Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis.
Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. 240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment. ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.


Corticosteroids, But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry.
The impact of Coronavirus disease 2019 (COVID-19) on patients with inflammatory bowel disease (IBD) is unknown. We sought to characterize the clinical course of COVID-19 among patients with IBD and evaluate the association among demographics, clinical characteristics, and immunosuppressant treatments on COVID-19 outcomes. Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of patients with IBD with confirmed COVID-19. We calculated age-standardized mortality ratios and used multivariable logistic regression to identify factors associated with severe COVID-19, defined as intensive care unit admission, ventilator use, and/or death. 525 cases from 33 countries were reported (median age 43 years, 53% men). Thirty-seven patients (7%) had severe COVID-19, 161 (31%) were hospitalized, and 16 patients died (3% case fatality rate). Standardized mortality ratios for patients with IBD were 1.8 (95% confidence interval [CI], 0.9-2.6), 1.5 (95% CI, 0.7-2.2), and 1.7 (95% CI, 0.9-2.5) relative to data from China, Italy, and the United States, respectively. Risk factors for severe COVID-19 among patients with IBD included increasing age (adjusted odds ratio [aOR], 1.04; 95% CI, 1.01-1.02), ≥2 comorbidities (aOR, 2.9; 95% CI, 1.1-7.8), systemic corticosteroids (aOR, 6.9; 95% CI, 2.3-20.5), and sulfasalazine or 5-aminosalicylate use (aOR, 3.1; 95% CI, 1.3-7.7). Tumor necrosis factor antagonist treatment was not associated with severe COVID-19 (aOR, 0.9; 95% CI, 0.4-2.2). Increasing age, comorbidities, and corticosteroids are associated with severe COVID-19 among patients with IBD, although a causal relationship cannot be definitively established. Notably, tumor necrosis factor antagonists do not appear to be associated with severe COVID-19.


Standardised measurement of physical capacity in young and middle-aged active adults with hip-related pain: recommendations from the first International Hip-related Pain Research Network (IHiPRN) meeting, Zurich, 2018.
Hip-related pain can significantly impact quality of life, function, work capacity, physical activity and family life. Standardised measurement methods of physical capacity of relevance to young and middle-aged active adults with hip-related pain are currently not established. The aim of this consensus paper was to provide recommendations for clinical practice and research on standardised measurement methods of physical capacity in young and middle-aged active adults with hip-related pain. Four areas of importance were identified: (1) clinical measures (range of motion, muscle strength, functional impairments), (2) laboratory-based measures (biomechanics and muscle function (muscle activity, size and adiposity)), (3) physical activity, and (4) return to sport/performance. The literature was reviewed, and a summary circulated to the working group to inform discussion at the consensus meeting. The working group developed clinical and research recommendations from the literature review, which were further discussed and modified within the working group at the consensus meeting. These recommendations were then presented to all 38 International Hip-related Pain Research Network (IHiPRN) participants for further discussion, refinement and consensus voting. Therefore, the recommendations voted on were based on a combination of current evidence and expert opinion. The consensus meeting voted on 13 recommendations, six of which were clinically orientated, and seven more research specific. We recommended that clinicians working with young and middle-aged active adults with hip-related pain assess strength using objective methods of measurement, and clinically assess performance of functional tasks, including walking and running. Physical activity should be quantified using both self-reported and objective measures, and patient expectations of recovery should be quantified prior to treatment. It was recommended that return to physical activity (including sport and occupation) be quantified, and sport-specific activities should be assessed prior to return to sport. The IHiPRN participants were uncertain regarding recommendations for range of motion assessment. Research recommendations were that the measurement properties of range of motion, strength and functional performance tests be investigated, reported and improved in both clinical and research settings. Reporting of movement-related parameters (biomechanics and muscle function) should be standardised and the relationship among movement-related parameters, symptoms, function, quality of life, and intra-articular and imaging findings should be investigated. Quantification of return to physical activity (including sport and occupational demands) is required in future research, and the return to sport continuum should be used. Future research is required to determine the best criteria for rehabilitation progression and return to physical activity following hip-related pain management.


Nuclear beta-catenin accumulation as a prognostic factor in Dukes' D human colorectal cancers.
Beta-catenin is well recognized to play a crucial role as a transcriptional factor during the early step of colorectal carcinogenesis. Some reports concerning the clinical implications of cytoplasmic and/or nuclear beta-catenin accumulation are available, though their results vary. On the other hand, the clinical implication of nuclear accumulation of beta-catenin in Dukes' D colorectal cancers (with distant metastasis) has not been investigated. To assess its value as a prognostic marker in this stage, we selected the cases with synchronous liver metastasis. Thirty-eight surgically resected primary and corresponding metastatic liver tumors were examined immunohistochemically and the relationships between nuclear beta-catenin accumulation and clinicopathological variables were analyzed. Of the 38 primary colorectal cancers analyzed, 11 (29%) showed nuclear accumulation of beta-catenin with cytoplasmic staining. Nuclear accumulation positivity was more frequently associated with lymph node metastasis than being negative [100% (11/11) vs. 67% (18/27), p=0.04]. There was a significant difference in median survival time between the nuclear beta-catenin positive group (1130 days) and the negative group (2102 days: p=0.037). Interestingly, all of the patients (9/9) in the former group had died when the recurrence was in the liver, while 42% (8/19) in the latter group had survived even if the recurrence was in the liver (p=0.03). In conclusion, though these results were obtained in a small series of patients, nuclear accumulation of beta-catenin may be a useful prognostic marker even in Dukes' D colorectal cancers.


Withdrawing a solid from a bath: How much liquid is coated?
A solid withdrawn from a liquid bath entrains a film. In this review, after recalling the predictions and results for pure Newtonian liquids coated on simple solids, we analyze the deviations to this ideal case exploring successively three potential sources of complexity: the liquid-air interface, the bulk rheological properties of the liquid and the mechanical or chemical properties of the solid. For these different complexities, we show that significant effects on the film thickness are observed experimentally and we summarize the theoretical analysis presented in the literature, which attempt to rationalize these measurements.


The N-terminus and alpha-5, alpha-6 helices of the pro-apoptotic protein Bax, modulate functional interactions with the anti-apoptotic protein Bcl-xL.
Bcl-2 family proteins are key regulators of mitochondrial integrity and comprise both pro- and anti-apoptotic proteins. Bax a pro-apoptotic member localizes as monomers in the cytosol of healthy cells and accumulates as oligomers in mitochondria of apoptotic cells. The Bcl-2 homology-3 (BH3) domain regulates interactions within the family, but regions other than BH3 are also critical for Bax function. Thus, the N-terminus has been variously implicated in targeting to mitochondria, interactions with BH3-only proteins as well as conformational changes linked to Bax activation. The transmembrane (TM) domains (alpha5-alpha6 helices in the core and alpha9 helix in the C-terminus) in Bax are implicated in localization to mitochondria and triggering cytotoxicity. Here we have investigated N-terminus modulation of TM function in the context of regulation by the anti-apoptotic protein Bcl-xL. Deletion of 29 amino acids in the Bax N-terminus (Bax 30-192) caused constitutive accumulation at mitochondria and triggered high levels of cytotoxicity, not inhibited by Bcl-xL. Removal of the TM domains (Bax 30-105) abrogated mitochondrial localization but resulted in Bcl-xL regulated activation of endogenous Bax and Bax-Bak dependent apoptosis. Inclusion of the alpha5-alpha6 helices/TMI domain (Bax 30-146) phenocopied Bax 30-192 as it restored mitochondrial localization, Bcl-xL independent cytotoxicity and was not dependent on endogenous Bax-Bak. Inhibition of function and localization by Bcl-xL was restored in Bax 1-146, which included the TM1 domain. Regardless of regulation by Bcl-xL, all N-terminal deleted constructs immunoprecipitated Bcl-xLand converged on caspase-9 dependent apoptosis consistent with mitochondrial involvement in the apoptotic cascade. Sub-optimal sequence alignments of Bax and Bcl-xL indicated a sequence similarity between the alpha5-alpha6 helices of Bax and Bcl-xL. Alanine substitutions of three residues (T14A-S15A-S16A) in the N-terminus (Bax-Ala3) attenuated regulation by the serine-threonine kinase Akt/PKB but not by Bcl-xL indicative of distinct regulatory mechanisms. Collectively, the analysis of Bax deletion constructs indicates that the N-terminus drives conformational changes facilitating inhibition of cytotoxicity by Bcl-xL. We speculate that the TM1 helices may serve as 'structural antagonists' for BH3-Bcl-xL interactions, with this function being regulated by the N-terminus in the intact protein.


