Impact on survival through consolidation radiotherapy for diffuse large B-cell lymphoma: a comprehensive meta-analysis.
Rituximab has improved response rates and overall survival in B-cell lymphoma (DLBCL). Radiotherapy is an effective treatment modality for lymphomas, but there is uncertainty on its use as consolidation after chemo-immunotherapy mainly in advanced stages. We evaluated its efficacy with a comprehensive meta-analysis and a systematic search of Pubmed, Embase, Cochrane, and abstracts from ASCO, ASH, ESMO and ASTRO published from June 1966 and December 2018. We identified 11 trials that evaluated consolidation radiotherapy following chemotherapy in a randomized fashion in 4'584 patients. The primary endpoint of this meta-analysis was PFS. As three of the eleven trials were retracted, this data is based on 2414 patients. For the primary endpoint (PFS), we found a hazard ratio (HR) of 0.77 (0.51 to 1.17, pooled (tau2: 0.25; I2: 85%), and a HR of 0.80 (0.53 to 1.21, pooled (bivariate meta-analysis). For overall survival, the HR is 0.93 (0.61 to 1.40; pooled (tau2: 0.25; I2: 74%) and 0.86 (0.58 to 1.27) in a bivariate meta-analysis. The lack of benefit did not change over time (p-value: 0.95 (tau2: 0.32; I2: 88%), and was also absent for PFS when stratifying for chemotherapy, the use of Rituximab, age, the dose of radiotherapy, application to patients in complete remission and with bulky disease. None of the trials used a PET-guided approach. This meta-analysis revealed no survival benefit when consolidation radiotherapy is given to unselected DLBCL patients following chemotherapy. These results need to be considered in future trials in the PET-CT era.


The case for primary salivary rhabdomyosarcoma.
Rhabdomyosarcomas of the parotid and submandibular glands have the histological appearance of a skeletal muscle tumor yet can be found in tissue with no striated muscular elements. We examine the potential cell-of-origin for rhabdomyosarcoma and whether salivary tumors represent primary malignancy or metastasis. We have previously established genetically engineered mouse models of rhabdomyosarcoma. In these mice, rhabdomyosarcoma is only induced when a Pax3:Foxo1 fusion oncogene is activated with concurrent loss of p53 function (for alveolar rhabdomyosarcoma) or loss of p53 function alone (for embryonal rhabdomyosarcoma) using Cre-lox technology. These mutations are only activated under the control of promoters specific for selected cell lineages, previously thought to be myogenesis-restricted. RT-PCR and immunohistochemistry for lineage-specific promoter gene products reveal these promoters are active in wild-type mouse salivary gland. Given that mouse rhabdomyosarcoma frequently originates in the salivary glands and these myogenic-related promoters are normally expressed in salivary tissue, a high likelihood exists that the salivary gland contains a cell-of-origin of this muscle-related cancer.


Endoscopic saphenous vein harvesting for CABG -- a randomized, prospective trial.
The saphenous vein is an established conduit for coronary revascularization. Disadvantages of traditional harvest technique are significant pain and morbidity. We compared the endoscopic harvest technique with the traditional method. 140 coronary artery bypass graft (CABG) patients were randomized into 2 groups: endoscopic vein harvesting (EVH; n = 80) and traditional open vein harvesting (OVH; n = 60). Analysis included preoperative risk factors for wound complication, harvesting time, graft injury, and intraoperative and postoperative complications. Patient follow-up lasted 3 months. The preoperative risk profiles of the groups were comparable. In the EVH group, 5 patients (7.1 %) had to be switched to the open technique. EVH time was 45 +/- 6.2 min vs. 31.1 +/- 6.5 min. Two patients (2.5 %) had to be revised because of bleeding complication vs. 6 (10 %) in the OVH group. No local infections or wound complications were observed in the EVH group vs. 11 (18 %) cases in the OVH group. Two OVH cases (3.6 %) were readmitted for wound debridement. All EVH patients reported less pain and were completely satisfied by the cosmetic results. EVH is a safe and efficient technique for CABG. Morbidity was significantly lower, with reduced pain and better cosmetic results. EVH time was significantly longer compared to the traditional harvesting technique.


Caspase recruitment domain 9, microbiota, and tryptophan metabolism: dangerous liaisons in inflammatory bowel diseases.
Inflammatory bowel diseases (IBDs) develop as a result of a combination of genetic predisposition, dysbiosis of the gut microbiota, and environmental influences. Here, we describe an example of how caspase recruitment domain 9 (CARD9), one of the numerous IBD susceptibility genes, participate to colitis susceptibility by shaping gut microbiota to produce tryptophan metabolites. Recent study showed that CARD9 mice are more susceptible to colitis as a result of impaired interleukin 22 signaling pathway. Furthermore, aryl hydrocarbon receptor (AhR) ligands from tryptophan metabolism by the gut microbiota participate to intestinal homeostasis by inducing production of interleukin 22 by intestinal immune cells. These data suggest an interaction between CARD9 and the ability of gut microbiota to produce AhR ligands. The microbiota from CARD9 mice fails to metabolize tryptophan leading to defective AhR activation which contributes to the susceptibility of mice to colitis by decreased interleukin 22 production. These effects were abrogated in the presence of AhR agonist. Reduced production of AhR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Correcting impaired microbiota functions, such as ability to produce AhR ligands, is an attractive strategy in IBD.


Transcatheter aortic valve thrombosis: incidence, clinical presentation and long-term outcomes.
To assess the incidence, management and long-term outcomes of transcatheter heart valve thrombosis (THVT). Between August 2007 and February 2016, 1396 patients were included in the Bern TAVI Registry and prospectively followed-up through echocardiographic and clinical evaluation. THVT was suspected in case of: (i) a mean transvalvular pressure gradient greater than 20 mmHg at transthoracic echocardiography, or (ii) an increase of more than 50% of the mean transvalvular pressure gradient compared with previous measurements or (iii) new symptoms or signs of heart failure with the presence of thrombus documented by transoesophageal echocardiography or multi-slice computed tomography. THVT occurred in 10 patients (0.71%) at variable time points after TAVI. Increased transvalvular pressure gradients were recorded in all patients and 7 out of 10 patients were symptomatic. Oral anticoagulant therapy (with vitamin K antagonists or non-Vitamin K antagonists) was initiated in all but two patients and resulted in normalization of transvalvular pressure gradients and amelioration of clinical status within 1 month. At long-term follow-up (between 10 and 25 months after valve thrombosis), echocardiographic findings were stable and no adverse events were reported. THVT is rarely detected at routine clinical and echocardiographic evaluation after TAVI. Oral anticoagulation appears effective to normalize transvalvular gradients in the majority of cases with stable clinical and haemodynamic evolution during long-term follow-up.


Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein.
Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate, and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiologic albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC.


Common marmosets (Callithrix jacchus) as a nonhuman primate model to assess the virulence of eastern equine encephalitis virus strains.
Eastern equine encephalitis virus (EEEV) produces the most severe human arboviral disease in North America (NA) and is a potential biological weapon. However, genetically and antigenically distinct strains from South America (SA) have seldom been associated with human disease or mortality despite serological evidence of infection. Because mice and other small rodents do not respond differently to the NA versus SA viruses like humans, we tested common marmosets (Callithrix jacchus) by using intranasal infection and monitoring for weight loss, fever, anorexia, depression, and neurologic signs. The NA EEEV-infected animals either died or were euthanized on day 4 or 5 after infection due to anorexia and neurologic signs, but the SA EEEV-infected animals remained healthy and survived. The SA EEEV-infected animals developed peak viremia titers of 2.8 to 3.1 log(10) PFU/ml on day 2 or 4 after infection, but there was no detectable viremia in the NA EEEV-infected animals. In contrast, virus was detected in the brain, liver, and muscle of the NA EEEV-infected animals at the time of euthanasia or death. Similar to the brain lesions described for human EEE, the NA EEEV-infected animals developed meningoencephalitis in the cerebral cortex with some perivascular hemorrhages. The findings of this study identify the common marmoset as a useful model of human EEE for testing antiviral drugs and vaccine candidates and highlight their potential for corroborating epidemiological evidence that some, if not all, SA EEEV strains are attenuated for humans.


Forms and functions of human SDR enzymes.
Short-chain dehydrogenases/reductases (SDR) are defined by distinct, common sequence motifs but constitute a functionally heterogenous superfamily of enzymes. At present, well over 1600 members from all forms of life are annotated in databases. Using the defined sequence motifs as queries, 37 distinct human members of the SDR family can be retrieved. The functional assignments of these forms fall minimally into three main groups, enzymes involved in intermediary metabolism, enzymes participating in lipid hormone and mediator metabolism, and open reading frames (ORFs) of yet undeciphered function. This overview, prepared just before completion of the human genome project, gives the different human SDR forms and relates them to human diseases.


Marine omega-3 fatty acids and coronary heart disease.
To provide an overview of the key earlier intervention studies with marine omega-3 fatty acids and to review and comment on recent studies reporting on mortality outcomes and on selected underlying mechanisms of action. Studies relating marine omega-3 fatty acid status to current or future outcomes continue to indicate benefits, for example, on incident heart failure, congestive heart failure, acute coronary syndrome, and all-cause mortality. New mechanistic insights into the actions of marine omega-3 fatty acids have been gained. Three fairly large secondary prevention trials have not confirmed the previously reported benefit of marine omega-3 fatty acids towards mortality in survivors of myocardial infarction. Studies of marine omega-3 fatty acids in atrial fibrillation and in cardiac surgery-induced atrial fibrillation have produced inconsistent findings and meta-analyses demonstrate no benefit. A study confirmed that marine omega-3 fatty acids reduce the inflammatory burden with advanced atherosclerotic plaques, so inducing greater stability. Recent studies of marine omega-3 fatty acids on morbidity of, and mortality from, coronary and cardiovascular disease have produced mixed findings. These studies raise new issues to be addressed in future research.


