedient method for detection of leptospirosis causative agents in rodents.
We have developed a thermal-stable, pathogenic Leptospira TaqMan PCR assay intended to support pathogen surveillance in reservoir populations. The assay is packaged specifically for use with a portable, ruggedized, real-time PCR thermocycler. Limit of detection was established at ≤ 100 fg (20 organisms). Sensitivity and specificity were 100% concordant with conventional PCR results using a broad test panel of human pathogenic and nonpathogenic Leptospira, genetic near neighbors, and clinically significant organisms. In blind testing using a panel (n=50) of pathogenic Leptospira infected and noninfected Rattus species samples, assay sensitivity results were 100% concordant with conventional PCR. Tests performed under field conditions using wild-collected rodent kidney extracts demonstrated the mobility of the system. During field evaluation, samples were processed and analyzed in 3 hours. Thermal stabilized reagents allowed transportation, storage, and analyses under ambient temperatures. The system provides a promising aid in leptospirosis control programs.


Telehealth and eHealth in nurse practitioner training: current perspectives.
Telehealth is becoming a vital process for providing access to cost-effective quality care to patients at a distance. As such, it is important for nurse practitioners, often the primary providers for rural and disadvantaged populations, to develop the knowledge, skills, and attitudes needed to utilize telehealth technologies in practice. In reviewing the literature, very little information was found on programs that addressed nurse practitioner training in telehealth. This article provides an overview of both the topics and the techniques that have been utilized for training nurse practitioners and nurse practitioner students in the delivery of care utilizing telehealth. Specifically, this article focuses on topics including 1) defining telehealth, 2) telehealth etiquette, 3) interprofessional collaboration, 4) regulations, 5) reimbursement, 6) security/Health Insurance Portability and Accountability Act (HIPAA), 7) ethical practice in telehealth, and 8) satisfaction of patients and providers. A multimodal approach based on a review of the literature is presented for providing the training: 1) didactics, 2) simulations including standardized patient encounters, 3) practice immersions, and 4) telehealth projects. Studies found that training using the multimodal approach allowed the students to develop comfort, knowledge, and skills needed to embrace the utilization of telehealth in health care.


Néel- and Bloch-Type Magnetic Vortices in Rashba Metals.
We theoretically study noncoplanar spin textures in polar magnetic conductors. Starting from the Kondo lattice model with the Rashba spin-orbit coupling, we derive an effective spin model with generalized Ruderman-Kittel-Kasuya-Yosida interactions including the anisotropic and antisymmetric exchange interactions. By performing simulated annealing for the effective model, we find that a vortex crystal of Néel type is stabilized even in the absence of a magnetic field. Moreover, we demonstrate that a Bloch-type vortex crystal, which is usually associated with the Dresselhaus spin-orbit coupling, can also be realized in our Rashba-based model. A magnetic field turns the vortex crystals into Néel- and Bloch-type Skyrmion-like crystals. Our results underscore that the interplay between the spin-orbit coupling and itinerant magnetism brings fertile possibilities of noncoplanar magnetic orderings.


Central Diabetes Insipidus and Hyperglycemic Hyperosmolar State Following Accidental Carbon Monoxide Poisoning.
Carbon monoxide poisoning is common and carries significant morbidity and mortality. The nervous system, particularly the brain, is frequently affected by it, owing to its high metabolic activity and oxygen requirements. Carbon monoxide damages the nervous system by both hypoxic and inflammatory mechanisms. Central diabetes insipidus is an extremely rare complication of carbon monoxide poisoning. Herein, we report the case of a young lady, who developed this complication and severe hypernatremia after accidental carbon monoxide poisoning. She also developed a hyperglycemic hyperosmolar state during the treatment for hypernatremia. To the best of our knowledge, both these entities have not been reported together in association with carbon monoxide poisoning. The purpose of this article is to emphasize the anticipation and early recognition of central diabetes insipidus in carbon monoxide poisoning. This can prevent severe hypernatremia and complications associated with its presence and treatment.


The Clinical Influence of Autophagy-Associated Proteins on Human Lung Cancer.
Exploitation of autophagy might potentially improve therapeutic strategy. Here, we analyzed the protein expression of autophagy-associated genes including LC3A, LC3B, Beclin-1, p62, and Atg5 in 88-131 primary lung tumors by immunohistochemistry (IHC) on tissue-microarrays (TMAs). Additionally, the DNA methylation pattern of LC3A was investigated by bisulfite sequencing (BS) and methylation-specific-PCR (MSP). It turned out that the higher expression of LC3A protein was associated with adenocarcinoma compared to squamous cell carcinoma of lung (p = 0.008), positive staining of LC3B was significantly related to tumor grade (p = 0.006), and the protein expression of Beclin-1 was significantly correlated to pN stage (p = 0.041). The expression of p62 and Atg5 was however not significantly associated with any clinicopathological parameters. Downregulation of LC3A was related to DNA methylation in lung cancer cell lines, while in primary lung tumor samples, protein expression of LC3A was not significantly correlated with DNA methylation, and the methylation status of LC3A was not related to clinicopathological features. Taken together, our results suggest that autophagy-associated proteins such as LC3A, LC3B, and Beclin-1 might be potential biomarkers for subclassification, differentiation, and local metastasis in primary lung tumor, and epigenetic mechanism is partially responsible for gene silencing of LC3A in lung cancer cell lines.