Cyanobacterial ribosomal RNA genes with multiple, endonuclease-encoding group I introns.
Group I introns are one of the four major classes of introns as defined by their distinct splicing mechanisms. Because they catalyze their own removal from precursor transcripts, group I introns are referred to as autocatalytic introns. Group I introns are common in fungal and protist nuclear ribosomal RNA genes and in organellar genomes. In contrast, they are rare in all other organisms and genomes, including bacteria. Here we report five group I introns, each containing a LAGLIDADG homing endonuclease gene (HEG), in large subunit (LSU) rRNA genes of cyanobacteria. Three of the introns are located in the LSU gene of Synechococcus sp. C9, and the other two are in the LSU gene of Synechococcus lividus strain C1. Phylogenetic analyses show that these introns and their HEGs are closely related to introns and HEGs located at homologous insertion sites in organellar and bacterial rDNA genes. We also present a compilation of group I introns with homing endonuclease genes in bacteria. We have discovered multiple HEG-containing group I introns in a single bacterial gene. To our knowledge, these are the first cases of multiple group I introns in the same bacterial gene (multiple group I introns have been reported in at least one phage gene and one prophage gene). The HEGs each contain one copy of the LAGLIDADG motif and presumably function as homodimers. Phylogenetic analysis, in conjunction with their patchy taxonomic distribution, suggests that these intron-HEG elements have been transferred horizontally among organelles and bacteria. However, the mode of transfer and the nature of the biological connections among the intron-containing organisms are unknown.


Assessment of Receipt of the First Home Health Care Visit After Hospital Discharge Among Older Adults.
Home health care is one of the fastest growing postacute services in the US and is increasingly important in the era of coronavirus disease 2019 and payment reform, yet it is unknown whether patients who need home health care are receiving it. To examine how often patients referred to home health care at hospital discharge receive it and whether there is evidence of disparities. This cross-sectional study used Medicare data regarding the postacute home health care setting from October 1, 2015, through September 30, 2016. The participants were Medicare fee-for-service and Medicare Advantage beneficiaries who were discharged alive from a hospital with a referral to home health care (2 379 506 discharges). Statistical analysis was performed from July 2019 to June 2020. Hospital referral to home health care. Primary outcomes included whether discharges received their first home health care visit within 14 days of hospital discharge and the number of days between hospital discharge and the first home health visit. Differences in the likelihood of receiving home health care across patient, zip code, and hospital characteristics were also examined. Among 2 379 506 discharges from the hospital with a home health care referral, 1 358 697 patients (57.1%) were female, 468 762 (19.7%) were non-White, and 466 383 (19.6%) were dually enrolled in Medicare and Medicaid; patients had a mean (SD) age of 73.9 (11.9) years and 4.1 (2.1) Elixhauser comorbidities. Only 1 284 300 patients (54.0%) discharged from the hospital with a home health referral received home health care services within 14 days of discharge. Of the remaining 1 095 206 patients (46.0%) discharged, 37.7% (896 660 discharges) never received any home health care, while 8.3% (198 546 discharges) were institutionalized or died within 14 days without a preceding home health care visit. Patients who were Black or Hispanic received home health at lower rates than did patients who were White (48.0% [95% CI, 47.8%-48.1%] of Black and 46.1% [95% CI, 45.7%-46.5%] of Hispanic discharges received home health within 14 days compared with 55.3% [95% CI, 55.2%-55.4%] of White discharges). In addition, disadvantaged patients waited longer for their first home health care visit. For example, patients living in high-unemployment zip codes waited a mean of 2.0 days (95% CI, 2.0-2.0 days), whereas those living in low-unemployment zip codes waited 1.8 days (95% CI, 1.8-1.8 days). Disparities in the use of home health care remain an issue in the US. As home health care is increasingly presented as a safer alternative to institutional postacute care during coronavirus disease 2019, and payment reforms continue to pressure hospitals to discharge patients home, ensuring the availability of safe and equitable care will be crucial to maintaining high-quality care.


Ratings of age of acquisition of 299 words across 25 languages: Is there a cross-linguistic order of words?
We present a new set of subjective age-of-acquisition (AoA) ratings for 299 words (158 nouns, 141 verbs) in 25 languages from five language families (Afro-Asiatic: Semitic languages; Altaic: one Turkic language: Indo-European: Baltic, Celtic, Germanic, Hellenic, Slavic, and Romance languages; Niger-Congo: one Bantu language; Uralic: Finnic and Ugric languages). Adult native speakers reported the age at which they had learned each word. We present a comparison of the AoA ratings across all languages by contrasting them in pairs. This comparison shows a consistency in the orders of ratings across the 25 languages. The data were then analyzed (1) to ascertain how the demographic characteristics of the participants influenced AoA estimations and (2) to assess differences caused by the exact form of the target question (when did you learn vs. when do children learn this word); (3) to compare the ratings obtained in our study to those of previous studies; and (4) to assess the validity of our study by comparison with quasi-objective AoA norms derived from the MacArthur-Bates Communicative Development Inventories (MB-CDI). All 299 words were judged as being acquired early (mostly before the age of 6 years). AoA ratings were associated with the raters' social or language status, but not with the raters' age or education. Parents reported words as being learned earlier, and bilinguals reported learning them later. Estimations of the age at which children learn the words revealed significantly lower ratings of AoA. Finally, comparisons with previous AoA and MB-CDI norms support the validity of the present estimations. Our AoA ratings are available for research or other purposes.


Role of nutrition in performance enhancement and postexercise recovery.
A number of factors contribute to success in sport, and diet is a key component. An athlete's dietary requirements depend on several aspects, including the sport, the athlete's goals, the environment, and practical issues. The importance of individualized dietary advice has been increasingly recognized, including day-to-day dietary advice and specific advice before, during, and after training and/or competition. Athletes use a range of dietary strategies to improve performance, with maximizing glycogen stores a key strategy for many. Carbohydrate intake during exercise maintains high levels of carbohydrate oxidation, prevents hypoglycemia, and has a positive effect on the central nervous system. Recent research has focused on athletes training with low carbohydrate availability to enhance metabolic adaptations, but whether this leads to an improvement in performance is unclear. The benefits of protein intake throughout the day following exercise are now well recognized. Athletes should aim to maintain adequate levels of hydration, and they should minimize fluid losses during exercise to no more than 2% of their body weight. Supplement use is widespread in athletes, with recent interest in the beneficial effects of nitrate, beta-alanine, and vitamin D on performance. However, an unregulated supplement industry and inadvertent contamination of supplements with banned substances increases the risk of a positive doping result. Although the availability of nutrition information for athletes varies, athletes will benefit from the advice of a registered dietician or nutritionist.


Cardiac autotransplantation for primary cardiac tumors.
Complete tumor resection is the optimal treatment of cardiac tumors. Anatomic accessibility and proximity to vital structures complicates resection of tumors involving the left heart. The results of standard resection and resection with orthotopic heart transplantation are dismal. We, therefore, reviewed our series of patients with complex left-sided primary cardiac tumors who underwent tumor resection with cardiac autotransplantation. Since April 1998, 11 consecutive patients with complex left atrial or left ventricular intracavitary cardiac tumors underwent 12 resections using cardiac autotransplantation-cardiac explantation, ex vivo tumor resection with cardiac reconstruction, and cardiac reimplantation. Demographics, tumor histology, operative data, and mortality were analyzed. Follow-up was complete in all patients. Complete resection by cardiac autotransplantation was used in 7 patients with left atrial sarcoma, 1 patient with left ventricular sarcoma, 2 patients with left atrial paraganglioma, and 1 patient with a complex giant left atrial myxoma. Eight patients had previous resection of their cardiac tumor, and 1 patient had a repeat autotransplantation for recurrent disease. There were no operative deaths. Median overall survival was 18.5 months in patients with sarcomas. All patients with benign tumors are alive without evidence of recurrence. Cardiac autotransplantation is a feasible technique for resection of complex left-sided cardiac tumors. Recurrent disease after previous resections can be safely treated with this technique. Operative mortality and overall survival seems favorable in this series of patients. Benefits of this technique include improved accessibility and ability to perform a complete tumor resection with reliable cardiac reconstruction.


Death in hospital following ICU discharge: insights from the LUNG SAFE study.
To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments ('treatment limitations'), and the subpopulations with treatment limitations. 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. ClinicalTrials.gov NCT02010073 .


Complete mitochondrial genome of the whitetip reef shark Triaenodon obesus from the British Indian Ocean Territory Marine Protected Area.
We present the first mitochondrial genome of Trianenodon obesus from the Chagos Archipelago in the British Indian Ocean Territory (BIOT) Marine Protected Area. The mitogenome was 16,702 bp in length and consisted of 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and a non-coding control region (D-loop). GC content was at 38.9%. The control region was 1064 bp in length. This mitogenome for the BIOT MPA T. obesus differed from the previously published T. obesus genome by 15 bp and the differences include a 2 bp insertion and 13 single nucleotide polymorphisms distributed across the mitogenome in the BIOT MPA sequence. Whole mitogenome sequence of T. obesus from the Chagos archipelago presented here fills existing gaps in genetic information on marine species from the BIOT MPA and provides additional tools for species specific assessments as to the effectiveness of MPA management. In addition, methods presented here lay the framework for genetic studies in remote locations with limited infrastructure.


