Arthrotome: a specific joint forming compartment in the avian somite.
Somitocoele cells previously have been shown to form the proximal part of the ribs, the intervertebral discs, and the intervertebral joints (synovial joints). To determine whether the somitocoele cells are necessary for the development of axial skeleton joints, we microsurgically ablated the somitocoele cells in epithelial somites of 2-day-old chick embryos. The operated embryos were analyzed after whole-mount skeletal preparations and in sections. Removal of the somitocoele cells led to two major outcomes: (1) Intervertebral joints failed to develop and resulted in the fusion of the superior articular process and the inferior articular process; (2) Adjacent vertebral bodies fused and lacked the intervertebral disc. These results demonstrate that somitocoele cells specifically give rise to intervertebral joints and discs. Furthermore, these results suggest that neighboring sclerotome cells cannot adapt to form vertebral joints in the absence of the somitocoele compartment. Thus, we provide for the first time experimental evidence for the existence of a joint forming compartment in the somites, which we term the "arthrotome."


Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus.
The t(X;18)(p11.2;q11.2) chromosomal translocation commonly found in synovial sarcomas fuses the SYT gene on chromosome 18 to either of two similar genes, SSX1 or SSX2, on the X chromosome. The SYT protein appears to act as a transcriptional co-activator and the SSX proteins as co-repressors. Here we have investigated the functional domains of the proteins. The SYT protein has a novel conserved 54 amino acid domain at the N-terminus of the protein (the SNH domain) which is found in proteins from a wide variety of species, and a C-terminal domain, rich in glutamine, proline, glycine and tyrosine (the QPGY domain), which contains the transcriptional activator sequences. Deletion of the SNH domain results in a more active transcriptional activator, suggesting that this domain acts as an inhibitor of the activation domain. The C-terminal SSX domain present in SYT-SSX translocation protein contributes a transcriptional repressor domain to the protein. Thus, the fusion protein has transcriptional activating and repressing domains. We demonstrate that the human homologue of the SNF2/Brahama protein BRM co-localizes with SYT and SYT-SSX in nuclear speckles, and also interacts with SYT and SYT-SSX proteins in vitro. This interaction may provide an explanation of how the SYT protein activates gene transcription.


National Risk Factors for Child Maltreatment after Trauma: Failure to Prevent.
The purpose of this study was to identify the risk factors for hospital readmission for child maltreatment after trauma, including admissions across different hospitals nationwide. The Nationwide Readmissions Database for 2010-2014 was queried for all patients younger than 18 years admitted for trauma. The primary outcome was readmission for child maltreatment. The secondary outcome was readmission for maltreatment presenting to a hospital different than the index admission hospital. A subgroup analysis was performed on patients without a diagnosis of maltreatment during the index admission. Multivariable logistic regression was performed for each outcome. There were 608,744 admissions identified and 44,569 (7.32%) involved maltreatment at the index admission. Readmission for maltreatment was found in 1,948 (0.32%) patients and 368 (18.89%) presented to a different hospital. The highest risk for readmission for maltreatment was found in patients with maltreatment identified at the index admission (odds ratios (OR) 9.48 [8.35-10.76]). The strongest risk factor for presentation to a different hospital was found with the lowest median household income quartile (OR 3.50 [2.63-4.67]). The subgroup analysis identified 647 (0.11%) children with readmission for maltreatment that was missed during the index admission. The strongest risk factor for this outcome was Injury Severity Score > 15 (OR 3.29 [2.68-4.03]). This study demonstrates that a significant portion of admissions for trauma in children and teenagers could be misrepresented as not involving maltreatment. These index admissions could be the only chance for intervention for child maltreatment. Identifying these at-risk individuals is critical to prevention efforts.


Abnormal factor VIII coagulant antigen in patients with renal dysfunction and in those with disseminated intravascular coagulation.
Factor VIII antigen (VIII:CAg) exhibits molecular weight heterogeneity in normal plasma. We have compared the relative quantities of VIII:CAg forms present in normal individuals (n = 22) with VIII:CAg forms in renal dysfunction patients (n = 19) and in patients with disseminated intravascular coagulation (DIC; n = 7). In normal plasma, the predominant VIII: CAg form, detectable by sodium dodecyl sulfate polyacrylamide gel electrophoresis, was of molecular weight 2.4 X 10(5), with minor forms ranging from 8 X 10(4) to 2.6 X 10(5) D. A high proportion of VIII:CAg in renal dysfunction patients, in contrast, was of 1 X 10(5) mol wt. The patients' high 1 X 10(5) mol wt VIII: CAg level correlated with increased concentrations of serum creatinine, F1+2 (a polypeptide released upon prothrombin activation), and with von Willebrand factor. Despite the high proportion of the 1 X 10(5) mol wt VIII:CAg form, which suggests VIII:CAg proteolysis, the ratio of Factor VIII coagulant activity to total VIII:CAg concentration was normal in renal dysfunction patients. These results could be simulated in vitro by thrombin treatment of normal plasma, which yielded similar VIII:CAg gel patterns and Factor VIII coagulant activity to antigen ratios. DIC patients with high F1+2 levels but no evidence of renal dysfunction had an VIII:CAg gel pattern distinct from renal dysfunction patients. DIC patients had elevated concentrations of both the 1 X 10(5) and 8 X 10(4) mol wt VIII:CAg forms. We conclude that an increase in a particular VIII:CAg form correlates with the severity of renal dysfunction. The antigen abnormality may be the result of VIII:CAg proteolysis by a thrombinlike enzyme and/or prolonged retention of proteolyzed VIII:CAg fragments.


Comparative study of the pro-atherosclerotic profile of students of medicine and physical education.
Recent studies have demonstrated a strong association between physical activity, low level of cardiorespiratory fitness and the presence of cardiovascular risk factors. Compare the level of physical activity, level of cardiorespiratory fitness and cardiovascular risk in students of medicine and physical education. At the first phase, the International Physical Activity Questionnaire (IPAQ) was used to quantify the physical activity level of 126 students from the 7th and 8th semesters of the physical education and medicine courses. At the second phase, 40 students were randomly selected (20 from each course) to undergo cardiovascular risk assessment and cardiorespiratory fitness. The following data were assessed 1) arterial pressure; 2) body mass index (BMI); 3) percentage of fat (electrical bioimpedance); 4) abdominal circumference (AC); 5) laboratory biochemical assessment; and 6) cardiorespiratory fitness (Kline's Test). The comparison of students of medicine and physical education, respectively, showed a higher frequency of individuals presenting: low level of physical activity (55% vs 15.0%; p = 0.008); pre-hypertension measured by SAP (80% vs 25.0%; p = 0.000) and by DAP (45% vs 5.0%; p = 0.003); overweight (50% vs 10.0%; p = 0.006); increased abdominal circumference (25% vs 0.0%; p = 0.017); increased total cholesterol (165 +/- 28 vs 142 +/- 28 mg/dl; p = 0.015); increased LDL-c (99 +/- 27 vs 81 +/- 23 mg/dl; p = 0.026); increased glycemia (81 +/- 8.0 vs 75 +/- 7.0 mg/dl; p = 0.013); lower cardiorespiratory fitness (48 +/- 8.0 vs 56 +/- 7.0 ml/kg/min; p = 0.001). Students of medicine presented lower levels of physical activity practice, lower level of cardiorespiratory fitness and higher frequency of cardiovascular risk factors, when compared to Physical Education students.


Positive and negative autoregulation of the adeno-associated virus type 2 genome.
The defective human parvovirus, adeno-associated virus (AAV), requires multiple functions provided by a coinfecting helper virus for viral replication. In addition, it has recently been shown that at least one AAV gene is also required for AAV DNA replication. In this paper, we investigate the autoregulation of the AAV genome by analyzing the expression of mutant AAV genomes upon transfection into adenovirus-infected human cells. Evidence is presented which indicates that the AAV genome regulates its own gene expression in at least two ways. First, either the AAV p5 gene or both the p5 and p19 genes appear to encode a trans activator of AAV transcription. Frameshift mutations within the p5 or p19 gene severely inhibited the synthesis and accumulation of all AAV transcripts. The defective accumulation of transcripts could be complemented in trans, in a manner independent of DNA replication, by cotransfection with a capsid deletion mutant. Second, evidence is presented which suggests that the p5 and p19 genes contain negative cis-active regulatory elements. Deletion of sequences within the p5 and p19 genes enhanced the accumulation of the p5 transcript in cis upon complementation with an AAV capsid deletion mutant, whereas certain deletions enhanced p40 RNA accumulation in the absence of trans activation by the p5 gene.


Endoscopic ultrasound-guided biliary access versus precut papillotomy in patients with failed biliary cannulation: a retrospective study.
Background and aims Precut papillotomy is widely used after failed biliary cannulation. Endoscopic ultrasound (EUS)-guided biliary access techniques are newer methods to facilitate access and therapy in failed cannulation. We evaluated the impact of EUS-guided biliary access on endoscopic retrograde cholangiopancreatography (ERCP) success and compared these techniques to precut papillotomy. Patients and methods We retrospectively compared two ERCP cohorts. One cohort consisted of biliary ERCPs (n = 1053) attempted in patients with native papillae and surgically unaltered anatomy in whom precut papillotomy and/or EUS-guided biliary access were routinely performed immediately after failed cannulation. This cohort was compared with a similar ERCP cohort (n = 1062) in which only precut papillotomy was available for failed cannulation. The following outcomes were compared: conventional cannulation success, rates of attempted advanced access techniques (precut or EUS), precut success, EUS-guided biliary access success, and ERCP failure rates. Results Although conventional cannulation success, rates of attempted advanced access technique (precut or EUS), and precut success were similar, the ERCP failure rate was lower when both EUS-guided biliary access and precut were available (1.0 % [95 % confidence interval (CI) 0.4 - 1.6]), compared with when only precut was possible for failed access (3.6 % [95 %CI 2.5 - 4.7]; P < 0.001). Success for EUS-guided biliary access (95.1 % [95 %CI 89.7 - 100]) was significantly higher than for precut (75.3 % [95 %CI 68.2 - 82.4]; P < 0.001), and mainly due to superiority in malignant obstruction (93.5 % vs. 64 %; P < 0.001). Conclusions EUS-guided biliary access decreases the rate of therapeutic biliary ERCP failure. Our results support the use of EUS-guided biliary access to optimize single-session ERCP success. In experienced hands, these techniques appear as effective, if not more so, than precut papillotomy.