[Congenital heart disease with right ventricular overloading in the elderly].
This study was undertaken to characterize the clinical pictures of long-standing overload of the right ventricle and to investigate its hemodynamics. 1. Myocardial cell injury of the right ventricle was studied. Histopathological examinations were performed by biopsy in patients with atrial septal defect (ASD). Cell diameter was more widely distributed in the disease compared to the control. The range of distribution was more markedly scattered in ASD with congestive heart failure. Change in the ultra-fine structure was also more remarkable in ASD with than without pump failure. 2. ASD with impending myocardial infarction was discussed as an example of associated acquired disease. 3. The occurrence of pulmonary hypertension could be monitored with recently developed color Doppler method. A representative case of ASD and pulmonary hypertension was presented and discussed. 4. Right ventricular overloading associated with arrhythmias was presented. The effects of arrhythmias on Ebstein's anomaly and Uhl disease were examined. In these anomalies, development of pump failure and life-threatening arrhythmias were serious problems in managing old patients. In summary, histo-pathological examinations, monitoring of pulmonary artery pressure by Doppler echocardiography and management of arrhythmias were necessary to evaluate prognosis of congenital heart disease in the elderly.


[The evaluation of useful breath actuated inhalers by preschool asthmatic children].
Clinical efficacy of breath actuated devices depend on value of Peak Inspiratory Flow (PIF), in consequence they are used in older children. Therefore the aim of our study was to assess the ability to use breath actuated inhalers in preschool stable asthmatic children. 156 children aged (mean and 95% CI) 4.5 (95% CI: 4.3-4.6) years participated in the study. Peak Inspiratory Flow Rate (PIFR) assessment with In Check (Clement Clark, U.K.) with resistance valve for Turbuhaler, Diskus, Easi Breathe devices was assessed. Minimal effective value of PIFR significantly frequent for Easi Breathe--98.1% (95% CI 94.5-99.4) compared with Diskus--78.2% (95% CI: 71.1-84.0) and Turbuhaler--71.8% (95% CI 64.3-78.3) (p < 0.05) was found. Significant correlation between PIFR and age of children for all devices was confirmed. We conclude that the use of breath actuated Easi Breathe devices seems to be effective in most preschool asthmatic children in stable period of disease. Use of dry powder inhalers should be preceded by assessments of PIFR with In Check.


Subtype-specific therapy for DLBCL: are we there yet?
In this issue of Blood, Offner et al report the results of LYM-2034, a phase 2 multinational trial in which 164 patients with nongerminal center B-cell–like diffuse large B-cell lymphoma (non-GCB DLBCL) were randomized to receive rituximab, cyclophosphamide, adriamycin, prednisone, and either vincristine (R-CHOP) or bortezomib (VR-CAP). DLBCL, previously recognized as a single disease entity, represents a heterogeneous group of diseases.


Novel SMAD3 variant identified in a patient with familial aortopathy modeled using a zebrafish embryo assay.
In human, pathogenic variants in smad3 are one cause of familial aortopathy. We describe a novel SMAD3 variant of unknown significance (VUS), V244F, in a patient who presented with aortic root dilation, right coronary artery ectasia, abdominal aortic aneurysm, right vertebral artery atresia, and cavernoma. Determination of variant pathogenicity impacted multiple aspects of the patient's care, including the most appropriate surgical threshold for which to recommend a valve-sparing aortic root replacement. To determine whether the newly identified SMAD3 variant, and whether SMAD3 induced aortopathy in general, can be assayed in a zebrafish embryo model, we injected smad3a mRNA into Tg[kdrl:mCherry] zebrafish embryos. By measuring the size of the dorsal aorta at 48hpf we found a correlation between pathogenic SMAD3 variants and increased dorsal aortic diameter. The newly identified V244F variant increased dorsal aortic diameter (p < 0.0001) similar to that of the pathogenic control variant T261I (p < 0.0084). In addition, we examined several previously identified variants of uncertain significance and found P124T (p < 0.0467), L296P (p < 0.0025) and A349P (p < 0.0056) to behave like T261I. These results demonstrate that the zebrafish embryo assay was successful in validating known pathogenic variants, classifying our newly identified variant V244F as likely pathogenic, and classifying previously identified variants P124T, L296P, and A349P as likely pathogenic. Overall, our findings identify a novel SMAD3 variant that is likely pathogenic as well as offer a new mechanism to model SMAD3 VUSs in vivo.