Differential hypertrophic effects of cardiotrophin-1 on adult cardiomyocytes from normotensive and spontaneously hypertensive rats.
Cardiotrophin-1 (CT-1) produces longitudinal elongation of neonatal cardiomyocytes, but its effects in adult cardiomyocytes are not known. Recent observations indicate that CT-1 may be involved in pressure overload left ventricular hypertrophy (LVH). We investigated whether the hypertrophic effects of CT-1 are different in cardiomyocytes isolated from adult normotensive and spontaneously hypertensive rats (SHR). Hypertrophy was evaluated by planimetry and confocal microscopy, contractile proteins were quantified by Western blotting and real-time RT-PCR, and intracellular pathways were analyzed with specific chemical inhibitors. CT-1 increased c-fos and ANP expression (p<0.01) and cell area (p<0.01) in cardiomyocytes from both rat strains. In Wistar cells, CT-1 augmented cell length (p<0.01) but did not modify either the transverse diameter or cell depth. In SHR cells, CT-1 increased cell length (p<0.05), cell width (p<0.01) and cell depth, augmented the expression of myosin light chain-2v (MLC-2v) and skeletal alpha-actin (p<0.01) and enhanced MLC-2v phosphorylation (p<0.01). The blockade of gp130 or LIFR abolished CT-1-induced growth in the two cell types. All distinct effects observed in cardiomyocytes from SHR were mediated by STAT3. Baseline angiotensinogen expression was higher in SHR cells, and CT-1 induced a 1.7-fold and 3.2-fold increase of angiotensinogen mRNA in cardiomyocytes from Wistar rats and SHR respectively. In addition, AT1 blockade inhibited the specific effects of CT-1 in SHR cells. Finally, ex vivo determinations revealed that adult SHR exhibited enhanced myocardial CT-1 (mRNA and protein, p<0.01), increased cell width (p<0.01) and concentric LVH compared with pre-hypertensive SHR. These findings reveal a specific cell-broadening effect of CT-1 in cardiomyocytes from adult SHR and suggest that the hypertensive phenotype of these cells may influence the hypertrophic effects of CT-1, probably by means of an exaggerated induction of angiotensinogen expression. We suggest that CT-1 might facilitate LVH in genetic hypertension through a cross-talk with the renin-angiotensin system.


Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men.
Clinical guidelines recommend measurement of the serum prostate-specific antigen (PSA) concentration during testosterone treatment of hypogonadal men to determine whether the increase is sufficiently high to warrant urologic referral. Prior studies of the effect of testosterone treatment on PSA concentrations have been conducted in men who were mildly to moderately hypogonadal. The objective of this work is to determine the PSA response to testosterone treatment of men who are severely hypogonadal. This retrospective cohort study was conducted at a single academic medical center. Eighty-five men participated who were severely hypogonadal as a result hypothalamic-pituitary or testicular disease. Changes in serum PSA concentrations were measured during testosterone treatment for up to 18 months. Testosterone treatment increased the median serum testosterone concentration from 36 ng/dL (interquartile range [IQR], 20-91 ng/dL) at baseline to 395 ng/dL (IQR, 266-542 ng/dL) at 6 to 18 months. This treatment resulted in a median increment in PSA above baseline of 0.70 ng/mL (IQR, 0.10-1.85 ng/mL) at 6 to 18 months. Apropos current Endocrine Society clinical guidelines, 31% of the men experienced a PSA increase above baseline greater than 1.4 ng/mL, and 13% reached an absolute PSA concentration of greater than 4.0 ng/mL. Four men were diagnosed with prostate cancer. The PSA response to testosterone replacement in men who are severely hypogonadal as a result of pituitary or testicular disease is greater than that previously reported in men with mild to moderate hypogonadism. These results suggest the magnitude of the PSA response to testosterone replacement is related to the degree of hypogonadism.


Communicating subcellular distributions.
To build more accurate models of cells and tissues, the ability to incorporate information on the distributions of proteins (and other macromolecules) will become increasingly important. This review describes current progress towards determining and representing protein subcellular patterns so that the information can be used as part of systems biology efforts. Approaches to decomposing an image of the subcellular pattern of a protein give critical information about the fraction of that protein in each of a number of fundamental patterns (e.g., organelles). Methods for learning generative models from images provide a means of capturing the essential properties and variation in those properties of cell shape and organelle patterns. The combination of models of fundamental patterns and vectors specifying the fraction of a protein in each of them provide a much better means of communicating subcellular patterns than the descriptive terms that are currently used. Communicating information about subcellular patterns is important not only for systems biology simulations but also for representing results from microscopy experiments, including high content screening and imaging flow cytometry, in a transportable and generalizable manner.


Lineage relationship of prostate cancer cell types based on gene expression.
Prostate tumor heterogeneity is a major factor in disease management. Heterogeneity could be due to multiple cancer cell types with distinct gene expression. Of clinical importance is the so-called cancer stem cell type. Cell type-specific transcriptomes are used to examine lineage relationship among cancer cell types and their expression similarity to normal cell types including stem/progenitor cells. Transcriptomes were determined by Affymetrix DNA array analysis for the following cell types. Putative prostate progenitor cell populations were characterized and isolated by expression of the membrane transporter ABCG2. Stem cells were represented by embryonic stem and embryonal carcinoma cells. The cancer cell types were Gleason pattern 3 (glandular histomorphology) and pattern 4 (aglandular) sorted from primary tumors, cultured prostate cancer cell lines originally established from metastatic lesions, xenografts LuCaP 35 (adenocarcinoma phenotype) and LuCaP 49 (neuroendocrine/small cell carcinoma) grown in mice. No detectable gene expression differences were detected among serial passages of the LuCaP xenografts. Based on transcriptomes, the different cancer cell types could be clustered into a luminal-like grouping and a non-luminal-like (also not basal-like) grouping. The non-luminal-like types showed expression more similar to that of stem/progenitor cells than the luminal-like types. However, none showed expression of stem cell genes known to maintain stemness. Non-luminal-like types are all representatives of aggressive disease, and this could be attributed to the similarity in overall gene expression to stem and progenitor cell types.


Lesson from an intriguing case of cryoglobulinemia.
Cryoglobulinemia is a pathological condition usually associated with hepatitis C virus (HCV) chronic liver disease and less commonly with autoimmune or lymphoproliferative disorders. The possible association of cryoglobulinemia with hepatitis B virus (HBV) infection is not widely accepted. In our patient, serum negativity for HCV markers initially led us to consider two other causes of cryoglobulinemia. Myelodysplastic disorders were excluded on the basis of hematological studies, while serum markers for active HBV infection were positive. Surprisingly, the detection of HCV RNA in the cryocrit, even in the absence of anti-HCV antibodies, suggested a pathogenetic role of HCV in this case of cryoglobulinemia. Negative "first level" tests for HCV in the serum do not completely exclude HCV involvement in the pathogenesis of cryoglobulinemia. Analysis of the cryoprecipitate is always essential for diagnosis.


Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model.
Disablement of cell death programs in cancer cells contributes to drug resistance and in some cases has been associated with altered translational control. As eukaryotic translation initiation factor 4E (eIF4E) cooperates with c-Myc during lymphomagenesis, induces drug resistance, and is a genetic modifier of the rapamycin response, we have investigated the effect of dysregulation of the ribosome recruitment phase of translation initiation on tumor progression and chemosensitivity. eIF4E is a subunit of eIF4F, a complex that stimulates ribosome recruitment during translation initiation by delivering the DEAD-box RNA helicase eIF4A to the 5' end of mRNAs. eIF4A is thought to prepare a ribosome landing pad on mRNA templates for incoming 40S ribosomes (and associated factors). Using small molecule screening, we found that cyclopenta[b]benzofuran flavaglines, a class of natural products, modulate eIF4A activity and inhibit translation initiation. One member of this class of compounds, silvestrol, was able to enhance chemosensitivity in a mouse lymphoma model in which carcinogenesis is driven by phosphatase and tensin homolog (PTEN) inactivation or elevated eIF4E levels. These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity.


Immune-to-brain signalling: the role of cerebral CD163-positive macrophages.
Systemic inflammation induces cytokine synthesis within the central nervous system. This results in sickness behaviour and may exacerbate ongoing neuroinflammatory disease. The precise mechanisms underlying the relay of signal from the periphery to the central nervous system are not entirely understood. CD163-positive macrophages occupy a unique position at the blood-brain barrier and upregulate prostaglandin-synthesizing enzymes in response to systemic inflammation. This finding suggests that they might play a role in signalling inflammation to the central nervous system. However, here we demonstrate that de novo brain cytokine transcription during systemic endotoxaemia may be prostaglandin-independent. We therefore set out to interrogate more directly the role of CD163-positive macrophages in immune-to-brain signalling. Intracerebroventricular injections of clodronate liposomes were used to selectively deplete CD163-positive macrophages. We show that de novo brain cytokine synthesis during systemic endotoxaemia persists in the absence of CD163-positive macrophages. Cerebral endothelial cells outnumber CD163-positive macrophages and are arguably better situated to signal circulating inflammatory stimuli to the brain.