Pancreatic stone protein predicts outcome in patients with peritonitis in the ICU.
To determine the value of pancreatic stone protein in predicting sepsis-related postoperative complications and death in the ICU. A prospective cohort study of postoperative patients admitted to the ICU. Blood samples for analysis were taken within 3 hours from admission to the ICU including pancreatic stone protein, white blood cell counts, C-reactive protein, interleukin-6, and procalcitonin. The Mannheim Peritonitis Index and Acute Physiology and Chronic Health Evaluation II clinical scores were also determined. Univariate and multivariate analyses were performed to determine the diagnostic accuracy and independent predictors of death in the ICU [Clinicaltrials.gov, NCT01465711]. An adult medical-surgical ICU in a teaching hospital in Germany. Ninety-one consecutive postoperative patients with proven diagnosis of secondary peritonitis admitted to the ICU were included in the study from August 17, 2007, to February 8, 2010. Peripheral vein blood sampling. Univariate analysis demonstrated that pancreatic stone protein has the highest diagnostic accuracy for complications and is the best predictor for death in the ICU. Pancreatic stone protein had the highest overall efficacy in predicting death with an odds ratio of 4.0 vs. procalcitonin (odds ratio 3.2), interleukin-6 (odds ratio 2.8), C-reactive protein (odds ratio 1.3), and WBCs (odds ratio 1.4). By multivariate analysis, pancreatic stone protein was the only independent predictor of death. In a population of patients with sepsis-related complications, serum-pancreatic stone protein levels demonstrate a high diagnostic accuracy to discriminate the severity of peritonitis and to predict death in the ICU. This test could be of value in the clinical diagnosis and therapeutic decision making in the ICU.


Prevalence and Factors Associated with Gaming Disorder in Latin America and the Caribbean: A Systematic Review.
We aimed to determine the prevalence and factors associated with gaming disorder (GD) in the population of Latin America and the Caribbean (LAC). A systematic review was performed (PROSPERO protocol registration: CRD42021230565). We included studies that identified participants with GD and/or factors associated with this condition, reported the prevalence of GD, or contained data that assisted in its estimation, were published after 2013 (the year of inclusion of GD in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders) and were carried out in a population residing in an LAC country. Evaluation of the quality of the studies was carried out using the Joanna Briggs Institute Critical appraisal checklist tool. A qualitative synthesis of the data was performed. Of the total of 1567 records identified, 25 passed the full-text review phase, and 6 met the selection criteria. These studies were published between 2018 and 2021 and had a cross-sectional design (three in Brazil, one in Ecuador, Mexico, and the other was multi-country, including a LAC country [Peru]). The prevalence of GD ranged from 1.1% to 38.2%. The three studies in Brazil had the highest figures of GD prevalence (20.4-38.2%). Four studies evaluated factors associated with GD. Characteristics regarding the game (type), pattern of use (hours played), as well as gender (higher in men), tobacco and alcohol consumption, poor interpersonal relationships, and the presence of mental disorders were found to be associated with GD in LAC. Evidence on the prevalence and factors associated with GD in LAC is limited. Studies on GD in LAC evaluate different population subgroups, describing a wide prevalence of this condition (present in up to 38 out of 100 evaluated). Characteristics such as the type and hours of use of the games, sociodemographic data, lifestyles, interpersonal relationships, and the presence of mental disorders increase the probability of presenting GD.


Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients.
Delayed graft function (DGF) is the need for dialysis in the first week after transplantation. Studied were risk factors for DGF in adult (age >/=16 yr) cadaveric renal transplant recipients by means of a multivariable modeling procedure. Only donor and recipient factors known before transplantation were chosen so that the probabilities of DGF could be calculated before transplantation and appropriate preventative measures taken. Data on 19,706 recipients of cadaveric allografts were obtained from the United States Renal Data System registry (1995 to 1998). Graft losses within the first 24 h after surgery were excluded from the analysis (n = 89). Patients whose DGF information was missing or unknown (n = 2820) and patients missing one or more candidate predictors (n = 2951) were also excluded. By means of a multivariable logistic regression analysis, factors contributing to DGF in the remaining 13,846 patients were identified. After validating the logistic regression model, a nomogram was developed as a tool for identifying patients at risk for DGF. The incidence of DGF was 23.7%. Sixteen independent donor or recipient risk factors were found to predict DGF. A nomogram quantifying the relative contribution of each risk factor was created. This index can be used to calculate the risk of DGF for an individual by adding the points associated with each risk factor. The nomogram provides a useful tool for developing a pretransplantation index of the likelihood of DGF occurrence. With this index in hand, better informed treatment and allocation decisions can be made.


Initial Characterization of the Two ClpP Paralogs of Chlamydia trachomatis Suggests Unique Functionality for Each.
Members of Chlamydia are obligate intracellular bacteria that differentiate between two distinct functional and morphological forms during their developmental cycle, elementary bodies (EBs) and reticulate bodies (RBs). EBs are nondividing small electron-dense forms that infect host cells. RBs are larger noninfectious replicative forms that develop within a membrane-bound vesicle, termed an inclusion. Given the unique properties of each developmental form of this bacterium, we hypothesized that the Clp protease system plays an integral role in proteomic turnover by degrading specific proteins from one developmental form or the other. Chlamydia spp. have five uncharacterized clp genes, clpX, clpC, two clpP paralogs, and clpB In other bacteria, ClpC and ClpX are ATPases that unfold and feed proteins into the ClpP protease to be degraded, and ClpB is a deaggregase. Here, we focused on characterizing the ClpP paralogs. Transcriptional analyses and immunoblotting determined that these genes are expressed midcycle. Bioinformatic analyses of these proteins identified key residues important for activity. Overexpression of inactive clpP mutants in Chlamydia spp. suggested independent function of each ClpP paralog. To further probe these differences, we determined interactions between the ClpP proteins using bacterial two-hybrid assays and native gel analysis of recombinant proteins. Homotypic interactions of the ClpP proteins, but not heterotypic interactions between the ClpP paralogs, were detected. Interestingly, protease activity of ClpP2, but not ClpP1, was detected in vitro This activity was stimulated by antibiotics known to activate ClpP, which also blocked chlamydial growth. Our data suggest the chlamydial ClpP paralogs likely serve distinct and critical roles in this important pathogen.IMPORTANCEChlamydia trachomatis is the leading cause of preventable infectious blindness and of bacterial sexually transmitted infections worldwide. Chlamydiae are developmentally regulated obligate intracellular pathogens that alternate between two functional and morphologic forms, with distinct repertoires of proteins. We hypothesize that protein degradation is a critical aspect to the developmental cycle. A key system involved in protein turnover in bacteria is the Clp protease system. Here, we characterized the two chlamydial ClpP paralogs by examining their expression in Chlamydia spp., their ability to oligomerize, and their proteolytic activity. This work will help understand the evolutionarily diverse Clp proteases in the context of intracellular organisms, which may aid in the study of other clinically relevant intracellular bacteria.


Parental expressed emotion and suicidal ideation in adolescents with bipolar disorder.
Family environmental variables are risk factors for recurrent courses of mood disorder in adolescents. The present study examined the association between parental expressed emotion (EE)-critical, hostile and/or emotionally overinvolved attitudes toward a concurrently ill offspring-and suicidal ideation in adolescents with bipolar disorder. The sample consisted of 95 adolescents with a bipolar I or II diagnosis who had experienced a mood episode in the prior 3 months. Participants (mean age=15.54 years, S.D.=1.4) were interviewed and completed questionnaires regarding current and past suicidal ideation prior to their participation in a treatment trial. Parents completed five-minute speech samples from which levels of EE were assessed. High EE attitudes in parents were associated with current suicidal ideation in adolescents. This relationship was independent of the effects of age, gender, current depressive or manic symptoms, comorbid diagnoses, bipolar I/II subtypes, family adaptability, and family cohesion. These results underscore the importance of addressing the emotional reactivity of caregivers in treating adolescents with bipolar disorder who have suicidal ideation.


Effective antitumor peptide vaccines can induce severe autoimmune pathology.
Immunotherapy has shown a tremendous success in treating cancer. Unfortunately, this success is frequently associated with severe autoimmune pathology. In this study, we used the transgenic RIP-gp mouse model to assess the antitumor therapeutic benefit of peptide vaccination while evaluating the possible associated autoimmune pathology. We report that palmitoylated gp33-41 peptide and poly-IC adjuvant vaccine (BiVax) generated ∼ 5-10 % of antigen specific T cell responses in wild type and supposedly immune tolerant RIP-gp mice. Boosting with BiVax in combination with αCD40 antibody (TriVax) or BiVax in combination with IL-2/αIL-2 antibody complexes (IL2Cx) significantly increased the immune responses (∼30-50%). Interestingly, although both boosts were equally effective in generating vast T cell responses, BiVax/IL2Cx showed better control of tumor growth than TriVax. However, this effect was associated with high incidence of diabetes in an antigen and CD8 dependent fashion. T cell responses generated by BiVax/IL2Cx, but not those generated by TriVax were highly resistant to PD-1/PD-L1 inhibitory signals. Nevertheless, PD-1 blockade enhanced the ability of TriVax to control tumor growth but increased the incidence of diabetes. Finally, we show that severe autoimmunity by BiVax/IL2Cx was prevented while preserving outstanding antitumor responses by utilizing a tumor antigen not expressed in the pancreas. Our data provides a clear evidence that peptide based vaccines can expand vast endogenous T cell responses which effectively control tumor growth but with high potential of autoimmune pathology.


