Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression.
Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied. BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets. Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression. Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.


p53-dependent induction of heat shock protein 27 (HSP27) expression.
Transcriptional activation of the p53 target genes plays a critical role in the cellular response to DNA damage, hypoxia, cellular stress and other signals regulating the cell cycle and apoptosis. The discovery of new p53 target genes continues to reveal novel mechanisms of action of this multifaceted protein. We used cDNA arrays to search for p53-regulated genes in prostate cancer cells. In this report, we describe robust induction of heat shock protein 27 (hsp27) in prostate cancer cells (DU145, LNCaP, PC3) following wild-type p53 expression from an adenoviral p53 expression vector (AdWTp53). A mutant p53 (R175H)-containing adenoviral expression vector did not induce hsp27. hsp27 expression was not altered in prostate cancer cells following expression of cyclin-dependent kinase inhibitors: p21(waf1/cip1) and p27(kip1) from adenoviral expression vectors. Treatment of cells with staurosporine, an apoptosis-inducing agent, did no affect hsp27 expression. These observations provide evidence that induction of hsp27 expression was wild-type p53-specific and was not due to non-specific effects of cell growth arrest and/or apoptosis. Previous studies and the experiment reported here show induction of hsp27 expression in response to androgen ablation, a physiological state that induces apoptosis in prostatic epithelial cells. The nature of p53 and hsp27 interactions in the regulation of apoptosis and/or cell growth needs to be further defined.


The development of polypharmacy. A longitudinal study.
To date, only a few studies have been carried out on the development and progress of polypharmacy in relation to morbidity in general practices in The Netherlands. The aim of this study was to investigate the relationship between an increase in long-term drug use and the incidence and severity of some chronic diseases, particularly in the elderly. Data on medication and morbidity of 1544 elderly people were collected for the period 1994-1997 from three family practices in the medication and morbidity Registration Network of Groningen (RNG) in the northern part of The Netherlands. Polypharmacy is defined as the long-term simultaneous use of two or more drugs; long-term is defined as >240 days in a year. We looked for differences in incidences of some chronic diseases in those subgroups of the elderly in whom multiple long-term drug use respectively increased, stayed constant or did not exist. Polypharmacy at the end of the period was predicted using regression analysis. Polypharmacy occurred in 42% of the elderly at the end of 1997, with major polypharmacy (>5 drugs) in only 4%. The average number of drugs used long-term increased from 1.3 to 1.8 in 4 years. Predictors for the increase of polypharmacy were the number of drugs at the start, age, diabetes, coronary ischaemic diseases and use of medication without a clear indication (P < 0.005). The average number of diseases also increased, especially in the elderly who showed the greatest increase in long-term drug use; however, there was no significant difference from the groups with a slow or no increase in drug use. Polypharmacy showed a slow increase over 4 years: almost 20% of the elderly developed polypharmacy, i.e. going from no drugs or one drug to two or more drugs. Polypharmacy develops mainly in elderly patients who already use several drugs, who are known to suffer from cardiovascular diseases, diabetes or stomach symptoms, those who often take drugs (especially sedatives/hypnotics) without clear indication and those who develop hypertension or atrial fibrillation over time.


Downregulation of lncRNA ANRIL represses tumorigenicity and enhances cisplatin-induced cytotoxicity via regulating microRNA let-7a in nasopharyngeal carcinoma.
Many studies have demonstrated that upregulation of long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) plays an oncogenic role in various tumors, including nasopharyngeal carcinoma (NPC). The aim of this study is to explore the effect of ANRIL in NPC progression and cisplatin (DDP)-induced cytotoxicity. The results showed that ANRIL was highly expressed and let-7a was downregulated in NPC tissues and cells. Luciferase assay revealed that ANRIL could negatively regulate miR-let-7a expression. ANRIL knockdown inhibited NPC cell proliferation and induced apoptosis, while anti-let-7a reversed these effects. Combination treatment of si-ANRIL and DDP led to a lower viability, a more DNA strand breaks damage and a higher comet tail length compared with any single treatment, whereas let-7a inhibitor abolished these effects. Furthermore, depletion of ANRIL exacerbated DDP-induced cytotoxicity in NPC cells in vivo. Taken together, these data indicated that knockdown of ANRIL represses tumorigenicity and enhances DDP-induced cytotoxicity via regulating microRNA let-7a in NPC cells, providing a promising therapeutic strategy for NPC patients.