Decontamination Strategies and Bloodstream Infections With Antibiotic-Resistant Microorganisms in Ventilated Patients: A Randomized Clinical Trial.
The effects of chlorhexidine (CHX) mouthwash, selective oropharyngeal decontamination (SOD), and selective digestive tract decontamination (SDD) on patient outcomes in ICUs with moderate to high levels of antibiotic resistance are unknown. To determine associations between CHX 2%, SOD, and SDD and the occurrence of ICU-acquired bloodstream infections with multidrug-resistant gram-negative bacteria (MDRGNB) and 28-day mortality in ICUs with moderate to high levels of antibiotic resistance. Randomized trial conducted from December 1, 2013, to May 31, 2017, in 13 European ICUs where at least 5% of bloodstream infections are caused by extended-spectrum β-lactamase-producing Enterobacteriaceae. Patients with anticipated mechanical ventilation of more than 24 hours were eligible. The final date of follow-up was September 20, 2017. Standard care was daily CHX 2% body washings and a hand hygiene improvement program. Following a baseline period from 6 to 14 months, each ICU was assigned in random order to 3 separate 6-month intervention periods with either CHX 2% mouthwash, SOD (mouthpaste with colistin, tobramycin, and nystatin), or SDD (the same mouthpaste and gastrointestinal suspension with the same antibiotics), all applied 4 times daily. The occurrence of ICU-acquired bloodstream infection with MDRGNB (primary outcome) and 28-day mortality (secondary outcome) during each intervention period compared with the baseline period. A total of 8665 patients (median age, 64.1 years; 5561 men [64.2%]) were included in the study (2251, 2108, 2224, and 2082 in the baseline, CHX, SOD, and SDD periods, respectively). ICU-acquired bloodstream infection with MDRGNB occurred among 144 patients (154 episodes) in 2.1%, 1.8%, 1.5%, and 1.2% of included patients during the baseline, CHX, SOD, and SDD periods, respectively. Absolute risk reductions were 0.3% (95% CI, -0.6% to 1.1%), 0.6% (95% CI, -0.2% to 1.4%), and 0.8% (95% CI, 0.1% to 1.6%) for CHX, SOD, and SDD, respectively, compared with baseline. Adjusted hazard ratios were 1.13 (95% CI, 0.68-1.88), 0.89 (95% CI, 0.55-1.45), and 0.70 (95% CI, 0.43-1.14) during the CHX, SOD, and SDD periods, respectively, vs baseline. Crude mortality risks on day 28 were 31.9%, 32.9%, 32.4%, and 34.1% during the baseline, CHX, SOD, and SDD periods, respectively. Adjusted odds ratios for 28-day mortality were 1.07 (95% CI, 0.86-1.32), 1.05 (95% CI, 0.85-1.29), and 1.03 (95% CI, 0.80-1.32) for CHX, SOD, and SDD, respectively, vs baseline. Among patients receiving mechanical ventilation in ICUs with moderate to high antibiotic resistance prevalence, use of CHX mouthwash, SOD, or SDD was not associated with reductions in ICU-acquired bloodstream infections caused by MDRGNB compared with standard care. ClinicalTrials.gov Identifier: NCT02208154.


Interactive mobile learning: a pilot study of a new approach for sport science and medical undergraduate students.
Mobile learning has increasingly become interwoven into the fabric of learning and teaching in the United Kingdom higher education sector, and as technological issues become addressed, this phenomena has accelerated. The aim of the study was to examine whether learning using a mobile learning device (Samsung NC10 Netbook) loaded with interactive exercises promoted learning compared with a traditional library exercise. Using a randomized trial, 55 students from an undergraduate sports science course (n = 28) and medical course (n = 27) volunteered to participate in this study. A mixed-model design ANOVA was used to examine the percent change in test score after a 3-wk intervention. Results showed that there was a significant difference between the two courses (P < 0.001), methods (P = 0.01), and trials (P < 0.001). The findings suggested that both methods augmented student knowledge and understanding in sports science and medical students. The sports science group demonstrated proportionally greater increases in test performance when exposed to the mobile interactive intervention compared with the traditional library approach. Qualitative data suggest an increased level of engagement with the Netbooks due to the stimulating interactive content. In conclusion, the Netbooks were an effective additional learning tool, significantly enhancing knowledge and understanding in students. Further research should ensure that participants are assessed for preferred learning styles, the subjective task value of expectancy value, and readiness for mobile learning to ascertain if this has an effect on the potential for using mobile learning and interactivity.


Key premises, a guide to Aedes aegypti (Diptera: Culicidae) surveillance and control.
The population densities of Aedes aegypti Linneaus in four towns in Trinidad were studied using standard house-to-house inspections of all water-holding containers to determine whether persistently positive containers and premises existed over a three-month period in the wet season, from May to July 2002. From a total of 1503 houses inspected, 223 were positive with 41 persistently positive over the three month period and classified as 'key premises'. The definition of the term key premises is described and the rationale for its utilization discussed. A total of 24,439 containers was inspected from Santa Margarita (6407), Mt Lambert (5709), St Augustine (5384) and Curepe (6939) of which 1.3% or 334 containers were positive for A. aegypti larvae and pupae. A total of 16,507 immatures of A. aegypti were retrieved from these containers which comprised 17 container types but when these were ranked according to productivity levels, only water drums (average 53.5%), buckets (22.2%), tubs and basins (8.0%), water tanks (5.4%), brick holes (4.2%) and tyres (2.0%) were significant (P < 0.001) producers. The role that key premises play in the introduction and re-infestation of A. aegypti-free communities is described and illustrated. These results suggest that A. aegypti control programmes could be more cost effective and sustainable by concentrating efforts on key premises and key containers to control mosquito densities and Dengue transmission while reducing manpower needs and insecticide use.


Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.
In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.


Unveiling the hidden epidemic: a review of stigma associated with sexually transmissible infections.
Stigma has long accompanied sexually transmissible infections (STI) and hindered prevention and control efforts. It not only acts as a formidable barrier to STI testing, treatment and disclosure, but has a multitude of consequences for the health and quality of life of infected individuals. This review summarises the literature related to STI stigma and offers practical approaches to counter STI-associated stigma through multi-level efforts. Specifically, it describes the key sources that breed and perpetuate stigma, outlines how STI-associated stigma has been conceptualised and measured in the literature, documents the impact of stigma on infected and uninfected individuals, and summarises the stigma reduction strategies recommended in the literature. Gaps in the literature are identified and areas for further research are suggested, along with practical strategies for moving forward.


Invited review: Improving neonatal survival in small ruminants: science into practice.
Neonatal mortality in small ruminant livestock has remained stubbornly unchanging over the past 40 years, and represents a significant loss of farm income, contributes to wastage and affects animal welfare. Scientific knowledge about the biology of neonatal adaptation after birth has been accumulating but does not appear to have had an impact in improving survival. In this paper, we ask what might be the reasons for the lack of impact of the scientific studies of lamb and kid mortality, and suggest strategies to move forward. Biologically, it is clear that achieving a good intake of colostrum, as soon as possible after birth, is crucial for neonatal survival. This provides fuel for thermoregulation, passive immunological protection and is involved in the development of attachment between the ewe and lamb. The behaviour of the lamb in finding the udder and sucking rapidly after birth is a key component in ensuring sufficient colostrum is ingested. In experimental studies, the main risk factors for lamb mortality are low birthweight, particularly owing to poor maternal nutrition during gestation, birth difficulty, litter size and genetics, which can all be partly attributed to their effect on the speed with which the lamb reaches the udder and sucks. Similarly, on commercial farms, low birthweight and issues with sucking were identified as important contributors to mortality. In epidemiological studies, management factors such as providing assistance with difficult births, were found to be more important than risk factors associated with housing. Social science studies suggest that farmers generally have a positive attitude to improving neonatal mortality but may differ in beliefs about how this can be achieved, with some farmers believing they had no control over early lamb mortality. Facilitative approaches, where farmers and advisors work together to develop neonatal survival strategies, have been shown to be effective in achieving management goals, such as optimising ewe nutrition, that lead to reductions in lamb mortality. We conclude that scientific research is providing useful information on the biology underpinning neonatal survival, such as optimal birthweights, lamb vigour and understanding the importance of sufficient colostrum intake, but the transfer of that knowledge would benefit from an improved understanding of the psychology of management change on farm. Developing tailored solutions, on the basis of adequate farm records, that make use of the now substantial body of scientific literature on neonatal mortality will help to achieve lower neonatal mortality.


Extra-pleural pneumonectomy.
The extra-pleural pneumonectomy (EPP) is a standardised surgical procedure born for pleural tuberculosis and later used in pleural cancer treatment, especially in malignant pleural mesothelioma (MPM). This systematic review aimed to focus on the actual overall EPP role in surgical oncology. The literature search was performed from January 1985 to January 2018 In PubMed, Embase, and Cochrane according to PRISMA protocol. The search was restricted to publications in English with the research words "extrapleural pneumonectomy", "malignant pleural mesothelioma", "pleural malignancies". The results were then filtered focusing only on papers with series of patients treated with EPP, for mesothelioma and non-mesothelioma malignancies. The search was restricted to publications in English. We found a 5-year overall survival (OS) ranging from 0 to 78%. The peri-operative mortality and morbidity ranged from 0 to 11.8% and 0 to 82.6%, respectively. The most represented and described post-operative complications reported were ARDS, pericardial tamponade, cardiac herniation, pulmonary embolism, respiratory infections, respiratory failure, atrial arrhythmia, myocardial infarction. In referral centres and selected patients, EPP is a cytoreductive or radical surgical treatment in extended pleural malignancies. Prospective studies are needed to standardise the timing of the procedure in a multimodality treatment program, according to the oncological and functional indications, to keep an acceptable complications rate and post-operative quality of life status.