Three species of Borrelia burgdorferi sensu lato (B. burgdorferi sensu stricto, B afzelii, and B. garinii) identified from cerebrospinal fluid isolates by pulsed-field gel electrophoresis and PCR.
A total of 36 European Borrelia burgdorferi sensu lato cerebrospinal fluid isolates (mainly from southern Germany) were analyzed by pulsed-field gel electrophoresis (PFGE) for large restriction fragment pattern (LRFP) and linear plasmid profiles. Analyzing this large panel of isolates, we detected all three species of B. burgdorferi sensu lato pathogenic for humans in cerebrospinal fluid from patients with Lyme neuroborreliosis by PFGE typing after MluI digestion: 21 B. garinii (58%), 10 B. afzelii (28%), and 4 B. burgdorferi sensu stricto (11%) strains as well as 1 isolate with bands characteristic of both B. afzelii and B. garinii. Species classification by PFGE typing was confirmed by 16S rRNA-specific PCR. Eighteen isolates (11 B. garinii, 6 B. afzelii, and 1 B. burgdorferi sensu stricto isolate) were further characterized by LRFP with four different restriction enzymes (ApaI, KspI, SmaI, and XhoI). All B. afzelii isolates showed identical patterns for each restriction enzyme group. Considerable heterogeneity was demonstrated within the B. garinii group. Subsequent analysis of plasmid profiles revealed only marginal differences for B. afzelii strains but different patterns for B. garinii isolates. In one B. afzelii strain we found a linear plasmid of about 110 kbp not described before. LRFP analysis by PFGE is a suitable tool for the molecular characterization of B. burgdorferi sensu lato strains and allows determination not only of the species but also of the subtypes within B. garinii.


Impacts of Bisphenol A and Ethinyl Estradiol on Male and Female CD-1 Mouse Spleen.
The endocrine disruptor bisphenol A (BPA) and the pharmaceutical 17α-ethinyl estradiol (EE) are synthetic chemicals with estrogen-like activities. Despite ubiquitous human exposure to BPA, and the wide-spread clinical use of EE as oral contraceptive adjuvant, the impact of these estrogenic endocrine disrupting chemicals (EDCs) on the immune system is unclear. Here we report results of in vivo dose response studies that analyzed the histology and microstructural changes in the spleen of adult male and female CD-1 mice exposed to 4 to 40,000 μg/kg/day BPA or 0.02 to 2 μg/kg/day EE from conception until 12-14 weeks of age. Results of that analysis indicate that both BPA and EE have dose- and sex-specific impacts on the cellular and microanatomical structures of the spleens that reveal minor alterations in immunomodulatory and hematopoietic functions. These findings support previous studies demonstrating the murine immune system as a sensitive target for estrogens, and that oral exposures to BPA and EE can have estrogen-like immunomodulatory affects in both sexes.


Factor analysis for gene regulatory networks and transcription factor activity profiles.
Most existing algorithms for the inference of the structure of gene regulatory networks from gene expression data assume that the activity levels of transcription factors (TFs) are proportional to their mRNA levels. This assumption is invalid for most biological systems. However, one might be able to reconstruct unobserved activity profiles of TFs from the expression profiles of target genes. A simple model is a two-layer network with unobserved TF variables in the first layer and observed gene expression variables in the second layer. TFs are connected to regulated genes by weighted edges. The weights, known as factor loadings, indicate the strength and direction of regulation. Of particular interest are methods that produce sparse networks, networks with few edges, since it is known that most genes are regulated by only a small number of TFs, and most TFs regulate only a small number of genes. In this paper, we explore the performance of five factor analysis algorithms, Bayesian as well as classical, on problems with biological context using both simulated and real data. Factor analysis (FA) models are used in order to describe a larger number of observed variables by a smaller number of unobserved variables, the factors, whereby all correlation between observed variables is explained by common factors. Bayesian FA methods allow one to infer sparse networks by enforcing sparsity through priors. In contrast, in the classical FA, matrix rotation methods are used to enforce sparsity and thus to increase the interpretability of the inferred factor loadings matrix. However, we also show that Bayesian FA models that do not impose sparsity through the priors can still be used for the reconstruction of a gene regulatory network if applied in conjunction with matrix rotation methods. Finally, we show the added advantage of merging the information derived from all algorithms in order to obtain a combined result. Most of the algorithms tested are successful in reconstructing the connectivity structure as well as the TF profiles. Moreover, we demonstrate that if the underlying network is sparse it is still possible to reconstruct hidden activity profiles of TFs to some degree without prior connectivity information.


Treatment and prevention of secondary CNS lymphoma.
Central nervous system (CNS) involvement in non-Hodgkin lymphoma is a serious, potentially preventable complication that can occur in 5 to 10% of patients. Its occurrence is directly correlated with pathologic aggressiveness and ranges from less than 3% in the indolent, less-aggressive histologies to as high as 50% in the very aggressive ones such as Burkitt lymphoma. Aggressive treatment once detected can improve neurologic outcome, but because it is often associated with contemporaneous systemic relapse, is rarely associated with long-term survival. Preventing its occurrence, therefore, remains an important goal of initial treatment. Despite there being some suggestive evidence that the addition of systemic rituximab and several intracerebrospinal fluid chemotherapy regimens may have decreased the incidence of CNS involvement, both optimal selection of those patients who should receive prophylaxis as well as the best prophylactic regimen remain active areas of investigation.


(10E,12E,14E)-9,16-Dioxoocta-deca-10,12,14-trienoic acid.
The title octa-deca-trienoic acid derivative, C(18)H(26)O(4), was isolated from Silene maritima With. (Caryophyllaceae), the first time this natural compound has been found in the Caryophyllales order. This fatty acid has an 18-carbon backbone with three double bonds on trans (E) conformation and two carbonyl. In the crystal, molecules are linked via pairs of O-H⋯O hydrogen bonds, forming inversion dimers.


Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection.
The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.


Mechanism of dynamic visual acuity recovery with vestibular rehabilitation.
To determine why dynamic visual acuity (DVA) improves after vestibular rehabilitation in people with vestibular hypofunction. Combined descriptive and intervention study. Outpatient department in an academic medical institution. Five patients (age, 42-66 y) and 4 age-matched controls (age, 39-67 y) were studied. Patients had vestibular hypofunction (mean duration, 177+/-188 d) identified by clinical (positive head thrust test, abnormal DVA), physiologic (reduced angular vestibulo-ocular reflex [aVOR] gain during passive head thrust testing), and imaging examinations (absence of tumor in the internal auditory canals or cerebellopontine angle). Vestibular rehabilitation focused on gaze and gait stabilization (mean, 5.0+/-1.4 visits; mean, 66+/-24 d). The control group did not receive any intervention. aVOR gain (eye velocity/head velocity) during DVA testing (active head rotation) and horizontal head thrust testing (passive head rotation) to control for spontaneous recovery. For all patients, DVA improved (mean, 51%+/-25%; range, 21%-81%). aVOR gain during the active DVA test increased in each of the patients (mean range, 0.7+/-0.2 to 0.9+/-0.2 [35%]). aVOR gain during passive head thrust did not improve in 3 patients and improved only partially in the other 2. For control subjects, aVOR gain during DVA was near 1. Our data suggest that vestibular rehabilitation increases aVOR gain during active head rotation independent of peripheral aVOR gain recovery.


Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo.
Aminopeptidase N (APN/CD13), a 150-kDa metalloproteinase, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression in several human malignancies. In the current study, we investigated the role of APN/CD13 in paclitaxel (PAC)-resistance of ovarian carcinoma (OVCA) cells. We first examined the correlation between APN/CD13 expression and IC50 values of PAC in a variety of OVCA cell lines. Next we investigated whether suppression of APN/CD13 using bestatin, an inhibitor of APN/CD13 activity or the siRNA technique influenced PAC-sensitivity in ES-2 cells, which highly express APN/CD13. Moreover, we investigated the effect of bestatin on peritoneal metastasis using nude mice. We found a negative correlation between APN/CD13 expression and chemosensitivity to PAC in various carcinoma cell lines. Subsequently, we found a significant increase in PAC-sensitivity of APN/CD13 expressing OVCA cells by suppression of this enzyme, using the addition of bestatin or the siRNA technique. Furthermore, in a peritoneal metastasis model using nude mice, combination treatment with PAC and bestatin caused a synergistic increase of survival time compared with PAC alone treatment. (mean survival time: 37.7 +/- 7.0 s and 27.1 +/- 6.6 days, respectively). The present findings showed that APN/CD13 may be involved in decreased sensitivity to PAC in OVCA cells and that the mechanism of this effect involves its enzyme activity at least in part. APN/CD13 may be a therapeutic target for the treatment of OVCA in combination with chemotherapy.


Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy.
Melatonin, as a new member of an expanding group of regulatory factors that control cell proliferation and loss, is the only known chronobiotic, hormonal regulator of neoplastic cell growth. At physiological circulating concentrations, this indoleamine is cytostatic and inhibits cancer cell proliferation in vitro via specific cell cycle effects. At pharmacological concentrations, melatonin exhibits cytotoxic activity in cancer cells. At both physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status through alterations in adhesion molecules and maintenance of gap junctional intercellular communication. In other cancer cell types, melatonin, either alone or in combination with other agents, induces apoptotic cell death. Biochemical and molecular mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cytoskeletal architecture and function, intracellular redox status, melatonin receptor-mediated signal transduction cascades, and fatty acid transport and metabolism. A major mechanism mediating melatonin's circadian stage-dependent tumor growth inhibitory action is the suppression of epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activity. This occurs via melatonin receptor-mediated blockade of tumor linoleic acid uptake and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE) which normally activates EGFR/MAPK mitogenic signaling. This represents a potentially unifying model for the chronobiological inhibitory regulation of cancer growth by melatonin in the maintenance of the host/cancer balance. It also provides the first biological explanation of melatonin-induced enhancement of the efficacy and reduced toxicity of chemo- and radiotherapy in cancer patients.


Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations.
Human immunodeficiency virus type 1 (HIV-1) infection is highly dependent on its capsid. The capsid is a large container, made of ∼1,300 proteins with altogether 4 million atoms. Although the capsid proteins are all identical, they nevertheless arrange themselves into a largely asymmetric structure made of hexamers and pentamers. The large number of degrees of freedom and lack of symmetry pose a challenge to studying the chemical details of the HIV capsid. Simulations of over 64 million atoms for over 1 μs allow us to conduct a comprehensive study of the chemical-physical properties of an empty HIV-1 capsid, including its electrostatics, vibrational and acoustic properties, and the effects of solvent (ions and water) on the capsid. The simulations reveal critical details about the capsid with implications to biological function.


Differential properties of cells in the feline primary visual cortex providing the corticofugal feedback to the lateral geniculate nucleus and visual claustrum.
We have examined the responses of 141 layer VI cells in the feline visual cortex. Within this group we compared the responses of a subpopulation of cells checked for connectivity by electrical stimulation in the dLGN and the visual claustrum. The antidromically identified corticogeniculate projecting cells had relatively short receptive fields, as judged from length response curves, measured quantitatively, and were located at the "short" end of the receptive field length spectrum seen in the general population. Of the 17 corticogeniculate projecting cells, 71% were S type cells, which were typically monocular and directionally selective, with relatively long latencies following electrical stimulation. The remaining 29% were C type cells, also directionally selective, but with a wider spread of ocular dominance preferences and shorter latencies following electrical stimulation. S and C type subpopulations did not differ in their receptive field lengths. The mean receptive field length for this subpopulation was 2.2 degrees +/- 0.27, the shortest field being 1 degrees and the longest 5 degrees. The five layer VI cells activated by electrical stimulation from electrodes within the dorsocaudal (visual) claustrum all had much longer receptive field lengths than the corticogeniculate population, often 10 degrees or longer and were monocular and directionally selective S type cells. These data indicate that the information carried in the corticogeniculate stream (and that from layer VI directly to layer IV carried by axon collaterals) is relatively tightly focused in spatial terms whilst the less spatially focused, long receptive field output from layer VI projects to the claustrum.


The basal ganglia optimize decision making over general perceptual hypotheses.
The basal ganglia are a subcortical group of interconnected nuclei involved in mediating action selection within cortex. A recent proposal is that this selection leads to optimal decision making over multiple alternatives because the basal ganglia anatomy maps onto a network implementation of an optimal statistical method for hypothesis testing, assuming that cortical activity encodes evidence for constrained gaussian-distributed alternatives. This letter demonstrates that this model of the basal ganglia extends naturally to encompass general Bayesian sequential analysis over arbitrary probability distributions, which raises the proposal to a practically realizable theory over generic perceptual hypotheses. We also show that the evidence in this model can represent either log likelihoods, log-likelihood ratios, or log odds, all leading proposals for the cortical processing of sensory data. For these reasons, we claim that the basal ganglia optimize decision making over general perceptual hypotheses represented in cortex. The relation of this theory to cortical encoding, cortico-basal ganglia anatomy, and reinforcement learning is discussed.


Novel phenanthridinone inhibitors of poly (adenosine 5'-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents.
To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5'-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. Randomized, prospective laboratory study. Research laboratory. Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-alpha, interleukin-1beta, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.


Differential effects of fenofibrate versus atorvastatin on the concentrations of E-selectin and vascular cellular adhesion molecule-1 in patients with type 2 diabetes mellitus and mixed hyperlipoproteinemia: a randomized cross-over trial.
Diabetic dyslipoproteinemia is characterized by hypertriglyceridemia, low HDL-cholesterol and often elevated LDL-cholesterol and is a strong risk factor for atherosclerosis. Adhesion molecule levels are elevated both in hyperlipoproteinemia and diabetes mellitus. It is unclear whether fibrate or statin therapy has more beneficial effects on adhesion molecule concentrations. Atorvastatin (10 mg/d) was compared to fenofibrate (200 mg/d) each for 6 weeks separated by a 6 week washout period in 11 patients (6 male, 5 female; 61.8 +/- 8.2 years; body mass index 29.8 +/- 3.1 kg/m2) with type 2 diabetes mellitus (HbA1c 7.3 +/- 1.1%) and mixed hyperlipoproteinemia using a randomized, cross-over design. Fasting blood glucose, HbA1c, lipid parameters, E-selectin, ICAM-1, VCAM-1, and fibrinogen concentrations were determined before and after each drug. Glucose and HbA1c concentrations remained unchanged during the whole study period. LDL cholesterol was reduced during atorvastatin therapy, triglycerides were lowered more effectively with fenofibrate. Comparison of pre- and postreatment concentrations of E-selectin showed a reduction during atorvastatin (-7%, p = 0.11) and fenofibrate (-10%, p < 0.05) therapy. Atorvastatin treatment reduced VCAM-1 levels by 4% (p < 0.05), while VCAM-1 concentrations remained unchanged (+1%, ns) during fenofibate therapy. However, direct comparisons of post-treatment levels during both forms of therapy were not of statistical significance. ICAM-1 levels were not influenced by either form of therapy. In addition to the different beneficial effects on lipid metabolism, both drugs appear to lower adhesion molecule plasma concentrations in a different manner in patients with type 2 diabetes and mixed hyperlipoproteinemia. Our observations should be confirmed in a larger cohort of such patients.


Rupatadine relieves allergic rhinitis: a prospective observational study.
Allergic rhinitis has reached epidemic levels for years in Belgium and substantially impacts the quality of life of patients. Observational, non-interventional studies can provide valuable data, supplementing findings from double-blind trials, on the true value of a drug therapy in daily practice. Rupatadine is a new, second-generation, selective oral H1-antihistamine. The primary objective of.this study was to evaluate the evolution of quality of life in patients treated with rupatadine in clinical practice. The impact of rupatadine on the severity of allergic rhinitis symptoms, the subject's evaluation of the treatment, and the safety of rupatadine were also evaluated. This prospective, non-interventional, observational, multicenter study included 2,838 adults aged over 18 years. The diagnosis of moderate to severe allergic rhinitis was confirmed. Patients were assessed with validated scales at baseline and after 6 weeks of treatment with rupatadine (10 mg, once daily). All outcome parameters improved significantly: mini-rhinoconjunctivitis quality of life questionnaire (mini- RQLQ, p < 0.001), total 5-symptom score (T5SS) severity (p < 0.001), visual analog scale (VAS) of symptom severity (p < 0.001), and the allergic rhinitis and its impact on asthma (ARIA) severity classification (p < 0.001). Compliance was very good in 72.2% of patients, and only a few minor adverse effects were reported. The therapeutic responses, evaluated by the patients, were complete relief in 21% and strong relief in 62%. This study, which included a wide cohort of allergic-rhinitis patients, confirmed the clinical benefit of rupatadine when prescribed in clinical practice, even for the most severe symptoms, including nasal congestion.


Growth and the regulation of myotomal muscle mass in teleost fish.
Teleost muscle first arises in early embryonic life and its development is driven by molecules present in the egg yolk and modulated by environmental stimuli including temperature and oxygen. Several populations of myogenic precursor cells reside in the embryonic somite and external cell layer and contribute to muscle fibres in embryo, larval, juvenile and adult stages. Many signalling proteins and transcription factors essential for these events are known. In all cases, myogenesis involves myoblast proliferation, migration, fusion and terminal differentiation. Maturation of the embryonic muscle is associated with motor innervation and the development of a scaffold of connective tissue and complex myotomal architecture needed to generate swimming behaviour. Adult muscle is a heterogeneous tissue composed of several cell types that interact to affect growth patterns. The development of capillary and lymphatic circulations and extramuscular organs--notably the gastrointestinal, endocrine, neuroendocrine and immune systems--serves to increase information exchange between tissues and with the external environment, adding to the complexity of growth regulation. Teleosts often exhibit an indeterminate growth pattern, with body size and muscle mass increasing until mortality or senescence occurs. The dramatic increase in myotomal muscle mass between embryo and adult requires the continuous production of muscle fibres until 40-50% of the maximum body length is reached. Sarcomeric proteins can be mobilised as a source of amino acids for energy metabolism by other tissues and for gonad generation, requiring the dynamic regulation of muscle mass throughout the life cycle. The metabolic and contractile phenotypes of muscle fibres also show significant plasticity with respect to environmental conditions, migration and spawning. Many genes regulating muscle growth are found as multiple copies as a result of paralogue retention following whole-genome duplication events in teleost lineages. The extent to which indeterminate growth, ectothermy and paralogue preservation have resulted in modifications of the genetic pathways regulating muscle growth in teleosts compared to mammals largely remains unknown. This review describes the use of compensatory growth models, transgenesis and tissue culture to explore the mechanisms of muscle growth in teleosts and provides some perspectives on future research directions.