Peer health workers and AIDS care in Rakai, Uganda: a mixed methods operations research evaluation of a cluster-randomized trial.
Settings with limited health care workers are challenging environments for delivery of antiretroviral therapy. One strategy to address this human resource crisis is to task shift through training selected patients as peer health workers (PHWs) to provide care to other individuals receiving antiretroviral therapy. To better understand processes of a cluster-randomized trial on the effect of these PHWs on AIDS care, we conducted a mixed methods operations research evaluation. Qualitative methods involved patients, PHWs, and clinic staff and included 38 in-depth interviews, 8 focus group discussions, and 11 direct observations. Quantitative methods included staff surveys, process, and virologic data analyses. Results showed that task shifting to PHWs positively affected structural and programmatic functions of care delivery--improving clinical organization, medical care access, and patient-provider communication--with little evidence for problems with confidentiality and inadvertent disclosure. Additionally, this evaluation elucidated trial processes including evidence for direct and indirect control arm contamination and evidence for mitigation of antiretroviral treatment fatigue by PHWs. Our results support the use of PHWs to complement conventional clinical staff in delivering AIDS care in low-resource settings and highlight how mixed methods operations research evaluations can provide important insights into community-based trials.


Experiences of nurses diagnosed with COVID-19 in Turkey: A qualitative study.
This study examined the experiences of nurses diagnosed with COVID-19 under the guidance of Meleis' Transitions Theory. Nurses, who make up the majority of healthcare professionals, are struggling with COVID-19, a silent war, on the front lines at the cost of their lives. The pandemic has deeply affected nurses' lives, and hundreds of nurses around the world have been diagnosed with COVID-19 and died. A descriptive qualitative approach was used in this study. Data were collected from 18 nurses who experienced COVID-19 symptoms, with a semistructured interview form prepared based on Meleis' Transitions Theory concepts. Interview transcripts were analyzed using a thematic analysis technique. The Consolidated Criteria for Reporting Qualitative Research checklist was used in the study. The six themes that emerged in the data analysis were emotions experienced when nurses tested positive for COVID-19, emotions experienced during the quarantine process, posttraumatic growth, methods of coping with COVID-19, nursing care after COVID-19 treatment, and metaphors about COVID-19. This study showed that being diagnosed with COVID-19 caused nurses to have both positive (posttraumatic growth, empathic and psychosocial nursing care) and negative experiences (fear of death, stigma, etc.). They tried to cope with adverse situations due to COVID-19 by obtaining social support, thinking positively, and engaging in domestic activities. To reduce COVID-19-related physical and psychological symptoms, appropriate policies should be developed for effective and rapid nursing workforce planning, extending the time allocated for postdiagnosis treatment, updating infection control and prevention guides, training nurses, and providing ongoing psychosocial counseling services that nurses can access.


The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care.
The relevance of registries as a key component for developing clinical research for rare diseases (RD) and improving patient care has been acknowledged by most stakeholders. As recent studies pointed to several limitations of RD registries our challenge was (1) to improve standardization and data comparability; (2) to facilitate interoperability between existing RD registries; (3) to limit the amount of incomplete data; (4) to improve data quality. This report describes the innovative concept of the DM-Scope Registry that was developed to achieve these objectives for Myotonic Dystrophy (DM), a prototypical example of highly heterogeneous RD. By the setting up of an integrated platform attractive for practitioners use, we aimed to promote DM epidemiology, clinical research and patients care management simultaneously. The DM-Scope Registry is a result of the collaboration within the French excellence network established by the National plan for RDs. Inclusion criteria is all genetically confirmed DM individuals, independently of disease age of onset. The dataset includes social-demographic data, clinical features, genotype, and biomaterial data, and is adjustable for clinical trial data collection. To date, the registry has a nationwide coverage, composed of 55 neuromuscular centres, encompassing the whole disease clinical and genetic spectrum. This widely used platform gathers almost 3000 DM patients (DM1 n = 2828, DM2 n = 142), both children (n = 322) and adults (n = 2648), which accounts for > 20% of overall registered DM patients internationally. The registry supported 10 research studies of various type i.e. observational, basic science studies and patient recruitment for clinical trials. The DM-Scope registry represents the largest collection of standardized data for the DM population. Our concept improved collaboration among health care professionals by providing annual follow-up of quality longitudinal data collection. The combination of clinical features and biomolecular materials provides a comprehensive view of the disease in a given population. DM-Scope registry proves to be a powerful device for promoting both research and medical care that is suitable to other countries. In the context of emerging therapies, such integrated platform contributes to the standardisation of international DM research and for the design of multicentre clinical trials. Finally, this valuable model is applicable to other RDs.


Assessing the impact of common method variance on higher order multidimensional constructs.
Researchers are often concerned with common method variance (CMV) in cases where it is believed to bias relationships of predictors with criteria. However, CMV may also bias relationships within sets of predictors; this is cause for concern, given the rising popularity of higher order multidimensional constructs. The authors examined the extent to which CMV inflates interrelationships among indicators of higher order constructs and the relationships of those constructs with criteria. To do so, they examined core self-evaluation, a higher order construct comprising self-esteem, generalized self-efficacy, emotional stability, and locus of control. Across 2 studies, the authors systematically applied statistical (Study 1) and procedural (Study 2) CMV remedies to core self-evaluation data collected from multiple samples. Results revealed that the nature of the higher order construct and its relationship with job satisfaction were altered when the CMV remedies were applied. Implications of these findings for higher order constructs are discussed.


Non-reciprocal Interspecies Hybridization Barriers in the Capsella Genus Are Established in the Endosperm.
The transition to selfing in Capsella rubella accompanies its recent divergence from the ancestral outcrossing C. grandiflora species about 100,000 years ago. Whether the change in mating system was accompanied by the evolution of additional reproductive barriers that enforced species divergence remained unknown. Here, we show that C. rubella and C. grandiflora are reproductively separated by an endosperm-based, non-reciprocal postzygotic hybridization barrier. While hybridizations of C. rubella maternal plants with C. grandiflora pollen donors resulted in complete seed abortion caused by endosperm cellularization failure, the reciprocal hybridization resulted in the formation of small seeds with precociously cellularized endosperm. Strikingly, the transcriptomic response of both hybridizations mimicked respectively the response of paternal and maternal excess hybridizations in Arabidopsis thaliana, suggesting unbalanced genome strength causes hybridization failure in both species. These results provide strong support for the theory that crosses between plants of different mating systems will be unbalanced, with the outcrosser behaving like a plant of increased ploidy, evoking a response that resembles an interploidy-type seed failure. Seed incompatilibity of C. rubella pollinated by C. grandiflora followed the Bateson-Dobzhansky-Muller model, involving negative genetic interaction of multiple paternal C. grandiflora loci with at least one maternal C. rubella locus. Given that both species only recently diverged, our data suggest that a fast evolving mechanism underlies the post-zygotic hybridization barrier(s) separating both species.


The effect of the Convention on International Trade in Endangered Species on scientific collections.
The Convention on International Trade in Endangered Species (CITES) was conceived in the spirit of cooperation, with the aim of ensuring that the international trade in wild animals and plants, including all parts and derivatives, did not threaten their survival. However, concerns have been raised by scientists that CITES hinders the cross-border movement of scientific specimens. To our knowledge, no empirical analysis has been undertaken to demonstrate the existence of this effect. We test for a CITES effect on the collection record of orchids from Brazil and Costa Rica using the collection records of bromeliads, which are not covered by CITES, as a control. Highly significant effects are found in both countries.


Genotype-Phenotype Associations of APC Mutations With Pouch Adenoma in Patients With Familial Adenomatous Polyposis.
Patients with familial adenomatous polyposis (FAP) may carry various adenomatous polyposis coli (APC) mutations. However, genotype-phenotype correlation for APC mutations is still debated and is yet to be evaluated with regard to pouch polyp formation. To evaluate the association between APC mutation type and exon location and the outcome of pouch adenoma. Forty-five FAP patients with defined pathogenic APC mutations, who underwent total proctocolectomy and ileal pouch anal anastomosis were classified by mutation type and location. Analysis was conducted for clinical and endoscopic parameters. Twenty patients had either indel/deletion mutations and 25 had nonsense/missense mutations. The indel/deletion group was associated with higher prevalence of preoperative hundreds of colonic adenomas (66.7% vs. 30%; P=0.030), lower rates of stapled versus sewn anastomosis (46.7% vs. 76%; P=0.060), of single stage surgery (13.3% vs. 44%; P=0.045) and with higher pouch adenoma formation rate (50% vs. 8%; P=0.002). Twenty-seven were carriers of exons 1 to 14 mutations and 18 were carriers of exon 15 mutations. Carriers of exon 15 mutations had higher prevalence of preoperative hundreds of colonic adenomas (55.6% vs. 22.2%; P=0.003) and a higher tendency for pouch and cuff adenoma formation rate. Adjusted odds ratio for pouch adenoma formation was 8.32 (1.42-48.80; P=0.019) for the indel/deletion group versus nonsense/missense, but no significant independent association was noted with mutation location. The mean number of pouch and cuff adenoma formation (per endoscopy) was higher among carriers of exon 15 mutations, but no significant independent association was noted the with mutation type. Type and location of APC mutation are associated with colonic polyp burden, surgical outcome and likelihood of developing pouch adenomas. These findings may contribute to surgical and endoscopic surveillance decisions for FAP patients.