Role of the cerebellar cortex in conditioned goal-directed behavior.
Learning a new goal-directed behavioral task often requires the improvement of at least two processes, including an enhanced stimulus-response association and an optimization of the execution of the motor response. The cerebellum has recently been shown to play a role in acquiring goal-directed behavior, but it is unclear to what extent it contributes to a change in the stimulus-response association and/or the optimization of the execution of the motor response. We therefore designed the stimulus-dependent water Y-maze conditioning task, which allows discrimination between both processes, and we subsequently subjected Purkinje cell-specific mutant mice to this new task. The mouse mutants L7-PKCi, which suffer from impaired PKC-dependent processes such as parallel fiber to Purkinje cell long-term depression (PF-PC LTD), were able to acquire the stimulus-response association, but exhibited a reduced optimization of their motor performance. These data show that PF-PC LTD is not required for learning a stimulus-response association, but they do suggest that a PKC-dependent process in cerebellar Purkinje cells is required for optimization of motor responses.


The presence of human papillomavirus-16/-18 E6, p53, and Bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer.
Cervical cancer is the second leading cause of death from cancer in women worldwide, and recent epidemiological studies have strongly implicated the sexually transmitted human papillomavirus (HPV) as a causative agent. The ability of high-risk HPVs to contribute to malignant progression seems to depend on expression of the viral E6 and E7 oncogenes. The E6 oncoprotein forms a complex with the cellular tumor suppressor protein p53, leading to degradation of p53 via ubiquitin-dependent proteolysis. Thus, E6 expression results in the loss of p53 function in cells, including stimulation of apoptosis and inhibition of the expression of the antiapoptotic protein bcl-2. Recently, we found increased bcl-2 expression in cervical carcinoma cell lines containing mutated or E6-inactivated p53 (X. L. Liang, S. Mungal, A. Ayscue, J. D. Meissner, P. Wodnicki, G. Gordon, S. Lockett, and B. Herman. J. Cell. Biochem., 57: 509-520, 1995). Based on these findings, we examined Papanicolaou smears from 94 women with varying degrees of cervical disease for the presence or absence of p53, HPV-16/18 E6, and bcl-2 proteins using immunofluorescence microscopy. Our findings indicate that there is a statistically significant, inverse association between the presence of p53 and invasive cervical disease [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7]. Moreover, the odds of being diagnosed with an invasive stage of cervical cancer were 3.7 times higher (95% CI, 1.6-8.8) for women positive for the E6 protein and 17 times higher (95% CI, 5.5-58.3) for women positive for the bcl-2 protein compared with women negative for E6 and bcl-2. Women with invasive cervical cancer were also 4.59 times more likely to test positive for the presence of more than one marker (95% CI, 1.8-11.8). Chi(2) analysis demonstrated a strong association between the presence of E6 and bcl-2 (P < 0.001) as well as between the presence of E6 of bcl-2 and diagnosis (P = 0.015 and < 0.001, respectively). In the multivariate analysis, the presence of bcl-2 (OR, 18.8; 95% CI, 5.5-67.8) and age at diagnosis (> or = 50 years; OR, 7.8; 95% CI, 2.5-24.5) showed significant association with Invasive cervical disease. These findings indicate that: (a) the presence of the bcl-2 protein is strongly associated with the development of invasive cervical disease: (b) the pattern of the presence of high-risk HPV-E6, p53, and bcl-2 proteins may be useful for identifying women at increased risk for the development of invasive cervical cancer; and (c) a defect in apoptosis may partially underlie the development of cervical cancer.


White Matter Changes-Related Gait and Executive Function Deficits: Associations with Age and Parkinson's Disease.
Background: White matter changes (WMC) are a common finding among older adults and patients with Parkinson's disease (PD), and have been associated with, e.g., gait deficits and executive dysfunction. How the factors age and PD influence WMC-related deficits is, to our best knowledge, not investigated to date. We hypothesized that advanced age and presence of PD leads to WMC-related symptoms while practicing tasks with a low complexity level, and low age and absence of PD leads to WMC-related symptoms while practicing tasks with a high complexity level. Methods: Hundred and thirty-eight participants [65 young persons without PD (50-69 years, yPn), 22 young PD patients (50-69 years, yPD), 36 old persons without PD (70-89 years, oPn) and 15 old PD patients (70-89 years, oPD)] were included. Presence and severity of WMC were determined with the modified Fazekas score. Velocity of walking under single and dual tasking conditions and the Trail Making Test (TMT) were used as gait and executive function parameters. Correlations between presence and severity of WMC, and gait and executive function parameters were tested in yPn, yPD, oPn, and oPD using Spearman's rank correlation, and significance between groups was evaluated with Fisher's z-transformed correlation coefficient. Results: yPn and yPD, as well as oPn and oPD did not differ regarding demographic and clinical parameters. Severity of WMC was not significantly different between groups. yPn and yPD displayed significant correlations of WMC with executive function parameters at low levels of task complexity, oPn at intermediate, and oPD at high complexity levels. Conclusion: This study argues for a relevant association of age and PD-related brain pathology with WMC-related gait and executive function deficits.


A model of beta-adrenergic effects on calcium and potassium current in bullfrog atrial myocytes.
A model of beta-adrenergic and muscarinic cholinergic effects on the bullfrog atrial myocyte has been developed to simulate the dose-dependent effects of isoprenaline (Iso) on the action potential duration (APD); i.e., low doses of Iso lengthen the APD, whereas high doses shorten the APD. In this model, the reduction in APD is the result of 1) calcium-dependent inactivation of calcium current (ICa) resulting from the enhancement of ICa by Iso and 2) an enhancement of potassium current (IK) due to both an Iso-induced increase in the rate of activation of IK and an increase in peak action potential height. The effect of acetylcholine (ACh) is simulated by a reduction in the Iso-induced increase in ICa and IK through a reduction in relative adenosine 3',5'-cyclic monophosphate concentration ([cAMP]), as well as activation of the ACh-sensitive potassium current. At low [Iso] levels in the presence of a high [ACh], the muscarinic cholinergic effects dominate the beta-adrenergic change. However, for a large [Iso] and a small [ACh], this pattern of changes in transmembrane currents is different; in this case the model predicts that ACh can actually increase APD.


Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis.
Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings.


In vitro antimicrobial activity of propolis and Arnica montana against oral pathogens.
Arnica and propolis have been used for thousands of years in folk medicine for several purposes. They possess several biological activities such as anti-inflammatory, antifungal, antiviral and tissue regenerative, among others. Although the antibacterial activity of propolis has already been demonstrated, very few studies have been done on bacteria of clinical relevance in dentistry. Also, the antimicrobial activity of Arnica has not been extensively investigated. Therefore the aim here was to evaluate in vitro the antimicrobial activity, inhibition of adherence of mutans streptococci and inhibition of formation of water-insoluble glucan by Arnica and propolis extracts. Arnica montana (10%, w/v) and propolis (10%, w/v) extracts from Minas Gerais State were compared with controls. Fifteen microorganisms were used as follows: Candida albicans--NTCC 3736, F72; Staphylococcus aureus--ATCC 25923; Enterococcus faecalis--ATCC 29212; Streptococcus sobrinus 6715; Strep. sanguis--ATCC 10556; Strep. cricetus--HS-6; Strep. mutans--Ingbritt 1600; Strep. mutans--OMZ 175; Actinomyces naeslundii--ATCC 12104, W 1053; Act. viscosus OMZ 105; Porphyromonas gingivalis; Porph. endodontalis and Prevotella denticola (the last three were clinical isolates). Antimicrobial activity was determined by the agar diffusion method and the zones of growth inhibition were measured. To assess cell adherence to a glass surface, the organisms were grown for 18 h at 37 degrees C in test-tubes at a 30 degree angle. To assay water-insoluble glucan formation, a mixture of crude glucosyltransferase and 0.125 M sucrose was incubated for 18 h at 37 degrees C in test-tubes at a 30 degree angle. Arnica and propolis extracts (20 microl) were added to these tubes to evaluate the % of inhibition of cell adherence and water-insoluble glucan formation. The propolis extract significantly inhibited all the microorganisms tested (p < 0.05), showing the largest inhibitory zone for Actinomyces spp. The Arnica extract did not demonstrate significant antimicrobial activity. Cell adherence and water-insoluble glucan formation were almost completely inhibited by the propolis extract at a final concentration of 400 microg/ml and 500 microg/ml, respectively. The Arnica extract showed slight inhibition of the adherence of the growing cells (19% for Strep. mutans and 15% for Strep. sobrinus) and of water-insoluble glucan formation (29%) at these same concentrations. Thus, the propolis extract showed in vitro antibacterial activity, inhibition of cell adherence and inhibition of water-insoluble glucan formation, while the Arnica extract was only slightly active in those three conditions.