Lessons from a trial of acupuncture and massage for low back pain: patient expectations and treatment effects.
A subanalysis of data derived from a randomized clinical trial was performed. To evaluate the association of a patient's expectation for benefit from a specific treatment with improved functional outcome. Psychosocial factors, ambiguous diagnoses, and lack of a clearly superior treatment have complicated the management of patients with chronic low back pain. The authors hypothesized that patient expectation for benefit from a specific treatment is associated with improved functional outcomes when that treatment is administered. In a randomized trial, 135 patients with chronic low back pain who received acupuncture or massage were studied. Before randomization, study participants were asked to describe their expectations regarding the helpfulness of each treatment on a scale of 0 to 10. The primary outcome was level of function at 10 weeks as measured by the modified Roland Disability scale. After adjustment for baseline characteristics, improved function was observed for 86% of the participants with higher expectations for the treatment they received, as compared with 68% of those with lower expectations (P = 0.01). Furthermore, patients who expected greater benefit from massage than from acupuncture were more likely to experience better outcomes with massage than with acupuncture, and vice versa (P = 0.03). The results of this study suggest that patient expectations may influence clinical outcome independently of the treatment itself. In contrast, general optimism about treatment, divorced from a specific treatment, is not strongly associated with outcome. These results may have important implications for clinical trial design and recruitment, and may help to explain the apparent success of some conventional and alternative therapies in trials that do not control for patient expectations. The findings also may be important for therapy choices made in the clinical setting.


Characterization of plasmid-borne afa-3 gene clusters encoding afimbrial adhesins expressed by Escherichia coli strains associated with intestinal or urinary tract infections.
The afa gene clusters encode afimbrial adhesins (AFA) that are expressed by uropathogenic and diarrhea-associated Escherichia coli strains and belong to a family of hemagglutinins recognizing the Dr blood group antigen as a receptor. This family so far includes AFA-I and AFA-III as well as the Dr and F1845 adhesins (B. Nowicki, A. Labigne, S. Moseley, R. Hull, S. Hull, and J. Moulds, Infect. Immun. 58:279-281, 1990). Reported in this work is the genetic organization of the afa-3 gene cluster cloned from a uropathogenic E. coli strain (A30) which expressed a subtype of AFA designated AFA-III. The amino acid sequence of AFA-III was deduced from the nucleotide sequence of the afaE3 gene and was found to be highly homologous to that of the Dr adhesin (98.1% identity). A polymerase chain reaction assay was developed to detect the presence of afa-3 gene clusters in E. coli strains. Study of the genetic support of the afa-3 gene clusters in the strains which showed positive amplification revealed that they were always located on large, 100-kb plasmids whether the strains originated from patients with cystitis or with diarrhea. Moreover, the cloned afa-3 gene clusters from A30 and from the diarrhea-associated strain AL845 appeared to be carried by 9-kb plasmid regions which displayed a similar genetic organization. Chloramphenicol was reported to be a potent inhibitor of receptor binding by the Dr adhesin (Nowicki et al., Infect. Immun. 58:279-281, 1990). AFA-III expressed by strains AL845 and AL847 appeared to mediate, like the Dr adhesin, chloramphenicol-sensitive hemagglutination, whereas AFA-III produced by A30 conferred chloramphenicol-resistant adherence. A comparison of the sequences of these four proteins indicated that the amino acid at position 52 of the processed AFA could be part of the receptor-binding domain.


Utilizing Forced Vital Capacity to Predict Low Lung Compliance and Select Intraoperative Tidal Volume During Thoracic Surgery.
Tidal volume selection during mechanical ventilation utilizes dogmatic formulas that only consider a patient's predicted body weight (PBW). In this study, we investigate whether forced vital capacity (FVC) (1) correlates better to total lung capacity (TLC) than PBW, (2) predicts low pulmonary compliance, and (3) provides an alternative method for tidal volume selection. One hundred thirty thoracic surgery patients had their preoperative TLC calculated via 2 methods: (1) pulmonary function test (PFT; TLCPFT) and (2) computed tomography 3D reconstruction (TLCCT). We compared the correlation between TLC and PBW with the correlation between TLC and FVC to determine which was stronger. Dynamic pulmonary compliance was then calculated from intraoperative ventilator data and logistic regression models constructed to determine which clinical measure best predicted low compliance. Ratios of tidal volume/FVC plotted against peak inspiratory pressure were utilized to construct a new model for tidal volume selection. Calculated tidal volumes generated by this model were then compared with those generated by the standard lung-protective formula Vt = 7 cc/kg. The correlation between FVC and TLC (0.82 for TLCPFT and 0.76 for TLCCT) was stronger than the correlation between PBW and TLC (0.65 for TLCPFT and 0.58 for TLCCT). Patients with very low compliance had significantly smaller lung volumes (forced expiratory volume at 1 second, FVC, TLC) and lower diffusion capacity of the lungs for carbon monoxide when compared with patients with normal compliance. An FVC cutoff of 3470 cc was 100% sensitive and 51% specific for predicting low compliance. The proposed equation Vt = FVC/8 significantly reduced calculated tidal volume by a mean of 22.5% in patients with low pulmonary compliance without affecting the mean tidal volume in patients with normal compliance (mean difference 0.9%). FVC is more strongly correlated to TLC than PBW and a cutoff of about 3.5 L can be utilized to predict low pulmonary compliance. The equation Vt = FVC/8 reduced mean calculated tidal volume in patients with low pulmonary compliance and/or small lungs.


Precious metal recovery from electronic waste by a porous porphyrin polymer.
Urban mining of precious metals from electronic waste, such as printed circuit boards (PCB), is not yet feasible because of the lengthy isolation process, health risks, and environmental impact. Although porous polymers are particularly effective toward the capture of metal contaminants, those with porphyrin linkers have not yet been considered for precious metal recovery, despite their potential. Here, we report a porous porphyrin polymer that captures precious metals quantitatively from PCB leachate even in the presence of 63 elements from the Periodic Table. The nanoporous polymer is synthesized in two steps from widely available monomers without the need for costly catalysts and can be scaled up without loss of activity. Through a reductive capture mechanism, gold is recovered with 10 times the theoretical limit, reaching a record 1.62 g/g. With 99% uptake taking place in the first 30 min, the metal adsorbed to the porous polymer can be desorbed rapidly and reused for repetitive batches. Density functional theory (DFT) calculations indicate that energetically favorable multinuclear-Au binding enhances adsorption as clusters, leading to rapid capture, while Pt capture remains predominantly at single porphyrin sites.


The Eftekhar and Kerboul classifications in assessment of developmental dysplasia of the hip in adult patients. Measurement of inter- and intraobserver reliability.
To measure the inter- and intraobserver reliability of two radiologic classification systems in the evaluation of severity of osteoarthritis secondary to developmental dysplasia of the hip in adult patients and to compare these systems to historically published data on two more commonly used classification systems described by Crowe and by Hartofikakidis. Eighty-six dysplastic hips on 66 anteroposterior standard pelvic x-rays were rated according to the criteria of Eftekhar and Kerboul by three observers with different levels of clinical training. To assess intraobserver reliability, the measurement was repeated 3 months later. Statistical analysis was performed by calculating the weighted kappa correlation coefficient and the overall kappa coefficient. Both classification systems showed a sufficient interobsever reliability, reaching a kappa coefficient of 0.73 for the system according to Eftekhar and 0.716 for the Kerboul classification system. Intraobserver reliability revealed a kappa coefficient of 0.778 for the Eftekhar system and 0.697 for the classification according to Kerboul. Both systems showed good inter- and intraobserver reliability for use in daily practice. However, they did not reach the known reliability of the grading systems published by Crowe and by Hartofikakidis. Because these systems are more frequently used, we would recommend one of them to grade the severity of osteoarthritis secondary to developmental dysplasia of the hip in adult patients instead of the ones described by Eftekhar or by Kerboul.


Microglial cells in astroglial cultures: a cautionary note.
Primary rodent astroglial-enriched cultures are the most popular model to study astroglial biology in vitro. From the original methods described in the 1970's a great number of minor modifications have been incorporated into these protocols by different laboratories. These protocols result in cultures in which the astrocyte is the predominant cell type, but astrocytes are never 100% of cells in these preparations. The aim of this review is to bring attention to the presence of microglia in astroglial cultures because, in my opinion, the proportion of and the role that microglial cells play in astroglial cultures are often underestimated. The main problem with ignoring microglia in these cultures is that relatively minor amounts of microglia can be responsible for effects observed on cultures in which the astrocyte is the most abundant cell type. If the relative contributions of astrocytes and microglia are not properly assessed an observed effect can be erroneously attributed to the astrocytes. In order to illustrate this point the case of NO production in activated astroglial-enriched cultures is examined. Lipopolysaccharide (LPS) induces nitric oxide (NO) production in astroglial-enriched cultures and this effect is very often attributed to astrocytes. However, a careful review of the published data suggests that LPS-induced NO production in rodent astroglial-enriched cultures is likely to be mainly microglial in origin. This review considers cell culture protocol factors that can affect the proportion of microglial cells in astroglial cultures, strategies to minimize the proportion of microglia in these cultures, and specific markers that allow the determination of such microglial proportions.


[Autopsy case of sarcomatoid malignant pleural mesothelioma].
A 61-year-old man with a sensation of chest compression was admitted to our hospital. He had hemothorax. After drainage with a chest tube, chest CT scan revealed multiple bilateral pulmonary nodules with slight pleural thickening. Open pleural biopsy was performed and the biopsy specimens showed tumor cells with sarcomatoid proliferation, but no definite epithelial pattern. Initial immunohistochemical staining was negative for keratin and carletinin, but positive for desmin, suggesting rhabdomyosarcoma. After supportive care, he died due to progression of the disease. Autopsy revealed extensive invasion suggesting mesothelioma, so the immunohistochemical staining was repeated. Because it revealed patchy staining for keratin and carletinin, this case was diagnosed as sarcomatoid mesothelioma. Differential diagnosis of sarcomatoid mesothelioma or rhabdomyosarcoma is made by immunohistochemical staining, but it is sometimes difficult. For the selection of the best treatment strategy for mesothelioma especially in the early stage, we should be aware of this difficulty.