Development of an ex vivo model for investigating the bacterial association to the gut epithelium of pigs.
To study enterotoxigenic Escherichia coli (ETEC) association to the gut of pigs, a simple and reproducible experimental model would be helpful. The aim of this experiment was to establish a model for studying the association of ETEC to the gut epithelium of pigs. Intestinal segments were prepared from 4 weaned pigs, which were tested susceptible to E. coli O149:F4 (homo- and heterozygotic; 2 pigs each) and O138:F18 (all homozygotic). Five segments were taken from 50% of the intestinal length measured from duodenum [mid small intestine (SI)], and 5 segments were taken from 90% distal to the duodenum (distal SI). The segments were immersed in Dulbecco's Modified Eagle Medium (DMEM) and kept on ice. Polyethylene tubing was inserted into either end of the segment and tied. The tissue was washed with 50 mL of PBS. The other end of segment was tied, 10 mL of DMEM alone or DMEM containing either E. coli F4 or F18 was inoculated, and the segment was sealed with Teflon plug. The segment was immersed in DMEM in a 300-mL infusion bottle in a shaking water bath at 37°C. After 1 h the segment was removed, tissue was washed with 50 mL of PBS, weighed, and homogenized in PBS. Final dilution of 10(-6) was prepared from the content and homogenate. The E. coli was enumerated on MacConkey agar. Data were analyzed according to a 2 × 3 × 2 parametric model including the effects of intestinal segment, E. coli strain, and site of SI with GLM procedure in SAS. A t-test was used to analyze the effect of genotype in F4-inoculated segment. The binding of E. coli on the tissue was 10 times higher (P < 0.001) for F4 than F18. The E. coli F18 was highest (P < 0.05) in mid SI whereas differences were not observed (P > 0.05) between sites of SI for F4. Fewer (P < 0.001) bacteria bound in the control and they associated more (P = 0.10) at distal than mid SI. The E. coli did not differ (P > 0.05) between genotypes in F4-inoculated segment. In conclusion, the ex vivo model may be feasible to investigate the ETEC association to the gut epithelium of pigs.


Comparing Methods for Identifying Biologically Implausible Values in Height, Weight, and Body Mass Index Among Youth.
As more epidemiologic data on childhood obesity become available, researchers are faced with decisions regarding how to determine biologically implausible values (BIVs) in height, weight, and body mass index. The purpose of the current study was 1) to track how often large, epidemiologic studies address BIVs, 2) to review BIV identification methods, and 3) to apply those methods to a large data set of youth to determine the effects on obesity and BIV prevalence estimates. Studies with large samples of anthropometric data (n > 1,000) were reviewed to track whether and how BIVs were defined. Identified methods were then applied to a longitudinal sample of 13,662 students (65% African American, 52% male) in 55 urban, low-income schools that enroll students from kindergarten through eighth grade (ages 5-13 years) in Philadelphia, Pennsylvania, during 2011-2012. Using measured weight and height at baseline and 1-year follow-up, we compared descriptive statistics, weight status prevalence, and BIV prevalence estimates. Eleven different BIV methods were identified. When these methods were applied to a large data set, severe obesity and BIV prevalence ranged from 7.2% to 8.6% and from 0.04% to 1.68%, respectively. Approximately 41% of large epidemiologic studies did not address BIV identification, and existing identification methods varied considerably. Increased standardization of the identification and treatment of BIVs may aid in the comparability of study results and accurate monitoring of obesity trends.


Current surgical approach to toxic megacolon.
Presented evidence illustrates that proctocolectomy performed as an emergency procedure is frequently less than adequate in salvaging patients with toxic megacolon, and a current mortality of 27 per cent is recorded. The mortality and morbidity of this disease are directly related to the delay in recognition and treatment of this complication and to iatrogenic perforation of the colon during colectomy, which results in fecal peritonitis. This is particularly evident when definitive operation is postponed for more than five days after the initial diagnosis of toxic megacolon. The rationale of current adherence to proctocolectomy for this complication is questioned, and a plea is made for the recognition of the life-saving potential for ileostomy-colostomy for selected patients and also for closer and earlier collaboration between surgeon and internist during the management of these patients.


Aspirin and stroke prevention.
According to meta-analyses aspirin provides a relative reduction in the rate of major vascular events of 19% in patients with arterial disease in general, whereas for patients with ischaemic cerebrovascular disease this reduction is only 13%. The discrepancy may well result from pathophysiological differences and not from a play of chance. There is no proven difference in efficacy according to dose. The evidence for this equivalence is most compelling in the range between 75 and 1300 mg daily, but still fairly convincing for doses between 30 and 50 mg. In contrast, side effects are clearly more frequent as the dose is higher. Other antiplatelet agents (sulfinpyrazone, ticlopidine, clopidogrel, dipyridamole, orally administered IIb/IIIa inhibitors) have no clear advantages over aspirin and in some cases definite disadvantages; the combination of aspirin and dipyridamole may be more efficacious than aspirin alone, but the evidence hinges on a single trial. If recurrent TIAs occur under treatment with aspirin, the rational response is not to change to a different antiplatelet agent, but to review the diagnosis and consider causes other than artery-to-artery embolism. Platelet aggregation can probably still occur despite complete acetylation of platelets, via pathways other than COX-1 inhibition, but in vitro aggregation tests are an unreliable measure.


Mechanism of transmitter release: voltage hypothesis and calcium hypothesis.
The calcium hypothesis of synaptic transmission has been challenged by experimental results using the crayfish neuromuscular junction that suggest that presynaptic depolarization can trigger transmitter release directly without calcium influx. Results from electrophysiological experiments using the same preparation do not support this voltage hypothesis, but are consistent with the calcium hypothesis. Voltage may modulate, but not elicit, transmitter release.


Antithrombotic therapy in coronary ischaemia: the expanding role of low-molecular-weight heparin.
Low-molecular-weight heparins (LMWHs) have been rigorously evaluated in the management of acute coronary ischaemia. The results of clinical trials suggest that LMWHs are effective in reducing major ischaemic outcomes in patients with unstable angina and non-Q-wave myocardial infarction. In one study, LMWH was shown to be more effective than heparin. The clinical utility of LMWHs given subcutaneously in a fixed-dose without the need for monitoring results in major cost savings. The accumulating evidence suggests that LMWHs are safe, effective alternatives to standard heparin in unstable coronary disease and offer practical and therapeutic advantages, representing an important advance in the management of acute coronary ischaemia.


Spectral tuning of lasing emission from optofluidic droplet microlasers using optical stretching.
We introduce tunable optofluidic microlasers based on active optical resonant cavities formed by optically stretched, dye-doped emulsion droplets confined in a dual-beam optical trap. To achieve tunable dye lasing, optically pumped droplets of oil dispersed in water are stretched by light in the dual-beam trap. Subsequently, resonant path lengths of whispering gallery modes (WGMs) propagating in the droplet are modified, leading to shifts in the microlaser emission wavelengths. Using this technique, we present all-optical, almost reversible spectral tuning of the lasing WGMs and show that the direction of tuning depends on the position of the pump beam focus on the droplet. In addition, we study the effects of temperature changes on the spectral position of lasing WGMs and demonstrate that droplet heating leads to red-tuning of the droplet lasing wavelength.


Safety and Activity of Metronomic Temozolomide in Second-Line Treatment of Advanced Neuroendocrine Neoplasms.
Platinum-based chemotherapy is the mainstay of front-line treatment of patients affected by pluri-metastatic intermediate/high grade NeuroEndocrine Neoplasms (NENs). However, there are no standard second-line treatments at disease progression. Previous clinical experiences have evidenced that temozolomide (TMZ), an oral analog of dacarbazine, is active against NENs at standard doses of 150 to 200 mg/mq per day on days 1 to 5 of a 28-day cycle, even if a significant treatment-related toxicity is reported. Metastatic NENs patients were treated at the ENETS (European NeuroEndocrine Tumor Society) center of excellence of Naples (Italy), from 2014 to 2017 with a second-line alternative metronomic schedule of TMZ, 75 mg/m2 per os "one week on/one week off". Toxicity was graded with NCI-CTC criteria v4.0; objective responses with RECIST v1.1 and performance status (PS) according to ECOG. Twenty-six consecutive patients were treated. Median age was 65.5 years. The predominant primary organs were pancreas and lung. Grading was G2 in 11 patients, G3 in 15. More than half of patients had a PS 2 (15 vs. 11 with PS 1). The median time-on-temozolomide therapy was 12.2 months (95% CI: 11.4-19.6). No G3/G4 toxicities were registered. Complete response was obtained in 1 patient, partial response in 4, stable disease in 19 (disease control rate: 92.3%), and progressive disease in 2. The median overall survival from TMZ start was 28.3 months. PS improved in 73% of patients. Metronomic TMZ is a suitable treatment for G2 and G3 NENs particularly in PS 2 patients. Prospective and larger trials are needed to confirm these results.


Prevalence of gastrointestinal pathogens in developed and developing countries: systematic review and meta-analysis.
Diarrhoeal illness is a leading cause of child mortality and morbidity worldwide. There are no precise or current estimates of the types and prevalence of pathogens associated with diarrheal illnesses in developed and developing settings. This systematic review assessed data from 60 studies published in the English language from five developing regions and developed countries worldwide to provide regional estimates of enteric pathogens affecting children. The random-effect method was used to establish the weighted average prevalence of pathogens in adults and children for each region. Significantly more pathogens were reported by studies from developing regions compared with Organisation for Economic Co-operation and Development countries (P<0.016). The identification rates of pathogens from community based and hospital based studies were similar (58.5% and 58.1% respectively, P<0.619). The overall detection of enteric pathogens in developing countries was higher in adults (74.8%; 95% CI 63.1-83.8%) compared with children (56.7%; 95% CI 53.0-60.4%) (P<0.001). Rotavirus was the most frequently detected pathogen in all regions with the highest rate, 24.8% (95% CI 18.0-33.1%), detected in the developed countries. This systematic review is the first to provide an estimate of the prevalence of enteric pathogens associated with diarrhoeal illnesses in adults and children in developed and developing settings. While pathogen detection rate is greater in developing regions the consistently high prevalence of rotavirus in both developed and developing settings underscores the urgent need for access to rotavirus vaccines. Increased travel between developing and developed countries increases disease risk, and hence developed countries have a vested interest in supporting vaccine accessibility in developing settings.