The reliability and usability of district health information software: case studies from Tanzania.
The District Health Information System (DHIS) software from the Health Information System Programme (HISP) based in South Africa is widely implemented in many developing countries as a health data analysis tool. Through the HISP Tanzania project, the DHIS was piloted in five districts in Tanzania. The objective of this study was to qualify and quantify the extent to which district health workers consider the adaptation of the DHIS software to the needs of the routine health management information system. In a period of 14 months (from June 2003 to August 2004) data were collected from health workers trained to use the software through a triangulation of various qualitative data collection techniques including interview, questionnaire, participant observations and retrospective testing. The software was evaluated in terms of reliability, usability and user satisfaction. In general the reliability of the software was rated high but its usability was rated to be low. The software was found not to accommodate some health data from various health programmes and there was a mismatch between the implemented online data entry forms/reports and their respective paper-based forms/reports. The study recommends improved design of the DHIS user interface (forms) and reports to replicate the paper-based forms in order to assure usability and reduce the incidences and impact of human errors in the keying-in of health data.


Current Perspectives in Mesenchymal Stromal Cell Therapies for Airway Tissue Defects.
Lung cancer is the leading cause of cancer death and respiratory diseases are the third cause of death in industrialized countries; for this reason the airways and cardiopulmonary system have been the focus of extensive investigation, in particular of the new emerging branch of regenerative medicine. Mesenchymal stromal cells (MSCs) are a population of undifferentiated multipotent adult cells that naturally reside within the human body, which can differentiate into osteogenic, chondrogenic, and adipogenic lineages when cultured in specific inducing media. MSCs have the ability to migrate and engraft at sites of inflammation and injury in response to cytokines, chemokines, and growth factors at a wound site and they can exert local reparative effects through transdifferentiation and differentiation into specific cell types or via the paracrine secretion of soluble factors with anti-inflammatory and wound-healing activities. Experimental and clinical evidence exists regarding MSCs efficacy in airway defects restoration; although clinical MSCs use, in the daily practice, is not yet completely reached for airway diseases, we can argue that MSCs do not represent any more merely an experimental approach to airway tissue defects restoration but they can be considered as a "salvage" therapeutic tool in very selected patients and diseases.


[A comparison between Rome III and Rome II criteria in diagnosing irritable bowel syndrome].
To determine the degree of agreement of Rome III and Rome II criteria in diagnosing irritable bowel syndrome (IBS) and to compare the clinical difference between the patients diagnosed with these two criteria. 3014 patients in the gastrointestinal outpatient department were enrolled consecutively and interviewed face to face with a standard questionnaire. (1) 480 patients were diagnosed as IBS with Rome III criteria. The overall detection rate was 15.9% (480/3014). The proportion of IBS subtypes was as follows: IBS with constipation 27.9% (134/480), IBS with diarrhea 32.7% (157/480), Mixed IBS 6.7% (32/480), Unsubtyped IBS 32.7% (157/480). No difference was observed between different sex and age groups; with Rome II criteria, 558 patients were diagnosed with a detection rate of 18.5% (558/3014). The proportion of IBS subtypes was as follows: constipation predominant IBS 33.2% (185/558), diarrhea predominant IBS 38.2% (213/558), others 28.7% (160/558). The detection rate was higher in female patients (P = 0.002), but there was no difference between different age groups. The detection rate of Rome III criteria was lower than that of Rome II criteria (P = 0.008). There was a good accordance between these two criteria in the diagnosis of IBS (P < 0.01). (2) Patients classified according to Rome III criteria complained more severe abdominal symptoms (P = 0.04) and abnormal bowel habit (P < 0.001) as well as a higher healthcare seeking rate in the last 3 months (35.6% vs 26.5%, P = 0.02) as compared with those classified according to Rome II criteria. (3) According to Rome III criteria, the severity of bowel habit was different among the four subtypes (C-IBS, M-IBS > D-IBS > U-IBS, P < 0.005) while no difference was observed on the abdominal symptoms and the healthcare seeking rates in the last 3 months. There is a good accordance between Rome II and Rome III criteria in diagnosing IBS. Compared to Rome II criteria, Rome III criteria has a lower detection rate. It is more practical in the clinical practice with clear definition of symptom frequency and easy way of subtyping IBS. The patients diagnosed with Rome III criteria had more severe symptoms and higher healthcare seeking rate, they are more suitable for clinical trial.


Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice.
Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apoptotic cells, as indicated by an increase in both terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling- and caspase 3-stained cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of approximately 2.5-fold was found not earlier than at 6 months. No increased mutation accumulation was observed in brain or spleen. These results support the hypothesis, that oxidative stress is an important causal factor of cancer in mammals.


The role of the TERC-63G>A and TERT-1327C>T telomerase polymorphisms in the study of men with acute coronary syndrome.
Telomerase is a ribonucleoprotein that maintains telomere length. Telomeres and telomerase are involved in cellular ageing and have been connected to some ageing related diseases, like cardiovascular disease. Telomerase dysfunction could be the main underlying mechanism in this connection but this point is still unclear. The aim of this article is to investigate the possible influence of cellular ageing, measured by two telomerase polymorphisms, TERC-63G>A (rs2293607) and TERT-1327C>T (rs2735940), on the whole spectrum of acute coronary artery disease (CAD). We studied 150 middle aged men admitted for an acute coronary syndrome (ACS). Cardiovascular risk factors prevalence was collected at admission. Severity variables analyzed were Killip class and number of vessels affected. Telomerase polymorphisms were studied by real time PCR in DNA samples extracted from peripheral blood leukocytes. Clinical follow-up had been developed for more than 600 days and a prognostic combined event was defined. C allele of TERT polymorphism was more prevalent among hypertensive patients (OR: 3.19; 95% CI: 1.37-7.42; P=0.006). None of polymorphisms showed any prognostic value or relation to CAD severity. Telomerase dysfunction could be involved in hypertension prevalence. This finding could support new screening strategies in high risk population. The two telomerase polymorphisms analyzed did not show any prognostic value or connection to CAD severity. However, further studies are required to determine the molecular mechanisms responsible for cellular ageing in ACS.


MR elastography monitoring of tissue-engineered constructs.
The objective of tissue engineering (TE) is to create functional replacements for various tissues; the mechanical properties of these engineered constructs are critical to their function. Several techniques have been developed for the measurement of the mechanical properties of tissues and organs; however, current methods are destructive. The field of TE will benefit immensely if biomechanical models developed by these techniques could be combined with existing imaging modalities to enable noninvasive, dynamic assessment of mechanical properties during tissue growth. Specifically, MR elastography (MRE), which is based on the synchronization of a mechanical actuator with a phase contrast imaging pulse sequence, has the capacity to measure tissue strain generated by sonic cyclic displacement. The captured displacement is presented in shear wave images from which the complex shear moduli can be extracted or simplified by a direct measure, termed the shear stiffness. MRE has been extended to the microscopic scale, combining clinical MRE with high-field magnets, stronger magnetic field gradients and smaller, more sensitive, radiofrequency coils, enabling the interrogation of smaller samples, such as tissue-engineered constructs. The following topics are presented in this article: (i) current mechanical measurement techniques and their limitations in TE; (ii) a description of the MRE system, MRE theory and how it can be applied for the measurement of mechanical properties of tissue-engineered constructs; (iii) a summary of in vitro MRE work for the monitoring of osteogenic and adipogenic tissues originating from human adult mesenchymal stem cells (MSCs); (iv) preliminary in vivo studies of MRE of tissues originating from mouse MSCs implanted subcutaneously in immunodeficient mice with an emphasis on in vivo MRE challenges; (v) future directions to resolve current issues with in vivo MRE in the context of how to improve the future role of MRE in TE.


Isoflurane preconditioning inhibits the effects of tissue-type plasminogen activator on brain endothelial cell in an in vitro model of ischemic stroke.
Tissue-type plasminogen activator (tPA) is the only treatment for ischemic stroke. However, tPA could induce the intracranial hemorrhage (ICH), which is the main cause of death in ischemic stroke patient after tPA treatment. At present, there is no treatment strategy to ameliorate tPA-induced brain injury after ischemia. Therefore, we investigated the effect of pre-treated isoflurane, which is a volatile anesthetic and has beneficial effects on neurological dysfunction, brain edema and infarct volume in ischemic stroke model. In this study, we used oxygen/glucose deprivation and reperfusion (OGD/R) condition to mimic an ischemic stroke in vitro. Matrix metalloproteinases (MMP) activity was measured in endothelial cell media. Also, neuronal cell culture was performed to investigate the effect of pretreated isoflurane on the neuronal cell survival after tPA-induced injury during OGD/R. Isoflurane pretreatment prevented tPA-induced MMP-2 and MMP-9 activity and suppressed tPA-triggered LRP/NF-κB/Cox-2 signaling after OGD/R. Neuronal cells, incubated with endothelial cell conditioned medium (EC-CM) after tPA + OGD/R, showed upregulation of pro-apoptotic molecules. However, neurons incubated with isoflurane-pretreated EC-CM showed increased anti-apoptotic molecules. Our findings suggest that isoflurane pretreatment could attenuate tPA-exaggerated brain ischemic injury, by reducing tPA-induced LRP/NF-κB/Cox-2 in endothelial cells, endothelial MMP-2 and MMP-9 activation, and subsequent pro-apoptotic molecule in neurons after OGD/R.