Mucosal-incision assisted biopsy for suspected gastric gastrointestinal stromal tumors.
To evaluate the diagnostic yield of the procedure, mucosal-incision assisted biopsy (MIAB), for the histological diagnosis of gastric gastrointestinal stromal tumor (GIST), we performed a retrospective review of the 27 patients with suspected gastric GIST who underwent MIAB in our hospitals. Tissue samples obtained by MIAB were sufficient to make a histological diagnosis (diagnostic MIAB) in 23 out of the 27 patients, where the lesions had intraluminal growth patterns. Alternatively, the samples were insufficient (non-diagnostic MIAB) in remaining 4 patients, three of whom had gastric submucosal tumor with extraluminal growth patterns. Although endoscopic ultrasound and fine needle aspiration is the gold standard for obtaining tissue specimens for histological and cytological analysis of suspected gastric GISTs, MIAB can be used as an alternative method for obtaining biopsy specimens of lesions with an intraluminal growth pattern.


Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity.
Transcription factor (TF) networks are a key determinant of cell fate decisions in mammalian development and adult tissue homeostasis and are frequently corrupted in disease. However, our inability to experimentally resolve and interrogate the complexity of mammalian TF networks has hampered the progress in this field. Recent technological advances, in particular large-scale genome-wide approaches, single-cell methodologies, live-cell imaging, and genome editing, are emerging as important technologies in TF network biology. Several recent studies even suggest a need to re-evaluate established models of mammalian TF networks. Here, we provide a brief overview of current and emerging methods to define mammalian TF networks. We also discuss how these emerging technologies facilitate new ways to interrogate complex TF networks, consider the current open questions in the field, and comment on potential future directions and biomedical applications.


BclxL changes conformation upon binding to wild-type but not mutant p53 DNA binding domain.
p53 can induce apoptosis through mitochondrial membrane permeabilization by interaction of its DNA binding region with the anti-apoptotic proteins BclxL and Bcl2. However, little is known about the action of p53 at the mitochondria in molecular detail. By using NMR spectroscopy and fluorescence polarization we characterized the binding of wild-type and mutant p53 DNA binding domains to BclxL and show that the wild-type p53 DNA binding domain leads to structural changes in the BH3 binding region of BclxL, whereas mutants fail to induce such effects due to reduced affinity. This was probed by induced chemical shift and residual dipolar coupling data. These data imply that p53 partly achieves its pro-apoptotic function at the mitochondria by facilitating interaction between BclxL and BH3-only proteins in an allosteric mode of action. Furthermore, we characterize for the first time the binding behavior of Pifithrin-mu, a specific small molecule inhibitor of the p53-BclxL interaction, and present a structural model of the protein-ligand complex. A rather unusual behavior is revealed whereby Pifithrin-mu binds to both sides of the protein-protein complex. These data should facilitate the rational design of more potent specific BclxL-p53 inhibitors.


Impact and outcomes of nutritional support team intervention in patients with gastrointestinal disease in the intensive care unit.
Nutritional support has become an important intervention for critically ill patients. Many studies have reported on the effects of nutritional support for the patients within the intensive care unit (ICU); however, no studies have specifically assessed patients with gastrointestinal diseases who may have difficulty absorbing enteral nutrition (EN) in the ICU.Sixty-two patients with gastrointestinal disease were admitted to the ICU between August 2014 and August 2016 at a single tertiary university hospital. We analyzed 2 different patient groups in a retrospective cohort study: those who received nutritional support team (NST) intervention and those who did not.Forty-four (71.0%) patients received nutritional support in ICU and 18 (29.0%) did not. Variables including male sex, high albumin or prealbumin level at the time of ICU admission, and short transition period into EN showed statistically significant association with lower mortality on the univariate analysis (all P < .05). Multivariate analysis revealed that longer length of hospital stay (P = .013; hazard ratio [HR], 0.972; 95% confidence interval [CI], 0.951-0.994), shorter transition into EN (P = .014; HR, 1.040; 95% CI, 1.008-1.072), higher prealbumin level (P = .049; HR, 0.988; 95% CI, 0.976-1.000), and NST intervention (P = .022; HR, 0.356; 95% CI, 0.147-0.862) were independent prognostic factors for lower mortality.In conclusion, NST intervention related to early initiated EN, and high prealbumin levels are beneficial to decrease mortality in the acutely ill patients with GI disease.


Unusual relatives of the multisubunit RNA polymerase.
Transcription, the first step of gene expression, is accomplished in all domains of life by the multisubunit RNA polymerase (msRNAP). Accordingly, the msRNAP is an ancient enzyme that is ubiquitous across all cellular organisms. Conserved in absolutely all msRNAPs is the catalytic magnesium-binding aspartate triad and the structural fold it is present on, the double ψ β barrel (DPBB). In-depth bioinformatics has begun to reveal a wealth of unusual proteins distantly related to msRNAP, identified due to their possession of the aspartate triad and DPBB folds. Three examples of these novel RNAPs are YonO of the Bacillus subtilis SPβ prophage, non-virion RNAP (nvRNAP) of the B. subtilis AR9 bacteriophage and ORF6 RNAP of the Kluyveromyces lactis cytoplasmic killer system. While YonO and AR9 nvRNAP are both bacteriophage enzymes, they drastically contrast. YonO is an incredibly minimal single-subunit RNAP, while AR9 nvRNAP is multisubunit bearing much more resemblance to the canonical msRNAP. ORF6 RNAP is an intermediate, given it is a single-subunit enzyme with substantial conservation with the msRNAP. Recent findings have begun to shed light on these polymerases, which have the potential to update our understanding of the mechanisms used for transcription and give new insights into the canonical msRNAP and its evolution. This mini-review serves to introduce and outline our current understanding of these three examples of novel, unusual RNAPs.


Anti-tumor necrosis factor and postoperative complications in Crohn's disease: systematic review and meta-analysis.
Anti-tumor necrosis factor (TNF) antibodies are efficacious in patients with Crohn's disease (CD) but the influence of these medications on surgical outcomes in CD patients has been frequently debated. The aim was to evaluate the impact of preoperative treatment with anti-TNF antibodies on postoperative complications in CD patients undergoing abdominal surgery. A systematic review and meta-analysis of comparative cohort studies was performed assessing postoperative complication rates in CD patients who were treated with anti-TNF antibodies within 3 months before surgery versus patients who were not. The primary outcome was overall complication rate within 1 month of surgery. Secondary outcomes included the rate of infectious and noninfectious complications. The quality of studies was assessed based on selection of patients and controls, comparability of the study groups, and assessment of outcomes. Odds ratios (OR) with 95% confidence intervals (CIs) were computed. A total of eight studies including 1641 patients were included in our meta-analysis. Preoperative infliximab therapy in CD patients undergoing abdominal surgery was associated with a trend toward an increased rate of total complications (OR 1.72, 95% CI, 0.93-3.19). Anti-TNF treatments were associated with a modestly increased risk of infectious complications (OR 1.50, 95% CI 1.08-2.08), mostly remote from the surgical site (OR 2.07 95% CI 1.30-3.30) and with a trend toward a higher rate of noninfectious complications (OR 2.00, 95% CI 0.89-4.46). Preoperative infliximab treatment is associated with an increased risk of postoperative infectious complications, mostly nonlocal. A trend toward an increased risk of noninfectious and overall complications was also observed.


Theoretical Framework of 1,3-Thiazolium-5-Thiolates Mesoionic Compounds: Exploring the Nature of Photophysical Property and Molecular Nonlinearity.
Inspired by a previous experimental study on the first-order hyperpolarizabilities of 1,3-thiazolium-5-thiolates mesoionic compounds using the hyper-Rayleigh scattering technique, we theoretically investigated the UV-vis absorption spectra and every-order polarizabilities of these mesoionic molecules. Based on the fact that the photophysical and nonlinear properties observed in the experiment can be perfectly replicated, our theoretical calculations explored the essential characteristics of the optical properties of the mesoionic compounds with different electron-donating groups at the level of electronic structures through various wave function analysis methods. The influence of the electron-donating ability of the donor on the optical properties of the molecules and the contribution of the mesoionic ring moiety to their optical nonlinearity are clarified, which have not been reported by any research so far. This work will help people understand the nature of optical properties of mesoionic-based molecules and provide guidance for the rational design of molecules with excellent photoelectric performance in the future.


Topical therapies for glaucoma: what family physicians need to know.
Medication classes historically used in the management of glaucoma include beta blockers, miotics, sympathomimetics and carbonic anhydrase inhibitors. Because topically applied medications are more site specific, they are preferred in the treatment of glaucoma. Compared with oral medications, topical agents are associated with a decreased incidence of systemic side effects. With topical administration, conjunctival and localized skin allergic reactions are relatively common, whereas severe reactions, including death, are rare. Recently introduced topical agents for glaucoma therapy include dorzolamide and brinzolamide, the first topical carbonic anhydrase inhibitors; brimonidine and apraclonidine, more ocular-specific alpha agonists; and latanoprost, a prostaglandin analog, which is a new class of glaucoma medication. Latanoprost has the unique side effect of increasing iris pigmentation. Like their predecessors, the newer agents lower intraocular pressure by a statistically significant degree. Preservation of visual field, the more substantial patient-oriented end point, continues to be studied.