The effect of interventions on balance self-efficacy in the stroke population: a systematic review and meta-analysis.
To conduct a systematic review of clinical trials that examined the effectiveness of interventions on balance self-efficacy among individuals with stroke. Systematic review. Searches of the following databases were completed in December 2014: MEDLINE (1948-present), CINAHL (1982-present), EMBASE (1980-present) and PsycINFO (1987-present) for controlled clinical trials that measured balance self-efficacy in adults with stroke. Reference lists of selected articles were hand-searched to identify further relevant studies. Two independent reviewers performed data extraction and assessed the methodological quality of the studies using the Physical Therapy Evidence Database Scale. Standardized mean differences (SMD) were calculated. A total of 19 trials involving 729 participants used balance self-efficacy as a secondary outcome. Study quality ranged from poor (n = 3) to good (n = 8). In the meta-analysis of 15 trials that used intensive physical activity interventions, a moderate beneficial effect on balance self-efficacy was observed immediately following the programs (SMD 0.44, 95% CI 0.11-0.77, P = 0.009). In the studies that included follow-up assessments, there was no difference between groups across retention periods (eight studies, SMD 0.32, 95% CI -0.17-0.80, P = 0.20). In the four studies that used motor imagery interventions, there was no between-group difference in change in balance self-efficacy (fixed effects SMD 0.68, 95% CI -0.33-1.69, P = 0.18). Physical activity interventions appear to be effective in improving balance self-efficacy after stroke.


Linear and curvilinear correlations of brain white matter volume, fractional anisotropy, and mean diffusivity with age using voxel-based and region-of-interest analyses in 246 healthy children.
In this study, we examined linear and curvilinear correlations of fractional anisotropy (FA), mean diffusivity (MD), and white matter volume with age by using brain structural and diffusion-tensor magnetic resonance imaging (MRI) in a large number of healthy children and voxel-based morphometry (VBM) and region-of-interest (ROI) analyses. We collected data by brain structural MRI in 246 healthy children, aged 5-18 years. FA and MD images were normalized using the normalization parameter of the corresponding structural MRI. Next, we analyzed the correlations between FA and age and between MD and age by estimating linear and logarithmic functions. We also analyzed the correlation between white matter volume and age by linear, quadratic, and cubic functions. Correlations between FA and age and between MD and age showed exponential trajectories in most ROIs in boys and girls, except for several fibers, such as the corpus callosum connecting the bilateral rectal gyri in boys. The correlation between white matter volume and age showed significant positive linear trajectories in most ROIs in boys and girls, except for a few fibers, such as the bilateral uncinate fasciculus. Additionally, maturational rates differed among major fibers, and in girls, the left superior longitudinal fasciculus, which connects the frontal and temporal lobes, showed a slower rate of maturation than other fibers. Our results may help to clarify the mechanisms of normal brain maturation from the viewpoint of brain white matter.


Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae.
Chronic drug users account for a third of all cases of AIDS in the United States and the progression to AIDS dementia is accelerated in opiate drug abusers. Clinically, microglial activation better correlates with HIV-associated neurocognitive disorders (HAND) than productive HIV-1 infection in the CNS. Moreover, pneumococcal pneumonia is the most common opportunistic infection in individuals with HAND. We show that coinfection with Streptococcus pneumoniae may be a contributing factor in the increased prevalence of HAND in the opioid-dependent population. To date, there have been no studies published implicating the Toll-like receptors (TLR) in the neurocognitive disorders associated with NeuroAIDS in the context of opportunistic infection. Our studies show for the first time, in a morphine-dependent model, synergistic increase and activation of TLR expression in the presence of HIV-1 protein TAT and S. pneumoniae with a significant increase in proinflammatory cytokines (IL-6, TNF-α) levels. Furthermore, concurrent increases in reactive oxygen species and nitric oxide production leading to increased caspase 3 activation are also observed in both murine and human microglial cells. These effects are recapitulated with TLR 2, 4, and 9 cognate ligands (Pam3CSK4, LPS, and CpG) and significantly attenuated in TLR 2 and 4 knock-out mice and TLR2/4 double knock-out mice. Therefor, our findings clearly suggest for the first time that activation of TLRs on microglia cells by morphine and TAT in the context of S. pneumoniae infection may be a potential mechanism for the increased prevalence of HAND in HIV-infected opioid-dependent patients.


Inhibitory and excitatory responses of olfactory receptor neurons of xenopus laevis tadpoles to stimulation with amino acids
Recordings were made from olfactory receptor neurons of Xenopus laevis tadpoles using the patch-clamp technique to investigate the responses of these cells to odorants. Four amino acids (glutamate, methionine, arginine and alanine) both individually and as a mixture were used as stimuli. Of the 156 olfactory neurons tested, 43 showed a response to at least one of the stimuli. Of the cells tested, 19 % responded to glutamate, 16 % to methionine, 12 % to arginine and 10 % to alanine. Each amino acid was able to induce both excitatory and inhibitory responses, although these occurred in different cells. Each amino acid produced approximately equal numbers of inhibitory and excitatory responses. Inhibitory responses could best be observed in the perforated-patch configuration using gramicidin as an ionophore and a recording configuration that is a current-clamp for fast signals and a voltage-clamp for slow signals. The diversity of the odorant responses, in particular the existence of excitatory and inhibitory responses, is not consistent with a single transduction pathway in olfactory neurons of Xenopus laevis tadpoles.


A 5-Year Review of Clinical Outcome Measures Published in the Journal of the American Podiatric Medical Association and the Journal of Foot and Ankle Surgery.
This investigation presents a review of all of the clinical outcome measures used by authors and published in the Journal of the American Podiatric Medical Association and the Journal of Foot and Ankle Surgery from January 1, 2011, to December 31, 2015. Of 1,336 articles published during this time frame, 655 (49.0%) were classified as original research and included in this analysis. Of these 655 articles, 151 (23.1%) included at least one clinical outcome measure. Thirty-seven unique clinical outcome scales were used by authors and published during this period. The most frequently reported scales in the 151 included articles were the American Orthopaedic Foot and Ankle Society scales (54.3%; n = 82), visual analog scale (35.8%; n = 54), Medical Outcomes Study Short Form Health Survey (any version) (10.6%; n = 16), Foot Function Index (5.3%; n = 8), Maryland Foot Score (4.0%; n = 6), and Olerud and Molander scoring system (4.0%; n = 6). Twenty-four articles (15.9%) used some form of original/subjective measure of patient satisfaction/expectation. The results of this investigation detail the considerable variety of clinical outcome measurement tools used by authors in the Journal of the American Podiatric Medical Association and the Journal of Foot and Ankle Surgery and might support the need for a shift toward the consistent use of a smaller number of valid, reliable, and clinically useful scales in the podiatric medical literature.


Visualizing Quantum Interference in Molecular Junctions.
Electron transport across a molecular junction is characterized by an energy-dependent transmission function. The transmission function accounts for electrons tunneling through multiple molecular orbitals (MOs) with different phases, which gives rise to quantum interference (QI) effects. Because the transmission function comprises both interfering and noninterfering effects, individual interferences between MOs cannot be deduced from the transmission function directly. Herein, we demonstrate how the transmission function can be deconstructed into its constituent interfering and noninterfering contributions for any model molecular junction. These contributions are arranged in a matrix and displayed pictorially as a QI map, which allows one to easily identify individual QI effects. Importantly, we show that exponential conductance decay with increasing oligomer length is primarily due to an increase in destructive QI. With an ability to "see" QI effects using the QI map, we find that QI is vital to all molecular-scale electron transport.


Segmental analysis of the renal tubule in buffer production and net acid formation.
Papillary and surface micropuncture in Munich-Wistar rats was used to assess the role of proximal segments of superficial and juxtamedullary (JM) nephrons, the distal tubule of superficial nephrons, and the terminal collecting duct in acid excretion. The relative role of these segments in ammonium production, bicarbonate reclamation, and net acid formation was assessed under hydropenic conditions and after a chronic acid load. In these two settings the proximal segment of both kinds of nephrons is the major site of ammonium production and bicarbonate reclamation. However, this segment's contribution to net acid formation was only significant during acidosis. On the other hand, segments beyond the distal tubule appear to be the major site of acid formation. In situ pH measurements were lower in these nephron segments and fell even more after the induction of an acidosis. Ammonia appears to enter fluid between the end of the distal tubule and the base of the collecting duct. In vivo pH measurements made near the bend of Henle's loop of JM nephrons were more alkaline than near the end of the proximal tubule of superficial nephrons. It is postulated that this difference in pH allows ammonium to dissociate, permitting the movement of ammonia out of the tubule lumen and into collecting duct fluid where it is protonated and, therefore, reentrapped. This process is enhanced by the ingestion of a chronic acid load.


New considerations about measuring airway hyperresponsiveness.
Measuring airway responsiveness to inhaled bronchoconstrictor stimuli, such as methacholine or histamine, has become an important tool in the diagnosis of asthma. This is measured by patients inhaling increasing doses or concentrations of the bronchoconstrictor stimulus until a given level of bronchoconstriction is achieved. Inhaled allergens initiate processes that increase airway inflammation and enhance airway hyperresponsiveness in asthmatic subjects. Studies using inhaled allergen challenges have provided insight into how changes in airway hyperresponsiveness are regulated by induced inflammatory processes. These changes in airway hyperresponsiveness (1-2 doubling doses) have been shown to be of much smaller magnitude than those demonstrated when asthmatics with stable airway hyperresponsiveness are compared to normals (4-8 doubling doses). These allergen-induced changes would be of little relevance in subjects with normal airway responsiveness, because they would not increase the degree of airway responsiveness into the asthmatic range. They are, however, important in asthmatics who already have airway hyperresponsiveness because they are similar to changes associated with worsening asthma control. It is likely that the mechanisms responsible for the changes in airway hyperresponsiveness following experimental allergen exposure are similar to those producing transient worsening of control in asthmatics. Nevertheless, it is unlikely that the mechanisms of the transient allergen-induced airway hyperresponsiveness will explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients when compared with normal individuals.