Stereotactic Body Radiation Therapy (SBRT) for Hepatocellular Carcinoma: High Rates of Local Control With Low Toxicity.
Stereotactic body radiotherapy (SBRT) is potentially curative treatment for small hepatocellular carcinomas (HCC), but data are limited on its efficacy and toxicity. We hypothesized that SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis. Thirty-seven nonmetastatic HCC patients received SBRT to 43 lesions between October 2012 and April 2016. Median dose was 50 Gy/5 fractions. All Child-Pugh (CP) ≥B patients underwent a planned 1-month break after the first 3 fractions to assess hepatic toxicity. Patients were treated without separately placed fiducial markers using Linac-based SBRT with breath-hold (67%) or 4D-computed tomography with compression belt (33%) to reduce motion. Patients underwent magnetic resonance imaging q3 months post-SBRT. Median age was 65 (range, 44 to 88). Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP≥B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP≥B8 patients had no grade ≥3 hepatic toxicity. SBRT for HCC is well-tolerated even in patients with advanced cirrhosis and prior liver-directed treatment and provides excellent LC even for larger lesions that cannot be controlled with radiofrequency ablation. LC with SBRT compares favorably to other liver-directed therapies. Prospective studies comparing SBRT with other liver-directed therapies are warranted.


Effects of neocortical lesions on the P300 component of the auditory evoked response.
P300 event-related potentials were recorded in 10 subjects with neocortical lesions, and 10 control subjects, using a basic oddball paradigm. In separate tests, subjects discriminated rare and frequent tones that differed with respect to frequency, or discriminated the tones in a noise background. Subjects were required to count the number of rare stimuli that occurred during test runs. Recordings were obtained from vertex (Cz) sites referenced to linked earlobe electrodes. Control subjects exhibited P300s on all test runs. Decreasing stimulus differences relative to frequency, or adding background noise, produced significant increases in P300 latency plus decreases in amplitude. In contrast, two of the 10 lesion subjects failed to demonstrate P300 responses, although both subjects accurately counted the rare stimuli. With the remaining lesion subjects, absent or significantly delayed P300 responses occurred in 53 percent of the test runs, while accurate counts of the rare stimuli were maintained in all test runs. Absent or delayed P300s in the lesion group was not correlated with location or extent of the lesions. These results indicate that, while the P300 is susceptible to neocortical damage, it reflects cognitive processing other than simply discriminating differences between rare and frequent stimuli.


Complement C3 and C5 deficiency affects fracture healing.
There is increasing evidence that complement may play a role in bone development. Our previous studies demonstrated that the key complement receptor C5aR was strongly expressed in the fracture callus not only by immune cells but also by bone cells and chondroblasts, indicating a function in bone repair. To further elucidate the role of complement in bone healing, this study investigated fracture healing in mice in the absence of the key complement molecules C3 and C5. C3(-/-) and C5(-/-) as well as the corresponding wildtype mice received a standardized femur osteotomy, which was stabilized using an external fixator. Fracture healing was investigated after 7 and 21 days using histological, micro-computed tomography and biomechanical measurements. In the early phase of fracture healing, reduced callus area (C3(-/-): -25%, p=0.02; C5(-/-): -20% p=0.052) and newly formed bone (C3(-/-): -38%, p=0.01; C5(-/-): -52%, p=0.009) was found in both C3- and C5-deficient mice. After 21 days, healing was successful in the absence of C3, whereas in C5-deficient mice fracture repair was significantly reduced, which was confirmed by a reduced bending stiffness (-45%; p=0.029) and a smaller callus volume (-17%; p=0.039). We further demonstrated that C5a was activated in C3(-/-) mice, suggesting cleavage via extrinsic pathways. Our results suggest that the activation of the terminal complement cascade in particular may be crucial for successful fracture healing.


Estimating the Impact of Health-related Behaviors on Geographic Variation in Cardiovascular Mortality: A New Approach Based on the Synthesis of Ecological and Individual-level Data.
Incidence of and mortality from cardiovascular disease (CVD) exhibit a strong geographical pattern, with inhabitants of more affluent neighborhoods showing a substantially lower risk of CVD mortality than inhabitants of deprived neighborhoods. Thus far, there is insufficient evidence as to what extent these differences can be attributed to differences in health-related behaviors. Using a Hierarchical Related Regression approach, we combined individual and aggregate (ecological) data to investigate the extent to which small-area variation in CVD mortality in Dutch neighborhoods can be explained by several behavioral risk factors (i.e., smoking, drinking, overweight, and physical inactivity). The proposed approach combines the benefits of both an ecological analysis (in terms of data availability and statistical power) and an individual-level analysis (in terms of identification of the parameters and interpretation of the results). After correcting for differences in age and sex, accounting for differences in the behavioral risk factors reduces income-related inequalities in CVD mortality by approximately 30%. Direct targeting of the excess prevalence of unhealthy behaviors in deprived neighborhoods is identified as a relevant strategy to reduce inequalities in CVD mortality. Our results also show that the proposed Hierarchical Related Regression approach provides a powerful method for the investigation of small-area variation in health outcomes.


Predicting New Anti-Norovirus Inhibitor With the Help of Machine Learning Algorithms and Molecular Dynamics Simulation-Based Model.
Hepatitis C virus (HCV) inhibitors are essential in the treatment of human norovirus (HuNoV). This study aimed to map out HCV NS5B RNA-dependent RNA polymerase inhibitors that could potentially be responsible for the inhibitory activity of HuNoV RdRp. It is necessary to develop robust machine learning and in silico methods to predict HuNoV RdRp compounds. In this study, Naïve Bayesian and random forest models were built to categorize norovirus RdRp inhibitors from the non-inhibitors using their molecular descriptors and PubChem fingerprints. The best model observed had accuracy, specificity, and sensitivity values of 98.40%, 97.62%, and 97.62%, respectively. Meanwhile, an external test set was used to validate model performance before applicability to the screened HCV compounds database. As a result, 775 compounds were predicted as NoV RdRp inhibitors. The pharmacokinetics calculations were used to filter out the inhibitors that lack drug-likeness properties. Molecular docking and molecular dynamics simulation investigated the inhibitors' binding modes and residues critical for the HuNoV RdRp receptor. The most active compound, CHEMBL167790, closely binds to the binding pocket of the RdRp enzyme and depicted stable binding with RMSD 0.8-3.2 Å, and the RMSF profile peak was between 1.0-4.0 Å, and the conformational fluctuations were at 450-460 residues. Moreover, the dynamic residue cross-correlation plot also showed the pairwise correlation between the binding residues 300-510 of the HuNoV RdRp receptor and CHEMBL167790. The principal component analysis depicted the enhanced movement of protein atoms. Moreover, additional residues such as Glu510 and Asn505 interacted with CHEMBL167790 via water bridge and established H-bond interactions after the simulation. http://zinc15.docking.org/substances/ZINC000013589565.


Nanoscale shift of the intensity distribution of dipole radiation.
The energy flow lines (field lines of the Poynting vector) for radiation emitted by a dipole are in general curves, rather than straight lines. For a linear dipole the field lines are straight, but when the dipole moment of a source rotates, the field lines wind numerous times around an axis, which is perpendicular to the plane of rotation, before asymptotically approaching a straight line. We consider an elliptical dipole moment, representing the most general state of oscillation, and this includes the linear dipole as a special case. Due to the spiraling near the source, for the case of a rotating dipole moment, the field lines in the far field are displaced with respect to the outward radial direction, and this leads to a shift of the intensity distribution of the radiation in the far field. This shift is shown to be independent of the distance to the source and, although of nanoscale dimension, should be experimentally observable.


Skeletal Involvement of Brucella melitensis in Children: A Systematic Review.
Brucellosis is a protean disease and should be excluded in any febrile child with a constellation of symptoms such as fever, malaise, sweating, arthralgia, and joint swelling in endemic areas. Skeletal system involvement is the most common source of complaints in brucellosis. The frequency of skeletal involvement in children is 6.4% to 73.5%. There are some controversies regarding the most common sites of involvement: sacroiliac versus peripheral joints. In the vast majority of cases, peripheral joint involvement in pediatric brucellosis has a monoarticular pattern, although there is no agreement about the most commonly involved peripheral joint. In this systematic review, published articles that describe the bone involvement of Brucella melitensis, as the most prevalent kind of the microorganism in the region, in children are evaluated.


The roles of thiol oxidoreductases in yeast replicative aging.
Thiol-based redox reactions are involved in the regulation of a variety of biological functions, such as protection against oxidative stress, signal transduction and protein folding. Some proteins involved in redox regulation have been shown to modulate life span in organisms from yeast to mammals. To assess the role of thiol oxidoreductases in aging on a genome-wide scale, we analyzed the replicative life span of yeast cells lacking known and candidate thiol oxidoreductases. The data suggest the role of several pathways in controlling yeast replicative life span, including thioredoxin reduction, protein folding and degradation, peroxide reduction, PIP3 signaling, and ATP synthesis.