Subcutaneous Adipose Tissue Type II Deiodinase Gene Expression Reduced in Obese Individuals with Metabolic Syndrome.
The present study aimed to evaluate the role of subcutaneous adipose tissue (SAT) type II deiodinase enzyme gene (DIO2) expression in developing metabolic syndrome (MetS). A total of 51 obese patients with MetS and without MetS and 13 healthy subjects enrolled in the study. Body mass index (BMI), waist circumference (WC), waist-to-hip circumference ratio (WHR), hip circumference, and systolic (SBP) and diastolic blood pressures (DBP) of all subjects were recorded. Fasting plasma glucose (FPG), fasting plasma insulin, high density lipoprotein- cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC) and triglyceride (TG) of all subjects were analyzed. Expression of the DIO2 gene in adipose tissue was determined by reverse transcription polymerase chain reaction (qRT-PCR). BMI, WC and WHR were not significantly difference between obese with and without MetS. SBP, DBP, FPG and TG were significantly higher in obese with MetS group than obese without MetS group. While the free triiodothyronine (T3) level was in the normal range in all group, it was significantly lower in the obese with MetS than both obese without MetS and control group. DIO2 expression was significantly lower in the obese with MetS group compared to the control. In correlation analysis, DIO2 expression was negatively correlated with DBP, TG and homeostasis model assessment of insulin resistance (HOMA-IR) levels and positively correlated with free T3. In conclusion, the reduction of SAT DIO2 expression is negatively correlated with DBP and TG levels that are associated with the MetS. This might have an effect on developing MetS. We believe that DIO2 gene may be an important molecular target for future studies in developing targeted treatment options for obese people with MetS.


Studying nanoparticles' 3D shape by aspect maps: Determination of the morphology of bacterial magnetic nanoparticles.
Magnetic nanoparticles (MNPs) are widely investigated due to their potential use in various applications, ranging from electronics to biomedical devices. The magnetic properties of MNPs are strongly dependent on their size and shape (i.e., morphology), thus appropriate tools to investigate their morphology are fundamental to understand the physics of these systems. Recently a new approach to study nanoparticle morphology by Transmission Electron Microscopy (TEM) analysis has been proposed, introducing the so-called Aspect Maps (AMs). In this paper, a further evolution of the AM method is presented, allowing determination of the nanoparticles' 3D shape by TEM image. As a case study, this paper will focus on magnetite nanoparticles (Fe3O4), with a mean size of ∼45 nm extracted from Magnetospirillum gryphiswaldense magnetostatic bacteria (MTB). The proposed approach gives a complete description of the nanoparticles' morphology, allowing estimation of an average geometrical size and shape. In addition, preliminary investigation of the magnetic properties of MTB nanoparticles was performed, giving some insight into interparticle interactions and on the reversal mechanism of the magnetization.


Detection of hypermethylated vimentin in urine of patients with colorectal cancer.
We demonstrated previously that urine contains low-molecular-weight (LMW) (<300 bp), circulation-derived DNA that can be used to detect cancer-specific mutations if a tumor is present. The goal of this study was to develop an assay to detect the colorectal cancer (CRC)-associated, circulation-derived, epigenetic DNA marker hypermethylated vimentin gene (mVIM) in the urine of patients with CRC. An artificial 18-nucleotide DNA sequence was tagged at the 5' end of the primers of the first PCR cycle to increase the amplicon size, which was then integrated into the primers of the second PCR cycle. A quantitative MethyLight PCR-based assay targeting a 39-nucleotide template was developed and used to quantify mVIM in CRC tissues and matched urine samples. mVIM was detected in 75% of LMW urine DNA samples from patients with CRC (n = 20) and in 10% of urine samples of control subjects with no known neoplasia (n = 20); 12 of 17 LMW urine DNA samples (71%) but only 2 of 17 high-molecular-weight urine DNA samples (12%) from patients with mVIM-positive tissues contained detectable mVIM, suggesting that the mVIM detected in LMW urine DNA is derived from the circulation. The detection of mVIM in urine was significantly associated with CRC compared with controls (P < 0.0001, by Fisher's exact test). A potential urine test for CRC screening using epigenetic markers is discussed.


Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass - prediction of viscosity through protein-protein interaction measurements.
The purpose of this work was to explore the relation between protein-protein interactions (PPIs) and solution viscosity at high protein concentration using three monoclonal antibodies (mAbs), two of the IgG4 subclass and one of the IgG1 subclass. A range of methods was used to quantify the PPI either at low concentration (interaction parameter (kD) obtained from dynamic light scattering, DLS) or at high concentration (solution storage modulus (G') from ultrasonic shear rheology). We also developed a novel method for the determination of PPI using the apparent radius of the protein at either low or high protein concentration determined using DLS. The PPI measurements were correlated with solution viscosity (measured by DLS using polystyrene nanospheres and ultrasonic shear rheology) as a function of pH (4-9) and ionic strength (10, 50 and 150 mM). Our measurements showed that the highest solution viscosity was observed under conditions with the most negative kD, the highest apparent radius and the lowest net charge. An increase in ionic strength resulted in a change in the nature of the PPI at low pH from repulsive to attractive. In the neutral to alkaline pH region the mAbs behaved differently with respect to increase in ionic strength. Two mAbs (A and B) showed little or no effect of increasing ionic strength, whereas mAb-C showed a remarkable decrease in attractive PPI and viscosity. Previous studies have mainly investigated mAbs of the IgG₁ and IgG₂ subclass. We show here, for the first time, that mAbs of the IgG₄ subclass behave similar as the other subclasses. By comparison of the three tested mAbs with mAbs investigated in other studies a clear linear trend emerges between the pH of strongest attractive PPI and highest solution viscosity. The determination of PPI using either kD or apparent radius is thus a useful prediction tool in the determination of solution conditions that favors low solution viscosity at high protein concentration of therapeutically used mAb molecules. The novel methodology using apparent radius is a simple and rapid alternative to determine relative PPI directly under formulation conditions. The method can potentially serve as a high-throughput screening tool in formulation development.


Fibrin induction of interleukin-8 expression in corneal endothelial cells in vitro.
Classically, acute and chronic inflammations are characterized by fibrin deposition and a dynamic influx of leukocytes. This leukocyte recruitment, and associated activation, is thought to be dependent on the generation of leukocyte chemotactic factors (LCF). Although the functional existence of LCF in ocular tissue has been demonstrated, the identity, source(s), and mechanisms of induction of these LCF are unclear. The authors investigate the hypothesis that in vitro corneal endothelial cells produce LCF in response to fibrin-induced activation. They further hypothesize that in vivo this fibrin-induced expression of LCF contributes to the leukocyte accumulation associated with ocular injury. Bovine corneal endothelial cells (BCEC) were co-cultured for 3 to 72 hours with physiologic concentrations of highly purified fibrin (0.125 to 2.0 mg/ml) polymerized in situ. At harvest, the conditioned medium was separated from the fibrin matrix by centrifugation and characterized for the presence and nature of polymorphonuclear leukocyte chemotactic activity. This fibrin-induced LCF was compared to known LCF, such as interleukin-8 (IL-8), using standard physical, chemical, and immunologic parameters. Conditioned medium from fibrin-treated BCEC exhibited a dose- and time-dependent induction of LCF activity, as verified by checkerboard analysis. This LCF activity was not immunoprecipitated by a polyclonal antibody to bovine fibrinogen, and it was heat stable (60 degrees C, 90 minutes) and protease labile. Isoelectric focusing and gel filtration analysis revealed a major peak of chemotactic activity at pH 8.5 to 9.0 and a molecular weight of 10 kd, respectively. Radioimmunoassay of conditioned medium from fibrin-treated BCEC for IL-8 demonstrated an 11-fold increase in IL-8 antigen for fibrin-treated BCEC compared to control BCEC. In vitro, fibrin induces BCEC expression of LCF activity that includes IL-8. In vivo, this fibrin induction of LCF from corneal endothelial cells probably serves to control both leukocyte recruitment and activation within the anterior chamber in general and to corneal endothelium in particular. These studies provide a foundation for understanding the nature, sources, and mechanisms of the LCF generation that contributes to endocular inflammation.


DNA nanopore translocation in glutamate solutions.
Nanopore experiments have traditionally been carried out with chloride-based solutions. Here we introduce silver/silver-glutamate-based electrochemistry as an alternative, and study the viscosity, conductivity, and nanopore translocation characteristics of potassium-, sodium-, and lithium-glutamate solutions. We show that it has a linear response at typical voltages and can be used to detect DNA translocations through a nanopore. The glutamate anion also acts as a redox-capable thickening agent, with high-viscosity solutions capable of slowing down the DNA translocation process by up to 11 times, with a corresponding 7 time reduction in signal. These results demonstrate that glutamate can replace chloride as the primary anion in nanopore resistive pulse sensing.