Thirdhand tobacco smoke: a tobacco-specific lung carcinogen on surfaces in smokers' homes.
Thirdhand tobacco smoke consists of substances remaining on the surfaces or in the dust of areas where people have smoked. While previous studies have demonstrated the presence of nicotine and various other constituents of tobacco smoke on surfaces in smokers' homes, none has investigated the presence of tobacco-specific carcinogens. We used liquid chromatography-tandem mass spectrometry to analyze surface dust samples from both the homes of smokers and nonsmokers for the powerful tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We positively identified NNK on surfaces in 33 of 37 smokers' homes (700±788 pg/100cm(2) [range, not detected-3,500 pg/100cm(2)]), but only in 3 of 19 nonsmokers' homes (235±176 pg/100cm(2) in the homes where NNK was detected [range, not detected-435 pg/100cm(2)]). The differences in occurrence and levels of NNK in the homes of smokers and nonsmokers were significant (p < .0001). The powerful tobacco-specific lung carcinogen NNK is present on surfaces in most homes occupied by smokers. Potential renters or buyers of apartments or homes should be notified if previous residents were smokers in order to avoid unnecessary exposure of their families to a potent lung carcinogen.


The determination of carbon dioxide concentration using atmospheric pressure ionization mass spectrometry/isotopic dilution and errors in concentration measurements caused by dryers.
An atmospheric pressure ionization mass spectrometry/isotopically labeled standard (APIMS/ILS) method has been developed for the determination of carbon dioxide (CO(2)) concentration. Descriptions of the instrumental components, the ionization chemistry, and the statistics associated with the analytical method are provided. This method represents an alternative to the nondispersive infrared (NDIR) technique, which is currently used in the atmospheric community to determine atmospheric CO(2) concentrations. The APIMS/ILS and NDIR methods exhibit a decreased sensitivity for CO(2) in the presence of water vapor. Therefore, dryers such as a nafion dryer are used to remove water before detection. The APIMS/ILS method measures mixing ratios and demonstrates linearity and range in the presence or absence of a dryer. The NDIR technique, on the other hand, measures molar concentrations. The second half of this paper describes errors in molar concentration measurements that are caused by drying. An equation describing the errors was derived from the ideal gas law, the conservation of mass, and Dalton's Law. The purpose of this derivation was to quantify errors in the NDIR technique that are caused by drying. Laboratory experiments were conducted to verify the errors created solely by the dryer in CO(2) concentration measurements post-dryer. The laboratory experiments verified the theoretically predicted errors in the derived equations. There are numerous references in the literature that describe the use of a dryer in conjunction with the NDIR technique. However, these references do not address the errors that are caused by drying.


Carbon nanotubes as electrodes for dielectrophoresis of DNA.
Dielectrophoresis can potentially be used as an efficient trapping tool in the fabrication of molecular devices. For nanoscale objects, however, the Brownian motion poses a challenge. We show that the use of carbon nanotube electrodes makes it possible to apply relatively low trapping voltages and still achieve high enough field gradients for trapping nanoscale objects, e.g., single molecules. We compare the efficiency and other characteristics of dielectrophoresis between carbon nanotube electrodes and lithographically fabricated metallic electrodes, in the case of trapping nanoscale DNA molecules. The results are analyzed using finite element method simulations and reveal information about the frequency-dependent polarizability of DNA.


Larval development and proteolytic activity of Anticarsia gemmatalis Hübner (Lepidoptera: Noctuidae) exposed to different soybean protease inhibitors.
Anticarsia gemmatalis represents a relevant factor for lowering soybean and other legume crop productivities. Protease inhibitors affect protein degradation and reduce the availability of amino acids, impairing the development and survival of insect pests. To evaluate the possible use of proteinaceous protease inhibitors in the management of this pest, the activities of midgut proteases and the growth and development of A. gemmatalis larvae exposed to soybean Bowman-Birk trypsin-chymotrypsin inhibitor (SBBI) and soybean Kunitz trypsin inhibitor (SKTI) were determined. The survival curves obtained using Kaplan-Meier estimators indicated that SKTI and SBBI stimulated larval survival. However, the development of A. gemmatalis was delayed, and prepupal weight decreased in the presence of both inhibitors. The results showed that SKTI and SBBI inhibited the trypsin-like and total proteolytic activities of larvae on the 12th day after eclosion. On the 15th day after eclosion, larvae exposed to SKTI increased the activities of trypsin and total proteases. Although SKTI and SBBI did not affect the survival of the insect, they had effects on midgut proteases in a stage wherein A. gemmatalis fed voraciously, increased the larval cycle, and decreased prepupal weight. These findings provide baseline information about the potential of proteinaceous protease inhibitors to manage the velvetbean caterpillar, avoiding chemical pesticides.


Effect of low visceral fat area on long-term survival of stage I-III colorectal cancer.
The prognostic significance of a low visceral fat area (VFA) in colorectal cancer (CRC) remains unclear. The aim of this study was to evaluate the prognostic effects of a low VFA on the long-term outcomes of patients with CRC after laparoscopic surgery. This retrospective study included 306 patients with stages I-III CRC who underwent R0 resection. VFA was preoperatively measured via computed tomography using image processing software. Relapse-free survival (RFS) and overall survival (OS) rates were analyzed using the Cox proportional hazards model and Kaplan-Meier curves. Low VFA was identified in 153 patients. The low VFA group had significantly lower RFS and OS rates than did the high VFA group (5-y RFS rates: 72 versus 89%, P = 0.0002; 5-y OS rates: 72 versus 92%, P = 0.0001). The independent significant predictors of RFS were T3 or T4 disease (hazard ratio [HR], 2.75; 95% confidence interval [CI], 1.12-6.76; P = 0.027), stage III CRC (HR, 3.49; 95% CI, 1.82-6.69; P < 0.001), low psoas muscle index (PMI; HR, 2.12; 95% CI, 1.19-3.79; P = 0.011), and low VFA (HR, 2.12; 95% CI, 1.16-3.86; P = 0.014). The independent significant predictors of OS were age ≥65 y (HR, 2.59; 95% CI, 1.13-5.92, P = 0.024), carbohydrate antigen 19-9 levels ≥37 ng/mL (HR, 2.32; 95% CI, 1.18-4.58; P = 0.015), stage III CRC (HR, 2.66; 95% CI, 1.37-5.17; P = 0.004), low PMI (HR, 2.00; 95% CI, 1.06-3.77; P = 0.031), and low VFA (HR, 2.42; 95% CI, 1.24-4.70; P = 0.009). A low preoperative VFA was significantly associated with worse RFS and OS rates in patients who underwent CRC resection.


Personality pathology and alcohol dependence at midlife in a community sample.
The present study examined the association between personality pathology (PP) and alcohol dependence (AD; both lifetime and in the past 12 months) among middle-aged to older adults incorporating three sources of assessment, specifically, diagnostic interviews as well as self- and informant reports. We collected data from a representative sample of community participants (N = 1,630; ages 54-65 years) and their informants (N = 1,462). Measures employed were the substance use disorder sections of the Mini-International Neuropsychiatric Interview Schedule for Mental Disorders, the Structured Interview for DSM-IV Personality (American Psychiatric Association, 2000, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text rev.; DSM-IV-TR SIDP) and the NEO-Personality Inventory-Revised (Costa, P. T., & McCrae, R. R., Revised NEO-Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) manual, 1992, Odessa, FL, Psychological Assessment Resources; self-report and informant versions). To complement the diagnostic interview for personality disorders (PDs), we utilized a PD-count technique derived from the five-factor model (FFM), which provided an index of PP liability. Factors representing lifetime and past-12 month AD were regressed on each of the 10 PP factors constructed from the SIDP interview, as well as self-report and informant FFM-count scores. Lifetime diagnosis of AD was positively associated with higher scores on several PP measures, including paranoid, schizotypal, antisocial, borderline, histrionic, and narcissistic PP. There was an inverse relation between lifetime AD and the factor score for obsessive-compulsive PP. With regard to AD in the past 12 months, antisocial, borderline, histrionic, and narcissistic PP factors were significantly associated with increased risk for AD, whereas the obsessive-compulsive and schizoid PP factors were associated with decreased risk for AD. The present data indicate that features of antisocial and borderline PP continue to exhibit a relatively strong association with risk for AD in later middle age.


Magnetic resonance imaging at microscopic resolution reveals subtle morphological changes in a mouse model of dopaminergic hyperfunction.
Structural abnormalities of the basal ganglia have been documented in several neuropsychiatric conditions associated with dysregulation of the dopamine system. However, the histological nature underlying these changes is largely unknown. Using magnetic resonance imaging at microscopic resolution (MRI, 9.4 T with 43 microm isotropic spatial resolution) and stereological techniques, we have investigated the effect of increased dopamine neurotransmission on brain morphology in mice with elevated extracellular dopamine, the dopamine transporter knockout (DAT-KO) mice. We first demonstrate the usefulness of MRI at microscopic resolution for the accurate identification and measurement of volumes of specific subregions, accounting for less than 0.03% (0.16 mm(3)) of the volume of a mouse brain. Furthermore, the MRI analysis reveals a significantly lower volume (-9%) of the anterior striatum of DAT-KO mice, while the volume of other dopamine-related structures such as the posterior striatum and the substantia nigra pars reticulata is unchanged in comparison to wild type littermates. Stereological analysis performed in the same brains reveals that one important structural factor accounting for this selective change in volume is a reduction of 18% in the absolute number of neuronal cell bodies. The feasibility of assessing accurately small morphological alterations in mouse models, where the molecular and histological pathologies can be easily compared in a controlled manner, provides a paradigm to examine the relevance of selective brain volumetric changes associated with a number of neuropathological conditions.