Objective sequence-based subfamily classifications of mouse homeodomains reflect their in vitro DNA-binding preferences.
Classifying proteins into subgroups with similar molecular function on the basis of sequence is an important step in deriving reliable functional annotations computationally. So far, however, available classification procedures have been evaluated against protein subgroups that are defined by experts using mainly qualitative descriptions of molecular function. Recently, in vitro DNA-binding preferences to all possible 8-nt DNA sequences have been measured for 178 mouse homeodomains using protein-binding microarrays, offering the unprecedented opportunity of evaluating the classification methods against quantitative measures of molecular function. To this end, we automatically derive homeodomain subtypes from the DNA-binding data and independently group the same domains using sequence information alone. We test five sequence-based methods, which use different sequence-similarity measures and algorithms to group sequences. Results show that methods that optimize the classification robustness reflect well the detailed functional specificity revealed by the experimental data. In some of these classifications, 73-83% of the subfamilies exactly correspond to, or are completely contained in, the function-based subtypes. Our findings demonstrate that certain sequence-based classifications are capable of yielding very specific molecular function annotations. The availability of quantitative descriptions of molecular function, such as DNA-binding data, will be a key factor in exploiting this potential in the future.


Mechanism of inhibition of MDA-MB-468 breast cancer cell growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Treatment of estrogen receptor (ER)-negative MDA-MB-468 human breast cancer cells with 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced formation of a nuclear aryl hydrocarbon (Ah) receptor complex as determined by ligand-binding and gel electrophoretic mobility shift assays. TCDD also induced CYP1A1-dependent activity in MDA-MB-468 cells, which represents the first ER-negative Ah receptor-positive human breast cancer cell line that has been identified. Treatment of this cell line with TCDD and related compounds also caused a 50% inhibition of cell growth, which resembled the growth inhibitory effects previously reported for epidermal growth factor (EGF). However, EGF expression is minimal in this cell line and is not induced by TCDD; moreover, EGF and TCDD induced a different pattern of oncogene expression and apoptosis in MDA-MB-468 cells. In contrast, TCDD caused a rapid and sustained induction of transforming growth factor alpha (TGF alpha) gene expression and secreted protein (nearly 2-fold); moreover, the growth-inhibitory effects of TCDD could be blocked by antibodies to the EGF receptor. In a separate experiment, it was shown that TGF alpha also inhibited growth of MDA-MB-468 cells. The results of this study indicate that the mechanism of growth inhibition of MDA-MB-468 cells by TCDD is due to induction of TGF alpha, which is a potent antimitogen in this cell breast cancer line.


Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in the medial prefrontal cortex and amygdala in rat.
D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity [phospho-extracellular signal-regulated kinase (pERK)] markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24-28 days old) increased c-fos- and pERK-stained neurons in both the prelimbic and infralimbic division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus of the central amygdala. Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in the mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in the infralimbic prefrontal cortex, prelimbic prefrontal cortex intercalated cells and lateral nucleus of the central amygdala, compared with saline control. In the synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared with context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS, the conjunction with extinction training led to an increase in iGluR subunit expression, compared with the extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei.


Combating Tuberculosis Infection: A Forbidding Challenge.
After 50 years drought, several drugs are looming from the pipeline to combat tuberculosis. They will serve as a boon to the field that has been burdened with primitive, inadequate treatments and drug-resistant bacterial strains. From the decades, due to lack of interest and resources, the field has suffered a lot. Learning from the flaws, scientists have renovated their approaches to the finding of new antitubercular drugs. The first line drugs take about six months or more for the entire treatment. The second line remedy for resistant-tuberculosis requires daily injections which carry severe side effects. Drug resistance remains a constant menace because patients stop the medication once they start feeling better. So new drugs are required to be explored which are effective against tuberculosis especially drug resistant tuberculosis. These drugs need to work well with other drugs as well as with antivirals used for the treatment of human immunodeficiency virus. It is also very important to be considered that the treatments need to be cheap, as tuberculosis primarily affects people more in the developing countries. Further, new drugs must cure the disease in short span of time than the current six to nine month regimen. Recently a few new and potent drugs such as bedaquiline, delamanid, teixobactin have been evolved which may serve as a nice step forward, with a better outcome. Teixobactin, a new antibiotic has been found to have promising action against resistant strains, is also under consideration.


Musculoskeletal symptoms and job strain among nursing personnel: a study over a three year period.
To examine the variation of symptoms from the neck, shoulders, and back over a three year period among female nursing personnel and the relation between job strain and musculoskeletal symptoms. At a county hospital the female nursing personnel answered a questionnaire at baseline and then once a year over a period of three years. There were 565, 553, 562, and 419 subjects who answered the questionnaire at the first, second, third, and fourth survey, respectively. Of the study group, 285 nursing personnel answered the questionnaire on four occasions. Ongoing symptoms of the neck, shoulders, and back were assessed by means of a 10 point (0-9) scale with the verbal end points "no symptoms" and "very intense symptoms." Cases were defined as nursing personnel reporting ongoing symptoms, score > 6, from at least one of the body regions. For assessments of job strain, a Swedish version of Karasek and Theorell's model was used. Of the 285 subjects, 13% were defined as cases at all four assessments, and 46% varied between cases and not cases during the study period. In the repeated cross sectional surveys the estimated rate ratio (RR) for being a case was between 1.1 and 1.5 when comparing the group with job strain and the group without job strain. For the combination of job strain and perceived high physical exertion the estimated RR was between 1.5 and 2.1. When the potential risk factors were assessed one, two, or three years before the assessment of symptoms the estimated RR for becoming a case was between 1.4 and 2.2 when comparing the group with job strain and the group without job strain. Almost half of the healthcare workers varied between being a case and not, over a three year period. The analysis indicated that job strain is a risk factor for musculoskeletal symptoms and that the risk is higher when it is combined with perceived high physical exertion.


Pre-Emptive Immunotherapy for Clearance of Molecular Disease in Childhood Acute Lymphoblastic Leukemia after Transplantation.
Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.


Dexamethasone facilitates discharge after outpatient anorectal surgery.
Corticosteroids can decrease pain and postoperative nausea and vomiting after ambulatory surgery. Therefore, we designed a study to evaluate if the routine use of dexamethasone would facilitate the early recovery process after anorectal surgery. A secondary aim of the study was to determine if dexamethasone would increase the incidence of postoperative wound complications. Eighty adult outpatients undergoing anorectal surgery with a standardized monitored anesthesia care technique were randomly assigned to receive either dexamethasone 4 mg IV or an equal volume of saline before the start of surgery. All patients were premedicated with midazolam 2 mg IV and received ketorolac 30 mg IV as a preemptive analgesic. A propofol infusion, 50 microg. kg(-1). min(-1) IV, was initiated and subsequently titrated to maintain an observer's assessment of alertness/sedation score of 2 or 3 (with 5 = awake/alert to 1 = asleep). Fentanyl 25 microg IV was administered 3-5 min before infiltrating the surgical field with a 30-mL local anesthetic mixture containing 15 mL of lidocaine 1% and 15 mL of bupivacaine 0.25% (with epinephrine 1:200,000 and sodium bicarbonate 3 mL). All patients were fast-tracked directly from the operating room to the step-down recovery area. Even though the incidences of postoperative pain and postoperative nausea and vomiting were small in both treatment groups, the time to "home readiness" was significantly shorter in the dexamethasone group. Importantly, there was no increase in the incidence of wound infections (8% vs 12%) or hematoma formation (3% vs 5%) in the dexamethasone (versus saline) group. We conclude that the administration of dexamethasone, 4 mg IV, shortened the time to home readiness without increasing the incidence of postoperative wound infections in a high-risk outpatient population undergoing anorectal surgery. A single dose of dexamethasone (4 mg IV) decreased the time to "home readiness" without increasing the incidence of postoperative wound complications in an outpatient population undergoing anorectal surgery.


Rapidly progressive glomerulonephritis in a child with Henoch-Schönlein Vasculitis and familial Mediterranean fever.
Henoch-Schonlein Vasculitis (HSV) is systemic small vessel vasculitis involving the skin, kidney, joints, and gastrointestinal tract. The proportion of patients reported to have renal involvement varies between 20% and 80%. Rapidly progressive glomerulonephritis (RPGN)is rare syndrome in children, characterized by clinical features of glomerulonephritis (GN) and rapid loss of renal function. We present a severe kidney involvement in a 14 year old boy with HSV in who is carring MEFV mutation. A 14 year old boy had developed sudden onset of palpable purpuric rash on his extensor surfaces of lower extremities. He had elevated an erythrocyte sedimentation rate (ESR) (45 mm/h), C-reactive protein (3.74 mg/dl), serum urea 66 mg/dl, serum creatinine 1.8 mg/dl. Also, he had hypocomplementemia. Antinuclear antibody, anti ds DNA, antineutrophil cytoplasmic antibody, anticardiolipine antibodies were negative. Urinalysis revealed macroscopic hematuria and proteinuria with a 24-h urinary protein excretion of 55 mg/m2/h. The renal biopsy specimen showed crescentic and necrotizing glomerulonephritis. He had also M694V/E148Q compound heterozygote mutation. Clinical symptoms and renal failure resolved with intermittant hemodialysis and medical therapy.