Temporal compliance trends in a cluster randomization with crossover trial of out-of-hospital cardiac arrest.
Low compliance to randomized nondrug interventions can affect treatment estimates of clinical trials. Cluster-randomized crossover may be appropriate for increasing compliance in the out-of-hospital cardiac arrest setting. The purpose was to determine whether the elapsed time from start of a nonblinded treatment period to episode enrollment date in a cluster-randomized crossover trial is associated with compliance to either a period of brief cardiopulmonary resuscitation (CPR) with electrocardiogram (ECG) rhythm analysis or a period of longer CPR with a delayed ECG rhythm analysis in patients with out-of-hospital cardiac arrest. The Resuscitation Outcomes Consortium PRIMED Analyze Late (AL) versus Analyze Early (AE) trial was a cluster-randomized crossover trial at 10 North American regional sites. Clusters were created based on local service preference with treatment periods varying from 3 to 12 months depending on the expected enrollment rate of each randomizing unit. Episodes on the AL arm had a target of 180 s from CPR start to shock assessment and were deemed compliant if total time was between 150 and 210 s. Episodes on the AE arm had a target of <30 s from CPR start to shock assessment and were deemed compliant if total time was <60 s. We used logistic regression to examine the association between compliance (yes/no) and the elapsed number of days from the start of the treatment period to the episode in the framework of generalized estimating equations, controlling for randomized treatment (Late, reference = Early) and treatment period length (reference = 3, 4-5, 6, 7-11, and 12 months). We had 8769 episodes in our analysis population. Overall compliance to the randomized arm was 63.5%. After adjusting for treatment arm and treatment period length, the odds of compliance for episodes occurring >300 days from treatment period start were 33% lower (odds ratio (OR): 0.67; 95% confidence interval (CI): 0.52, 0.86) than for those <60 days from treatment period start. There was no significant difference in compliance between episodes before and immediately after a cluster crossed over to the opposite arm (OR: 0.81; 95% CI: 0.57, 1.16). A major challenge was the lack of synchronicity between training cycles and agency crossover dates. We found a significant decrease in compliance to the AL versus AE cardiac arrest intervention as the elapsed time from start of treatment period increased. We did not find a difference in compliance immediately before and after a crossover. While these results suggest that future cluster with crossover trials in the out-of-hospital setting be designed with short treatment periods and frequent crossovers, provider logistical concerns must also be considered.


Design and inference for cancer biomarker study with an outcome and auxiliary-dependent subsampling.
In cancer research, it is important to evaluate the performance of a biomarker (e.g., molecular, genetic, or imaging) that correlates patients' prognosis or predicts patients' response to treatment in a large prospective study. Due to overall budget constraint and high cost associated with bioassays, investigators often have to select a subset from all registered patients for biomarker assessment. To detect a potentially moderate association between the biomarker and the outcome, investigators need to decide how to select the subset of a fixed size such that the study efficiency can be enhanced. We show that, instead of drawing a simple random sample from the study cohort, greater efficiency can be achieved by allowing the selection probability to depend on the outcome and an auxiliary variable; we refer to such a sampling scheme as outcome and auxiliary-dependent subsampling (OADS). This article is motivated by the need to analyze data from a lung cancer biomarker study that adopts the OADS design to assess epidermal growth factor receptor (EGFR) mutations as a predictive biomarker for whether a subject responds to a greater extent to EGFR inhibitor drugs. We propose an estimated maximum-likelihood method that accommodates the OADS design and utilizes all observed information, especially those contained in the likelihood score of EGFR mutations (an auxiliary variable of EGFR mutations) that is available to all patients. We derive the asymptotic properties of the proposed estimator and evaluate its finite sample properties via simulation. We illustrate the proposed method with a data example.