Physics of the Jagla model as the liquid-liquid coexistence line slope varies.
The slope of the coexistence line of the liquid-liquid phase transition can be positive, negative, or zero. All three possibilities have been found in Monte-Carlo simulations of a modified spherically symmetric two-scale Jagla model. Since the liquid-liquid critical point frequently lies in a region of the phase diagram that is difficult to access experimentally, it is of great interest to study critical phenomena in the supercritical region. We therefore study the properties of the Widom line, defined in the one-phase region above the critical point as an extension of the coexistence line near which the loci of various response functions extrema asymptotically converge with each other. This phenomenon is predicted by the scaling theory according to which all response functions can be expressed asymptotically in the vicinity of a critical point as functions of the diverging correlation length. We find that the method of identifying the Widom line as the loci of heat capacity maxima becomes unfruitful when the slope of the coexistence line approaches zero in the T-P plane. In this case, the specific heat displays no maximum in the one-phase region because, for a horizontal phase coexistence line, according to the Clapeyron equation, the enthalpy difference between the coexisting phases is zero, and thus the critical fluctuations do not contribute to enthalpy fluctuations. The extension of the coexistence line beyond the critical point into the one-phase region must in this case be performed using density fluctuations. Although the line of compressibility maxima bifurcates into a symmetrical pair of lines, it remains well-defined. We also study how the glass transition changes as the slope of the coexistence line in the T-P plane approaches zero. We find that for the case of positive slopes, diffusivity shows a fragile-to-strong transition upon crossing the Widom line, while for horizontal slope, diffusivity shows the behavior typical for fragile liquids.


Exploration of clients living with HIV needs for reporting on experiences with sex.
Talking about sex with people living with HIV receives insufficient attention in health care. A cross-sectional and exploratory study describes the preferences of people living with HIV to talk about sex with specialized HIV physicians and nurses in a clinic in Barcelona (Spain). A 27-item self-administered questionnaire was used between June 2017 and May 2018. One hundred fourteen people agreed to participate. Data were analyzed using multivariate logistic regression. Most of the participants reported "never or almost never" having been asked about sex practices in visits with the HIV specialist physician (n = 65 [57.0%]) or nurse (n = 74 [64.9%]). Older participants stated that neither physicians nor nurses talked about sex during visits. Women felt that physicians hardly ever asked about their sexual practices. Men who had sex with other men indicated that their physicians always asked about their sex practices compared with heterosexuals living with HIV. Health professionals should reformulate how to talk about sex with people living with HIV to facilitate communication and provide adequate care.


'Real relationships': sociable interaction, material culture and imprisonment in a secure psychiatric unit.
Research into the character of social relationships in psychiatric inpatient facilities has focused on face-to-face interaction between individuals and within groups in the communal areas of wards. Using theories developed in material culture and media studies, this article argues that patients' relationships to goods, namely, photographs, cards and gifts from family or friends, televisions and radios, are important mediators and constituents of sociability. In an ethnographic study of a medium-secure psychiatric unit, I show how these goods are put to use in private space in ways that reflect and mitigate the constraints of incarceration and stigmatization. The data were derived from 3 months of participant observation on a male and a female ward at a unit in the south of England, including a series of anthropological interviews with 19 patients. This article highlights two important findings. First, potentially isolating activities are perceived by patients as sociable, in that watching television and looking at photographs in their room helps to counter feelings of loneliness and isolation. Second, potentially sociable activities, exchanging goods or watching the communal television, are often practiced in such a way as to maintain distance between patients in acknowledgment of the constrained and volatile nature of these relationships. This suggests that patients aspire to retain a sense of the artificiality of their situation, preferring to confine their notion of 'real' relationships to those that exist outside the institution.


Granulomatous epididymitis related to Rhodotorula glutinis infection in a dog.
A 4-year-old, male Great Dane dog developed severe swelling of the scrotum on 9 December 1991, and the testes and epididymides were removed surgically on 12 December 1992. The cut surface of the epididymides consisted of hard connective tissue and several small abcesses with slight hemorrhage. Histopathologically, the seminiferous tubules in the testes had only a few spermatogenic cells, but Sertoli cells were well preserved. Both epididymides consisted entirely of a proliferation of fibrous connective tissue, and only a few ducts deferens containing cell debris, neutrophils, and macrophages in the lumina were present. In all lesions of the epididymides, the macrophages contained periodic acid-Schiff- and Grocott's silver-positive round granules, 5-8 microns in diameter. Microbiologically, smooth salmon-pink colonies consisting of ovoidal yeast, about 10 microns in diameter, were isolated from the samples of epididymides but not from those of the testes. The isolated yeast had microbiological characteristics of Rhodotorula glutinis. From these observations, we diagnosed the present case as granulomatous epididymitis due to Rhodotorula infection.


Early mobilisation and rehabilitation in Swiss intensive care units: a cross-sectional survey.
Patients in intensive care units (ICUs) are at high risk of developing physical, functional, cognitive, and mental impairments. Early mobilisation aims to improve patient outcomes and is increasingly considered the standard of care. This survey aimed to investigate the characteristics, current use and variations of early mobilisation and rehabilitation in Swiss ICUs. We conducted a cross-sectional survey among all ICU lead physicians, who provided data on their institutional characteristics, early mobilisation and rehabilitation practices, and their perceptions of the use and variation of early rehabilitation practices in Switzerland. The survey response rate was 44% (37/84). Among ICUs caring for adults (34/37), 26 were in the German-speaking region, five in the French-speaking region, and three in the Italian-speaking region. All ICUs regularly involved physiotherapy in the rehabilitation process and 50% reported having a specialised physiotherapy team. All ICUs reported performing early mobilisation, starting within the first 7 days after ICU admission. About half reported the use of a rehabilitation (45%) or early mobilisation protocol (50%). Regular, structured, interdisciplinary rounds or meetings of the ICU care team to discuss rehabilitation measures and goals for patients were stated to be held by 53%. The respondents stated that 82% of their patients received early mobilisation measures during their ICU stay. Most frequently provided mobilisation measures included passive range of motion (97%), passive chair position in bed (97%), active range of motion muscle activation and training (88%), active side to side turning (91%), sitting on the edge of the bed (94%), transfer from bed to a chair (97%), and ambulation (94%). The proportion of ICUs providing a specific early mobilisation measure, the proportion of patients receiving it, and the time dedicated to it varied across language regions, hospital types, ICU types, and ICU sizes. Almost one third of the ICU lead physicians considered early rehabilitation to be underused in their own ICU and about half considered it to be underused in Switzerland more generally. ICU lead physicians stressed lack of personnel, financial resources, and time as key causes for underuse. Moreover, they highlighted the importance of early and systematic or protocol-based rehabilitation and interprofessional approaches that are adaptive to the patients' rehabilitation needs and potential. This survey suggests that almost all ICUs in Switzerland practice some form of early mobilisation with the aim of early rehabilitation. However, the described approaches, as well as the reported use of early mobilisation measures were heterogenous across Swiss ICUs.


Round atelectasis: another pulmonary pseudotumor.
Round atelectasis is a relatively rare form of collapse, associated with pleural thickening, pleural effusions, or pleural plaques. The mass is always in a subpleural location and has a characteristic comet-tail-shaped structure. Recognition of this entity can avert more invasive procedures.


Temporal and regional variations in the use of preoperative radiation therapy for rectal cancer.
Preoperative (preop) chemoradiation therapy improves local control and reduces toxicity for stage II/III rectal cancer better than postoperative (postop) chemoradiation therapy. We examined the temporal and regional variations in the use of preop radiotherapy (RT) across the United States. Patients with stage II/III rectal cancer diagnosed between 1998 and 2005 who had a primary site resection were identified from the SEER database. The rate of preop RT use over time was plotted. Regression models were used to analyze regional variations. From 1998 to 2005, an increase of 1.7 in the ratio of preop RT/postoperative RT was noted, whereas the ratio of RT/no RT increased only by 0.7. The ratio of preop RT/postop RT increased from 0.5 to 1 in 5 years (1998-2003) but from 1 to 1.5 in 2 years (2003-2005). Multivariate regression analysis showed: patients with stage II disease were more likely than those with stage III disease, younger patients were more likely than older patients, and males were more likely than females to receive preop RT. Whites were more likely to receive preop RT than nonwhites for stage III disease only. Patients treated in the San Francisco region, Hawaii, New Mexico, Seattle, and Los Angeles were more likely to receive preop RT than were patients in the Connecticut, Detroit, Iowa, Utah, Atlanta, and San Jose/Monterey regions. The increasing use of preop RT varies across US regions and patient subgroups. Further studies should evaluate potentially modifiable factors contributing to these variations.


Prognostic value of tumour thickness in cutaneous malignant melanoma.
The relation between survival and histological features in 91 patients with malignant melanoma was studied and the results were analysed by Clayton's method for interpretation of censored survival data. There was a significant correlation between tumour thickness and survival. The risk of dying from malignant melanoma after 10 years of follow up was less than 15% if the primary tumour was less than 1.5 mm thick but more than 80% if the lesion was thicker than 8 mm. The type of melanoma, level of invasion, mitotic rate, and presence of ulceration also correlated with survival, but these variables are related to tumour thickness.


Myotonic dystrophy protein kinase is expressed in embryonic myocytes and is required for myotube formation.
Myotonic dystrophy (DM1) is a multi-systemic disease caused by a triplet nucleotide repeat expansion in the 3' untranslated region of the gene coding for myotonic dystrophy protein kinase (DMPK). The primary pathophysiology of DM1 is thought to result from RNA transport and processing defects. The function of DMPK in development or any potential role in DM1 remains unknown. Here we report a novel role for DMPK in myogenesis. We have discovered a specific expression pattern of DMPK in mouse and chick embryonic development. DMPK is expressed in postmitotic cardiac and skeletal myocytes and developmental signaling centers. During cardiac myocyte maturation, DMPK migrates from perinuclear to cellular membrane localization. Manipulating DMPK levels in cultured cardiac and skeletal myocytes has revealed a key role for DMPK in myocyte differentiation. Overexpression of DMPK induces cell rounding and apoptosis in myocytes. In addition, DMPK is necessary for myogenin expression in differentiating C2C12 myoblasts.


Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury.
Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.


Protection of swimming-induced oxidative stress in some vital organs by the treatment of composite extract of Withania somnifera, Ocimum sanctum and Zingiber officinalis in male rat.
Composite methanolic extract of roots of Withania somnifera, leaves of Ocimum sanctum, and rhizomes of Zingiber officinalis was administered by gavage at the dose of 40 mg 100 g(-1) body weight day(-1) to rat orally for 15 days prior to experimentation followed by co-administration of above extract at the same dose for 28 days of swimming to find out the remedial effect of this extract on exhaustive physical exercise-induced oxidative damage. Swimming resulted significant diminution (p<0.05) in the activities of catalase and superoxide dismutase along with elevation (p<0.05) in the levels of thiobarbituric acid reactive substances and conjugated dienes in cardiac, skeletal, hepatic tissues, cerebrum and cerebellum in respect to control. The levels of all these parameters were resettled significantly (p<0.05) towards the extract pretreated cum co-treated swimming group. The antioxidative potency of this composite extract was compared with standard non-enzymatic antioxidant (vitamin-E) in forced swimming state. The above extract has no general toxic effect as reflected here from the study of transaminase activities in liver and kidney. Results lead to conclude that the composite extract of above three plant parts has a therapeutic protective effect on forced swimming-induced oxidative stress in vital organs.


A comparative anatomic and physiologic overview of the porcine heart.
Despite advances during the last 2 decades in every aspect of cardiovascular research (interventional cardiology, cardiopulmonary resuscitation, and so forth), Western societies still are plagued by the consequences of cardiovascular disease. Consequently the discovery of new regimens and therapeutic interventions is of utmost importance. Research using human subjects is associated with substantial methodologic and ethical considerations, and the quest for an appropriate animal model for the human cardiovascular system has led to swine. The porcine heart bears a close resemblance to the human heart in terms of its coronary circulation and hemodynamic similarities and offers ease of implementation of methods and devices from human healthcare facilities. A thorough comprehension of the anatomy and physiology of the porcine cardiovascular system should focus on differences between swine and humans as well as similarities. Understanding these differences and similarities is essential to extrapolating data appropriately and to addressing the social demand for the ethical use of animals in biomedical research.


Cooperative behavior of biased probes in crowded interacting systems.
We study, via extensive numerical simulations, dynamics of a crowded mixture of mutually interacting (with a short-range repulsive potential) colloidal particles immersed in a suspending solvent, acting as a heat bath. The mixture consists of a majority component - neutrally buoyant colloids subject to internal stimuli only, and a minority component - biased probes (BPs) also subject to a constant force. In such a system each of the BPs alters the distribution of the colloidal particles in its vicinity, driving their spatial distribution out of equilibrium. This induces effective long-range interactions and multi-tag correlations between the BPs, mediated by an out-of-equilibrium majority component, and prompts the BPs to move collectively assembling in clusters. We analyse the size-distribution of the self-assembling clusters in the steady-state, their specific force-velocity relations and also properties of the effective interactions emerging between the BPs.


Biosensors for the Detection of Bacterial and Viral Clinical Pathogens.
Biosensors are measurement devices that can sense several biomolecules, and are widely used for the detection of relevant clinical pathogens such as bacteria and viruses, showing outstanding results. Because of the latent existing risk of facing another pandemic like the one we are living through due to COVID-19, researchers are constantly looking forward to developing new technologies for diagnosis and treatment of infections caused by different bacteria and viruses. Regarding that, nanotechnology has improved biosensors' design and performance through the development of materials and nanoparticles that enhance their affinity, selectivity, and efficacy in detecting these pathogens, such as employing nanoparticles, graphene quantum dots, and electrospun nanofibers. Therefore, this work aims to present a comprehensive review that exposes how biosensors work in terms of bacterial and viral detection, and the nanotechnological features that are contributing to achieving a faster yet still efficient COVID-19 diagnosis at the point-of-care.


Vascular smooth muscle cells express multiple type I receptors for TGF-beta, activin, and bone morphogenetic proteins.
Vascular smooth muscle cells (VSMCs) are known to produce activins, bone morphogenetic proteins and transforming growth factor-betas (TGF-betas). To determine whether these TGF-beta superfamily members exert autocrine effects on VSMCs we examined whether specific type I receptors (ALKs) for such peptides were expressed by the cells. RNA from both quiescent or growth-factor-activated VSMCs was reverse transcribed then cDNAs encoding ALK-2, ALK-3, ALK-5, and ALK-6 were amplified and characterised using specific PCR primers. All four ALK mRNAs were abundantly expressed. The ALK-5 fragment harbored a deletion of 12 nucleotides, removing 4 extracellular amino acids (Gly-Pro-Ser-Val) adjacent to its transmembrane domain. This deletion, which may arise from anomalous splicing of heteronuclear RNA, is likely to influence formation of the ALK-5:type II receptor complex through conformational changes associated with removal of a putative hinge region containing proline. Our finding that multiple ALKs are expressed by VSMCs would account for the multiplicity of effects TGF-beta peptides exert on these cells.


The role of the gut flora in the metabolism of cyclamate.
1. [(14)C]Cyclamate was not metabolized when incubated with the liver, spleen, kidney or blood of rats of rabbits kept on a cyclamate-containing diet, and that had become converters of cyclamate into cyclohexylamine. 2. [(14)C]Cyclamate was converted into cyclohexylamine when incubated under anaerobic conditions with the contents of the caecum, colon or rectum or with the faeces of cyclamate-pretreated rats. Similar results were obtained with cyclamate-pretreated rabbits. With cyclamate-pretreated guinea pigs, which did not readily convert cyclamate into cyclohexylamine, the colon contents showed only low activity in this respect. 3. The faeces of a human converter of [(14)C]cyclamate into cyclohexylamine were also very active, but became less active when cyclamate was removed from his diet. 4. On subculturing the organisms from the contents of the colon and rectum of rats, the ability to convert cyclamate into cyclohexylamine was lost during three subcultures, but the loss of the activity was considerably decreased by subculturing in the presence of cyclamate. 5. Incubation of rat faeces in broths containing cyclamate increased their ability to metabolize cyclamate, but similar treatment of rabbit and human faeces suppressed this activity. 6. When rats are kept on a cyclamate diet the number of clostridia in the faeces increased considerably. In human dietary cyclamate did not appear to alter the counts of various faecal micro-organisms. 7. The gut organisms that appear to develop the ability to convert cyclamate into cyclohexylamine are clostridia in rats, enterobacteria in rabbits and enterococci in man. 8. [(14)C]Cyclohexylamine injected into the caecum or colon of rats is readily absorbed and excreted in the urine. 9. It appears that on continued intake of cyclamate the gut flora develop the ability to convert cyclamate into cyclohexylamine, which is then absorbed and excreted mainly in the urine, although a small proportion is metabolized to other compounds.


A novel actin-microtubule cross-linking kinesin, NtKCH, functions in cell expansion and division.
• Kinesins with a calponin homology domain (KCHs) have been identified recently as a plant-specific subgroup of the kinesin-14 family and are suspected to act as microtubule-actin filament cross-linkers. The cellular function, however, has remained elusive. • In order to address the function of KCHs, we isolated NtKCH, a novel KCH homologue from tobacco BY-2 cells. Following synchronization, NtKCH transcripts were shown to be abundant during mitosis, whereas, during interphase, expression was low. • Using fluorescent-tagged cell lines and immunolabelling techniques, the localization of tobacco KCH was found to differ depending on the cell cycle. During interphase, NtKCH mainly associated with cortical microtubules, whereas a subfraction also co-localized with perinuclear actin cables. In dividing cells, NtKCH accumulated at the pre-prophase band and at the phragmoplast. However, it remained absent from spindle microtubules, but, instead, concentrated at two agglomerations in proximity to the two cell poles. • This work develops a detailed model for the dual localization and function of NtKCH during cell division vs cell expansion. This model implies two dynamic states of KCHs that differ with regard to actin interaction. This allows the modulation of force generation by KCH in a cell cycle-dependent capture mechanism.


Genetic incorporation of unnatural amino acids into proteins in Mycobacterium tuberculosis.
New tools are needed to study the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), to facilitate new drug discovery and vaccine development. We have developed methodology to genetically incorporate unnatural amino acids into proteins in Mycobacterium smegmatis, BCG and Mtb, grown both extracellularly in culture and inside host cells. Orthogonal mutant tRNATyr/tyrosyl-tRNA synthetase pairs derived from Methanococcus jannaschii and evolved in Escherichia coli incorporate a variety of unnatural amino acids (including photocrosslinking, chemically reactive, heavy atom containing, and immunogenic amino acids) into proteins in response to the amber nonsense codon. By taking advantage of the fidelity and suppression efficiency of the MjtRNA/pIpaRS pair in mycobacteria, we are also able to use p-iodophenylalanine to induce the expression of proteins in mycobacteria both extracellularly in culture and inside of mammalian host cells. This provides a new approach to regulate the expression of reporter genes or mycobacteria endogenous genes of interest. The establishment of the unnatural amino acid expression system in Mtb, an intracellular pathogen, should facilitate studies of TB biology and vaccine development.