Tolerance of sponge assemblages to temperature anomalies: resilience and proliferation of sponges following the 1997-8 El-Niño southern oscillation.
Coral reefs across the world are under threat from a range of stressors, and while there has been considerable focus on the impacts of these stressors on corals, far less is known about their effect on other reef organisms. The 1997-8 El-Niño Southern Oscillation (ENSO) had notable and severe impacts on coral reefs worldwide, but not all reef organisms were negatively impacted by this large-scale event. Here we describe how the sponge fauna at Bahia, Brazil was influenced by the 1997-8 ENSO event. Sponge assemblages from three contrasting reef habitats (reef tops, walls and shallow banks) at four sites were assessed annually from 1995 to 2011. The within-habitat sponge diversity did not vary significantly across the study period; however, there was a significant increase in density in all habitats. Multivariate analyses revealed no significant difference in sponge assemblage composition (ANOSIM) between pre- and post-ENSO years for any of the habitats, suggesting that neither the 1997-8 nor any subsequent smaller ENSO events have had any measurable impact on the reef sponge assemblage. Importantly, this is in marked contrast to the results previously reported for a suite of other taxa (including corals, echinoderms, bryozoans, and ascidians), which all suffered mass mortalities as a result of the ENSO event. Our results suggest that of all reef taxa, sponges have the potential to be resilient to large-scale thermal stress events and we hypothesize that sponges might be less affected by projected increases in sea surface temperature compared to other major groups of reef organisms.


Depressive symptoms, HIV medication adherence, and HIV clinical outcomes in Tanzania: a prospective, observational study.
Depressive symptoms have been shown to independently affect both antiretroviral therapy (ART) adherence and HIV clinical outcomes in high-income countries. We examined the prospective relationship between depressive symptoms and adherence, virologic failure, and suppressed immune function in people living with HIV/AIDS in Tanzania. Data from 403 study participants who were on stable ART and engaged in HIV clinical care were analyzed. We assessed crude and adjusted associations of depressive symptoms and ART adherence, both at baseline and at 12 months, using logistic regression. We used logistic generalized estimating equations to assess the association and 95% confidence intervals (CI) between depressive symptoms and both virologic failure and suppressed immune function. Ten percent of participants reported moderate or severe depressive symptoms at baseline and 31% of participants experienced virologic failure (>150 copies/ml) over two years. Depressive symptoms were associated with greater odds of reported medication nonadherence at both baseline (Odds Ratio [OR] per 1-unit increase = 1.18, 95% CI [1.12, 1.24]) and 12 months (OR = 1.08, 95% CI [1.03, 1.14]). By contrast, increases in depressive symptom score were inversely related to both virologic failure (OR = 0.93, 95% CI [0.87, 1.00]) and immune system suppression (OR = 0.88, 95% CI [0.79, 0.99]), though the association between depressive symptoms and clinical outcomes was less precise than for the association with nonadherence. Findings indicate a positive association between depressive symptoms and nonadherence, and also an inverse relationship between depressive symptoms and clinical outcomes, possibly due to informative loss to follow-up.


British Military freezing cold injuries: a 13-year review.
Cold injuries have been a recurrent feature of warfare for millennia and continue to present during British Military operations today. Those affecting the peripheries are divided into freezing cold injury (FCI) and non-FCI. FCI occurs when tissue fluids freeze at around -0.5°C and is commonly referred to as frostnip or frostbite. All FMED7 notes held at the Institute of Naval Medicine's Cold Weather Injury Clinic (CIC) from 2002 to 2014 were searched for the terms 'frostbite' and 'frostnip' and then analysed to identify common themes. In total 245 results were found and from these, 149 patients with a positive FCI diagnosis were identified and formed the cohort of this study. Royal Marines (RM) represented over 50% of patients and Arctic training in Norway accounted for over two thirds of the total cases. The extremities were almost always those areas which were affected by FCI. Further analysis of the RM cases showed the majority of those injured were of the most junior rank (Marine/Private or Lance Corporal). A lack of supporting climatic and activity data meant that it was difficult to draw additional conclusions from the data collected. In future, a greater emphasis should be placed on collection of climatic and additional data when FCIs are diagnosed. These data should be collated at the end of each deployment and published as was regularly done historically. It is hoped that these data could then be used as the starting point for an annual climatic study day, where issues related to FCIs could be discussed in a Tri-Service environment and lessons learned disseminated around all British Forces personnel.


Spiritual Experiences of Women with Breast Cancer in Singapore: a Qualitative Study.
Although there has been increasing emphasis on the importance of spirituality in patients with cancer, few studies have examined the spiritual experiences of an ethnically diverse sample of Asian women with breast cancer. The objective of this study was to examine the spiritual experiences of Singaporean women with breast cancer in the first year of diagnosis. A qualitative exploratory study design was used and data were gathered using individual semi-structured interviews. Purposive sampling selected the participants and data saturation sample size was reached after interviews with 28 participants. Data were analyzed using Braun and Clarke's thematic approach. The participants were aged between 28 and 64 years and included women from the three major ethnic groups. The three themes that emerged from the data included transcendental experiences, meaning and purpose, and changing perspectives. This study informs that while spiritual needs are common, Singaporean women in their first year of the breast cancer diagnosis express spirituality in culturally specific ways. The clinical implications of the study emphasize the importance of addressing women's spiritual concerns, with attention to cultural differences so as to render holistic patient-centered care.


Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease.
Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible.


Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy.
Insomnia, whether short-term or chronic, is a common condition. It has a negative impact on vulnerable patient groups, including active military personnel and veterans, patients with coexisting psychiatric and medical disorders, those in life transitions such as menopause, and elderly persons. Although cognitive behavioral therapy for insomnia (CBTI) is first-line treatment for insomnia, its high cost and a lack of trained providers has prevented widespread uptake. Now, digital CBTI (dCBTI) is emerging as a scalable option with the potential to overcome these barriers in managed care. The first part of this article reviews the epidemiology and pathophysiology of insomnia with a focus on vulnerable patient groups. The second part explores the rapidly evolving landscape of nondrug therapy for insomnia. The underlying concepts and supporting evidence for CBTI and dCBTI are presented, including their utility in vulnerable patient groups.


Viewing objects and planning actions: on the potentiation of grasping behaviours by visual objects.
How do humans interact with tools? Gibson (1979) suggested that humans perceive directly what tools afford in terms of meaningful actions. This "affordances" hypothesis implies that visual objects can potentiate motor responses even in the absence of an intention to act. Here we explore the temporal evolution of motor plans afforded by common objects. We presented objects that have a strong significance for action (pinching and grasping) and objects with no such significance. Two experimental tasks involved participants viewing objects presented on a computer screen. For the first task, they were instructed to respond rapidly to changes in background colour by using an apparatus mimicking precision and power grip responses. For the second task, they received stimulation of their primary motor cortex using transcranial magnetic stimulation (TMS) while passively viewing the objects. Muscular responses (motor evoked potentials: MEPs) were recorded from two intrinsic hand muscles (associated with either a precision or power grip). The data showed an interaction between type of response (or muscle) and type of object, with both reaction time and MEP measures implying the generation of a congruent motor plan in the period immediately after object presentation. The results provide further support for the notion that the physical properties of objects automatically activate specific motor codes, but also demonstrate that this influence is rapid and relatively short lived.


Catenarin Prevents Type 1 Diabetes in Nonobese Diabetic Mice via Inhibition of Leukocyte Migration Involving the MEK6/p38 and MEK7/JNK Pathways.
Inflammation contributes to leukocyte migration, termed insulitis, and β-cell loss in type 1 diabetes (T1D). Naturally occurring anthraquinones are claimed as anti-inflammatory compounds; however, their actions are not clear. This study aimed to investigate the effect and mechanism of catenarin on the inflammatory disease, T1D. Catenarin and/or its anthraquinone analogs dose-dependently suppressed C-X-C chemokine receptor type 4 (CXCR4)- and C-C chemokine receptor type 5 (CCR5)-implicated chemotaxis in leukocytes. Catenarin, the most potent anthraquinone tested in the study, prevented T1D in nonobese diabetic mice. Mechanistic study showed that catenarin did not act on the expression of CCR5 and CXCR4. On the contrary, catenarin inhibited CCR5- and CXCR4-mediated chemotaxis via the reduction of the phosphorylation of mitogen-activated protein kinases (p38 and JNK) and their upstream kinases (MKK6 and MKK7), and calcium mobilization. Overall, the data demonstrate the preventive effect and molecular mechanism of action of catenarin on T1D, suggesting its novel use as a prophylactic agent in T1D.


Cell responses to growth factors: the role of receptor tyrosine kinase intracellular domain fragments.
Growth factor activation of receptor tyrosine kinases (RTKs) provokes well-described canonical second messenger pathways that transmit biochemical signals in the cytoplasm and to the nucleus to initiate cellular responses. The proteolytic liberation of intracellular domain fragments (ICDs) from activated RTKs and the nuclear translocation of these ICDs represent a more recently identified and noncanonical mechanism by which RTKs communicate with the nucleus. Several reports have added previously unknown facets to the ICD mechanism and have enlarged the scope of ICDs as second messengers.


Establishment of a 3D In Vitro Model to Accelerate the Development of Human Therapies against Corneal Diabetes.
To establish an in vitro model that would mirror the in vivo corneal stromal environment in diabetes (DM) patients. Human corneal fibroblasts from Healthy (HCFs), Type 1DM (T1DM) and Type 2DM (T2DM) donors were isolated and cultured for 4 weeks with Vitamin C stimulation in order to allow for extracellular matrix (ECM) secretion and assembly. Our data indicated altered cellular morphology, increased cellular migration, increased ECM assembly, and severe mitochondrial damage in both T1DM and T2DMs when compared to HCFs. Furthermore, we found significant downregulation of Collagen I and Collagen V expression in both T1DM and T2DMs. Furthermore, a significant up regulation of fibrotic markers was seen, including α-smooth muscle actin in T2DM and Collagen III in both T1DM and T2DMs. Metabolic analysis suggested impaired Glycolysis and Tricarboxylic acid cycle (TCA) pathway. DM has significant effects on physiological and clinical aspects of the human cornea. The benefits in developing and fully characterizing our 3D in vitro model are enormous and might provide clues for the development of novel therapeutics.