Poorer baseline performance status is associated with increased thromboembolism risk in metastatic cancer patients treated with immunotherapy.
Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in cancer patients. However, the association of VTE with immunotherapy remains poorly defined. We therefore evaluated the frequency of VTE in patients receiving immunotherapy and tried to determine predisposing factors. A total of 133 adult metastatic cancer patients treated with immunotherapy for any cancer between were included. Baseline demographics, ECOG performance status, type of tumors, and baseline blood count parameters were recorded. Possible predisposing factors were evaluated with univariate and multivariate analyses. The median age was 60 (interquartile range (IQR) 48-66) years, and the median follow-up was 10.1 (IQR 5.8-18.5) months. Renal cell carcinoma (26.3%) and melanoma (24.1%) were most common diagnoses. Fifteen patients (11.3%) had an episode of VTE. Most of the VTEs were diagnosed as pulmonary emboli (10/15; 67%). Eighty percent (12/15) of these VTE cases were detected incidentally. Patients with a baseline ECOG performance status of 1 or more (29.3% of patients) had a significantly increased risk of venous thrombosis (ECOG ≥1 vs. 0, HR: 3.023, 95% CI: 1.011-9.039, p=0.048). Other factors, including patient age, tumor type, body mass index, baseline thrombocyte, neutrophil, and lactate dehydrogenase levels were not significantly associated with VTE risk. In this study, we observed VTE development in more than 10% of immunotherapy-treated patients and increased VTE risk in patients with poorer ECOG status. With the asymptomatic nature of VTEs in most cases, a high index of suspicion level for VTE is required in patients treated with immunotherapy.


Giant frontal mucocele complicated by subdural empyema: treatment of a rare association.
Giant frontal mucocele (GFM) is an extremely rare cause of frontal lobe syndrome. Subdural empyema (SDE) is an uncommon complication of paranasal sinisutis, for which craniotomy and decompressive craniotomy are the most effective surgical procedures. A 54-year-old man was brought unconscious to the emergency room where recurrent generalized seizures occurred. Heroine abuse, HCV-related hepatitis, prolonged antibiotic therapy for treatment of purulent rhinorrhea, along with recent personality changes were reported. High white blood cell count, pansinusitis, GFM, SDE and cerebritis were documented. The patient underwent bifrontal craniotomy in emergency, extensive drilling of the inner aspect of the frontal bone, surgical toilet of the enlarged frontal sinus and its "cranialization". Prevotella intermedia and Fusobacterium nucleatum were isolated and antibiotic therapy was started intravenously and then continued orally for 3 months. 2 years later the patient has recovered, though minor signs of frontal lobe syndrome persist. To the authors knowledge, this is the first case of GFM with SDE reported in the literature. Although decompressive craniectomy is advocated in extreme conditions, as in this case, "internal decompressive craniectomy", obtained with craniotomy and cranialization of the frontal sinuses, is strongly advocated in cases of SDE associated with megasinuses.


[Disturbed synthesis of eicosanoids in patients with metabolic syndrome].
The work was designed to study levels of serum prostaglandin F1a (6-keto-PGF1a), thromboxane B2, and leukotriene B4 (LTB4)--stable products of cyclooxygenase and lipogenase-catalyzed reactions of arachidonic acid, in patients with metabolic syndrome (MS) differing in glucose homeostasis. It was shown that MS is associated with excess production of anti-inflammatory oxilipines (LTB4) regardless of the presence or absence of insulin resistance. LTB4 are known to influence inflammatory processes due to compensatory synthesis of vasodilating eicosanoids (6-keto-PGF1a) that antagonize vasoconctriction and inflammation. Combination of MS with insulin resistance in patients with elevated LTB4 and 6-keto-PGF1a levels is associated with enhanced synthesis of thromboxane A2 responsible for vasoconstriction, platelet formation, and development of endothelial dysfunction. The study suggests disturbed synthesis of eicosanoids in patients with MS and their important role in pathogenesis of this condition.


Gender mainstreaming practice: considerations for HIV/AIDS community organisations.
Gender is well recognised as a critical consideration for HIV/AIDS organisations. Since the 1990s, HIV/AIDS policy-makers, donors, non-governmental organisations and transnational corporations have adopted gender mainstreaming as the process for integrating gender into development programmes and institutions. There is an increasing body of literature on the successes and challenges of practicing gender mainstreaming within organisational environments, however, little has been said about this practice within HIV/AIDS-specific organisational environments. As a contribution to this gap, this reflective paper aims to generate debate about some of the considerations for gender mainstreaming practice in HIV/AIDS organisations. It draws on the author's experience conducting a gender mainstreaming review with a southern African HIV/AIDS capacity-strengthening organisation, as well as a review of the development literature on gender mainstreaming. The paper looks at three key issues facing gender mainstreaming: (1) donor requirements on disaggregating data by sex; (2) connecting gender mainstreaming with the priorities of community HIV/AIDS organisations; and (3) the role of resistance to gender mainstreaming as neo-colonial. Preliminary understandings of these issues suggest that current approaches to gender mainstreaming may not be flexible enough to consider the multiple ways gender and HIV/AIDS interact in different sociocultural contexts. There is an urgent need for further debate and in-depth research into these issues, given the challenge they pose for HIV/AIDS organisations and donors that have chosen to make gender mainstreaming a criterion for HIV/AIDS funding.