Phenotypic and genotypic characteristics of Neisseria meningitidis disease-causing strains in Argentina, 2010.
Phenotypic and genotypic characterization of 133 isolates of Neisseria meningitidis obtained from meningococcal disease cases in Argentina during 2010 were performed by the National Reference Laboratory as part of a project coordinated by the PAHO within the SIREVA II network. Serogroup, serotype, serosubtype and MLST characterization were performed. Minimum Inhibitory Concentration to penicillin, ampicillin, ceftriaxone, rifampin, chloramphenicol, tetracycline and ciprofloxacin were determined and interpreted according to CLSI guidelines. Almost 49% of isolates were W135, and two serotype:serosubtype combinations, W135:2a:P1.5,2:ST-11 and W135:2a:P1.2:ST-11 accounted for 78% of all W135 isolates. Serogroup B accounted for 42.1% of isolates, and was both phenotypically and genotypically diverse. Serogroup C isolates represented 5.3% of the dataset, and one isolate belonging to the ST-198 complex was non-groupable. Isolates belonged mainly to the ST-11 complex (48%) and to a lesser extent to the ST-865 (18%), ST-32 (9,8%) and the ST-35 complexes (9%). Intermediate resistance to penicillin and ampicillin was detected in 35.4% and 33.1% of isolates respectively. Two W135:2a:P1.5,2:ST-11:ST-11 isolates presented resistance to ciprofloxacin associated with a mutation in the QRDR of gyrA gene Thr91-Ile. These data show serogroup W135 was the first cause of disease in Argentina in 2010, and was strongly associated with the W135:2a:P1.5,2:ST-11 epidemic clone. Serogroup B was the second cause of disease and isolates belonging to this serogroup were phenotypically and genotypically diverse. The presence of isolates with intermediate resistance to penicillin and the presence of fluorquinolone-resistant isolates highlight the necessity and importance of maintaining and strengthening National Surveillance Programs.


Natural vitamin C intake and the risk of head and neck cancer: A pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.
Evidence of associations between single nutrients and head and neck cancer (HNC) is still more limited and less consistent than that for fruit and vegetables. However, clarification of the protective mechanisms of fruit and vegetables is important to our understanding of HNC etiology. We investigated the association between vitamin C intake from natural sources and cancer of the oral cavity/pharynx and larynx using individual-level pooled data from ten case-control studies (5,959 cases and 12,248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. After harmonization of study-specific exposure information via the residual method, adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using unconditional multiple logistic regression models on quintile categories of 'non-alcohol energy-adjusted' vitamin C intake. In the presence of heterogeneity of the estimated ORs among studies, we derived those estimates from generalized linear mixed models. Higher intakes of vitamin C were inversely related to oral and pharyngeal (OR = 0.54, 95% CI: 0.45-0.65, for the fifth quintile category versus the first one, p for trend<0.001) and laryngeal cancers (OR = 0.52, 95% CI: 0.40-0.68, p for trend = 0.006), although in the presence of heterogeneity among studies for both sites. Inverse associations were consistently observed for the anatomical subsites of oral and pharyngeal cancer, and across strata of age, sex, education, body mass index, tobacco, and alcohol, for both cancer sites. The inverse association of vitamin C intake from foods with HNC may reflect a protective effect on these cancers; however, we cannot rule out other explanations.


Impact of presence of excipients in drug analysis in fed-state gastric biorelevant media.
In this study, the influence of the presence of excipients in sample preparation and clean-up steps required prior to drug analysis in milk-based media which simulate the in vivo properties of the fed state stomach was investigated. 15 excipients, normally present in solid dosage forms of five APIs tested (atenolol, paracetamol, furosemide, nifedipine and propafenone hydrochloride) were mixed (one at a time) with the active pharmaceutical ingredient of interest either via vortexing, co-grinding or shaking of the physical mixture and dissolved in Fed State Simulated Gastric Fluid (FeSSGF). The objective of the study was the assessment of the extraction efficiency of three protein precipitation protocols (using MeOH, ΑCN and 10% w/v TCA), typically used in drug analysis, in milk-based biorelevant media in the presence of the excipients. The mixing technique, fat content of the medium and excipient and solvent effects were investigated. The efficiency of three different protein precipitation reagents in drug extraction when dissolved as API:excipient mixtures in the fed-state medium was compared against the equivalent drug amount recovered in the absence of the excipient in FeSSGF. Most excipients had a significant negative effect (p < 0.05) on drug recovery in the milk-based medium as indicated by the multiple linear regression (MLR) analysis performed. For magnesium stearate and HPMC, the % recovery values were the lowest in four out of the five drugs studied, with a range of 10-100% depending on the API, mixing technique and protein precipitation protocol selected. The negative excipient-dependent effect was more profound in nifedipine and propafenone hydrochloride, the most lipophilic compounds of the study. Acetonitrile was the most effective extraction reagent for most drugs in the presence of excipients, followed by methanol and 10% w/v trichloroacetic acid. Data analysis also revealed a dependence of the extraction method efficiency on the medium lipid content. Application of the above extraction protocols in commercially available formulations highlighted the need for assessment of the effect of excipients in extraction efficiency, before transferring the method directly to dissolution studies of formulations in milk-based fed gastric media. In conclusion, the presence of excipients and the selection of protein precipitation protocol are parameters which can affect significantly the efficiency of protein precipitation when FeSSGF is used as dissolution medium and need to be taken into consideration when developing a quantitative method based on the above sample clean-up technique.


Trauma history in African-American women living with HIV: effects on psychiatric symptom severity and religious coping.
Women living with HIV (WLHIV) have rates of post-traumatic stress disorder (PTSD) up to 5 times higher than the general population. Individuals living with HIV and a concurrent diagnosis of PTSD have poorer HIV-related outcomes; however, the prevalence and impact of PTSD on African-American WLHIV seeking mental health treatment is unknown. The aim of this study is to examine the associations between PTSD symptoms with psychiatric symptom severity and psychological/religious coping strategies in African-American WLHIV who are seeking mental health treatment. This is a cross-sectional study of 235 African-American WLHIV attending an urban community mental health clinic. Bivariate analyses were conducted to evaluate associations between a PTSD symptoms scale (PSS≥21 versus PSS<21) and (1) psychiatric severity, (2) coping strategies, and (3) religious coping strategies. Thirty-six percent reported symptoms consistent with PTSD (PSS≥21). These women were significantly more likely to have worse mental health symptoms and were more likely to employ negative psychological and religious coping strategies. On the contrary, women with a PSS<21 reported relatively low levels of mental health symptoms and were more likely to rely on positive psychological and religious coping strategies. Over one-third of African-American WLHIV attending an outpatient mental health clinic had symptoms associated with PTSD. These symptoms were associated with worse mental health symptoms and utilization of dysfunctional religious and nonreligious coping strategies. Untreated PTSD in WLHIV predicts poorer HIV-related health outcomes and may negatively impact comorbid mental health outcomes. Screening for PTSD in WLHIV could identify a subset that would benefit from evidence-based PTSD-specific therapies in addition to mental health interventions already in place. PTSD-specific interventions for WLHIV with PTSD may improve outcomes, improve coping strategies, and allow for more effective treatment of comorbid mental health disorders.


[Implementation of parliamentary act D. Lgs 25/02 and definition of "moderate risk"].
This paper describes the position of the Joint Working Group of the Italian Association of Industrial Hygienists (AIDII), the Italian Society of Occupational Health and Industrial Hygiene (SIMLII) and the Italian Society of Toxicology (SITOX) on "Analysis of Parliamentary Act D.Lgs 25/02 and role of the Scientific Societies in the definition of Limit Values". The positive aspects of the new law which implements the European Directive 98/24 are discussed, including the abolition of the rigid periodicity of medical examinations as stated by the old rule D.P.R. 303/56. The Authors also address various parts of the law which appear to be unclear and controversial and highlight the expected difficulties arising for the employers and the safety and health professionals during the application of this new piece of legislation. Moreover, a number of discrepancies are noted between the new Italian law and the original Directive or other current Italian rules such as i. the translation of the term "slight risk", as from the original Directive, into "moderate risk", and the resulting non compulsoriness of health surveillance and biological monitoring of the workers in presence of a "moderate risk", ii. the concurrent exclusion, under the same circumstances, of the occupational physician from risk assessment procedures and iii. the upward modification of the previously established (D.Lgs 277/91) occupational exposure limits for lead. Moreover, the Authors examine and criticize--both in semantic and in toxicological terms--a recent proposal for the definition of "moderate risk" made by an ad hoc Consulting Committee of the Labour Ministry, in which the term "moderate" has been interpreted either as "low" or as "irrelevant for health effects", clearly two very different meanings. Besides, it would be inappropriate to define the conditions of a moderate risk based only on the level of exposure to the chemical (expressed as a fraction of the corresponding limit value), without considering the two other components of risk assessment for that chemical (hazard and susceptibility). Even worse would be the use of simplified models based on "algorithms", which might be useful in a preliminary phase of risk assessment, but easily could lead to an under- or over-estimation of risk, particularly when used by non professionals. In conclusion, the Working Group recommend that the new law be amended in order to clarify its most controversial aspects, whose misinterpretation could severely jeopardize the protection of the workers' safety and health at work.


Transplant Recipients Using Tacrolimus Had Higher Utilization of Healthcare Services Than Those Receiving Cyclosporine in Taiwan.
To date, population-based studies on the healthcare service utilization among stable heart, kidney, and liver transplant recipients with different calcineurin inhibitors are still scarce. Therefore, we used the Taiwan National Health Insurance Research Database to conduct a nationwide cross-sectional study to estimate the healthcare utilization of stable transplant recipients with tacrolimus or cyclosporine (n = 3,482). The sampled patients in this study comprised 377 heart, 1,693 kidney, and 1,412 liver transplant recipients between 1 January 2011 and 31 December 2011. Each subject was followed for a 1-year period to evaluate his/her healthcare service utilization. Outcome variables of the healthcare service utilization were stated as below: numbers of outpatient visits, outpatient costs, numbers of inpatient days, inpatients costs, and total costs of all healthcare services. As for all healthcare service utilization, stable transplant recipients on tacrolimus had significantly more outpatient visits (40.7 vs. 38.6), outpatient costs (US$10,383 vs. US$8,155), and total costs (US$12,516 vs. US$10,372) of all healthcare services than those on cyclosporine during the 1-year follow-up period. Additionally, further analysis showed that heart transplant recipients receiving tacrolimus incurred 1.7-fold higher inpatient costs compared to patients receiving cyclosporine. We concluded that transplant recipients using tacrolimus had significantly higher utilization of all healthcare services than those receiving cyclosporine as immunosuppressive therapy.