Dual diagnosis: developmental disability complicated by mental illness.
When mental retardation is complicated by mental illness, the clinical result is "dual diagnosis." Though recognized as such only since the 1970s, these patients have long been the subset of the developmentally disabled most resistant to integration into the community. The maladaptive behavior or mental illness often prevents training for the retardation or other developmental disability. Because these patients are no longer placed in the back wards of state institutions, the modern expectation is that even this most difficult group can be influenced by positive behavior support directed by a psychologist and medication treatment programs prescribed by a psychiatrist. In addition, program specialists structure the work, play, and learning environment of the patients. These activities, living conditions, and peer relationships will form a dynamic interaction with the behavior therapy and the medication. The challenge of adapting to this interaction is met by an interdisciplinary team. Subject to bizarre behavior and difficult to diagnose and treat, patients with both mental retardation and mental illness are best directed to providers trained for these patients.


A review on applications of liposomes in textile processing.
This review discusses the properties of liposomes and their role in the textile process, including textile preparation and dyeing. Liposomes have a surface activity effect due to a hydrophilic head group and hydrophobic hydrocarbon tail. Its preparations do not tend to foam, which advantageously distinguishes them from other textile auxiliaries. According to the carrier role of liposomes, they can be used in several textile processes such as textile finishing and dyeing with several types of dyes and fibers. Each application is discussed in this review paper. Several types of dyes are encapsulated by liposomes in the dyeing process and their presence indicates that they have retardant and leveling effects according to their gradual release of dyes. In addition, the presence of liposomes in the textile process can improve the mechanical properties of textile products, resulting in better wash fastness properties and leveling effect and handle properties. The best character of liposomes is a reduction in temperature of process resulting to save energy and they are environment degradable materials.


Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain.
There is a growing evidence that chemokines and their receptors play a role in inducing and maintaining neuropathic pain. In the present study, unilateral chronic constriction injury (CCI) of rat sciatic nerve under aseptic conditions was used to investigate changes for stromal derived factor-1 (SDF1) and its CXCR4 receptor in lumbal (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) from both sides of naïve, CCI-operated and sham-operated rats. All CCI-operated rats displayed mechanical allodynia and thermal hyperalgesia in hind paws ipsilateral to CCI, but forepaws exhibited only temporal changes of sensitivity not correlated with alterations in SDF1 and CXCR4 proteins. Naïve DRG displayed immunofluorescence for SDF1 (SDF1-IF) in the satellite glial cells (SGC) and CXCR4-IF in the neuronal bodies with highest intensity in small- and medium-sized neurons. Immunofluorescence staining and Western blot analysis confirmed that unilateral CCI induced bilateral alterations of SDF1 and CXCR4 proteins in both L4-L5 and C7-C8 DRG. Only lumbal DRG were invaded by ED-1+ macrophages exhibiting SDF1-IF while elevation of CXCR4-IF was found in DRG neurons and SGC but not in ED-1+ macrophages. No attenuation of mechanical allodynia, but reversed thermal hyperalgesia, in ipsi- and contralateral hind paws was found in CCI-operated rats after i.p. administration of CXCR4 antagonist (AMD3100). These results indicate that SDF1/CXCR4 changes are not limited to DRG associated with injured nerve but that they also spread to DRG non-associated with such nerve. Functional involvement of these alterations in DRG non-associated with injured nerve in neuropathic pain remains to be elucidated.


Conservative surgical management of tubal pregnancy.
In an attempt to maintain optimal fertility in the patient treated for midtubal pregnancy, an investigation of conservative surgical procedure was made. The technic developed utilizes tubal excision, reanastomosis, and a single hydrotubation with Dextran. Tubal patency was maintained without the use of stents that may damage the fimbria. The procedure is compared to other conservative technics and its advantages discused. Thus far 2 patients have undergone this excision and reanastomosis, and both patients successfully established intrauterine gestations within 2 months of returning to normal active coital frequency. Both were in the midtrimester of pregnancy at the time of this report.


Allergic conjunctivitis as a risk factor for regression and haze after photorefractive keratectomy.
To analyze the relation between allergic conjunctivitis and the results of photorefractive keratectomy performed with an excimer laser in myopic eyes. Fifty-seven myopic eyes in 57 Japanese patients were classified into three groups: a normal group (30 eyes of 30 patients), a treatment group composed of eyes with allergic conjunctivitis that were treated with fluorometholone and cromolyn sodium eyedrops from month 3 until the end of the 12- to 18-month follow-up period (16 eyes of 16 patients), and a no-treatment group composed of eyes with allergic conjunctivitis that received no allergic treatment until the end of the follow-up period (11 eyes of 11 patients). Preoperative and postoperative examinations included evaluation of corrected and uncorrected visual acuity and grading of corneal haze. In the no-treatment group, the mean corneal haze score +/- SD of 0.8 +/- 0.98 was significantly greater than the normal group score of 0.38 +/- 0.49 (P = .02). There was no significant difference in the haze score between the treated and normal groups. A refractive outcome of +/- 1 diopter was obtained in 30 (100%) of the 30 patients in the normal group, 15 (93.8%) of 16 patients in the treatment group, and four (36.4%) of the 11 patients in the no-treatment group. Visual acuity was 20/40 or better after photorefractive keratectomy in 30 patients (100%) in the normal group, 15 patients (93.8%) in the treatment group, and six patients (54.5%) in the no-treatment group. These findings suggest that untreated allergic conjunctivitis is a significant risk factor for haze and myopic regression after photorefractive keratectomy.


Copper deficiency reduces interleukin-2 (IL-2) production and IL-2 mRNA in human T-lymphocytes.
Although dietary copper (Cu) deficiency has been associated with decreased production of interleukin-2 (IL-2) by activated splenic mononuclear cells in rodent models, the basis for this relationship and its relevance for humans remain unknown. To address these matters, we have developed an in vitro model of cellular copper deficiency by treating Jurkat, a human T-lymphocyte cell line, with low concentrations of 2,3,2-tetraamine (2,3,2-tet), a high affinity copper chelator. Exposure to 5-20 micromol/L 2,3,2-tet for 35 h decreased cell copper and the activity of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) by 30-40% and IL-2 production by 60-70% in cultures activated with phytohemagglutinin and phorbol myristate acetate. Similarly, IL-2 mRNA levels were 40-70% lower in chelator-treated cells than in untreated cells at 3-12 h after activation. In contrast, chelator treatment had no significant effect on cell viability, growth, protein synthesis or mitochondrial activity. The presence of a slight molar excess of copper, but not zinc or iron, during exposure to 2,3,2-tet prevented the chelator-induced decrease in Cu,Zn-SOD activity and the reductions in IL-2 mRNA and bioactivity. Moreover, binding of diferric transferrin (Tf) and cellular uptake of Tf-59Fe by Jurkat cells were not increased by 2,3,2-tet, indicating that chelator-treated cells were not iron deficient. Finally, incubation of human peripheral blood mononuclear cells (PBMC) with 2,3,2-tet decreased mitogen-induced IL-2 production by 50% compared with untreated controls. These data indicate that a decline in copper status decreases IL-2 production by activated human T-cells due to reduced synthesis and/or stability of IL-2 mRNA.


Single cell proteomics in biomedicine: High-dimensional data acquisition, visualization, and analysis.
New insights on cellular heterogeneity in the last decade provoke the development of a variety of single cell omics tools at a lightning pace. The resultant high-dimensional single cell data generated by these tools require new theoretical approaches and analytical algorithms for effective visualization and interpretation. In this review, we briefly survey the state-of-the-art single cell proteomic tools with a particular focus on data acquisition and quantification, followed by an elaboration of a number of statistical and computational approaches developed to date for dissecting the high-dimensional single cell data. The underlying assumptions, unique features, and limitations of the analytical methods with the designated biological questions they seek to answer will be discussed. Particular attention will be given to those information theoretical approaches that are anchored in a set of first principles of physics and can yield detailed (and often surprising) predictions.


Preventing the airborne spread of Staphylococcus aureus by persons with the common cold: effect of surgical scrubs, gowns, and masks.
Transmission of Staphylococcus aureus via air may play an important role in healthcare settings. This study investigates the impact of barrier precautions on the spread of airborne S. aureus by volunteers with experimentally induced rhinovirus infection (ie, the common cold). Prospective nonrandomized study. Wake Forest University School of Medicine (Winston-Salem, NC).Participants. A convenience sample of 10 individuals with nasal S. aureus carriage selected from 593 students screened for carriage. Airborne S. aureus dispersal was studied in the 10 participants under the following clothing conditions: street clothes, surgical scrubs, surgical scrubs and a gown, and the latter plus a face mask. After a 4-day baseline period, volunteers were exposed to a rhinovirus, and their clinical course was followed for 12 days. Daily swabs of nasal specimens, pharynx specimens, and skin specimens were obtained for quantitative culture, and cold symptoms were documented. Data were analyzed by random-effects negative binomial models. All participants developed a common cold. Incidence rate ratios (IRRs) indicated that, compared with airborne levels of S. aureus during sessions in which street clothes were worn, airborne levels decreased by 75% when surgical scrubs were worn (P<.001), by 80% when scrubs and a surgical gown were worn (P<.001), and by 82% when scrubs, a gown, and a face mask were worn (P<.001). The addition of a mask to the surgical scrubs and gown did not reduce the airborne dispersal significantly (IRR, 0.92; P>.05). Male volunteers shed twice as much S. aureus as females (incidence rate ratio, 2.04; P=.013). The cold did not alter the efficacy of the barrier precautions. Scrubs reduced the spread of airborne S. aureus, independent of the presence of a rhinovirus-induced cold. Airborne dispersal of S. aureus during sessions in which participants wore surgical scrubs was not significantly different from that during sessions in which gowns and gowns plus masks were also worn.


Feasibility, acceptability and effectiveness of an online alternative to face-to-face consultation in general practice: a mixed-methods study of webGP in six Devon practices.
To evaluate the feasibility, acceptability and effectiveness of webGP as piloted by six general practices. Mixed-methods evaluation, including data extraction from practice databases, general practitioner (GP) completion of case reports, patient questionnaires and staff interviews. General practices in NHS Northern, Eastern and Western Devon Clinical Commissioning Group's area approximately 6 months after implementing webGP (February-July 2016). Six practices provided consultations data; 20 GPs completed case reports (regarding 61 e-consults); 81 patients completed questionnaires; 5 GPs and 5 administrators were interviewed. Attitudes and experiences of practice staff and patients regarding webGP. WebGP uptake during the evaluation was small, showing no discernible impact on practice workload. The completeness of cross-sectional data on consultation workload varied between practices.GPs judged 41/61 (72%) of webGP requests to require a face-to-face or telephone consultation. Introducing webGP appeared to be associated with shifts in responsibility and workload between practice staff and between practices and patients.81/231 patients completed a postal survey (35.1% response rate). E-Consulters were somewhat younger and more likely to be employed than face-to-face respondents. WebGP appeared broadly acceptable to patients regarding timeliness and quality/experience of care provided. Similar problems were presented by all respondents. Both groups appeared equally familiar with other practice online services; e-consulters were somewhat more likely to have used them.From semistructured staff interviews, it appeared that, while largely acceptable within practice, introducing e-consults had potential for adverse interactions with pre-existing practice systems. There is potential to assess the impact of new systems on consultation patterns by extracting routine data from practice databases. Staff and patients noticed subtle changes to responsibilities associated with online options. Greater uptake requires good communication between practice and patients, and organisation of systems to avoid conflicts and misuse. Further research is required to evaluate the full potential of webGP in managing practice workload.


Target of Rapamycin Inhibition in Chlamydomonas reinhardtii Triggers de Novo Amino Acid Synthesis by Enhancing Nitrogen Assimilation.
The Target of Rapamycin (TOR) kinase is a central regulator of growth and metabolism in all eukaryotic organisms, including animals, fungi, and plants. Even though the inputs and outputs of TOR signaling are well characterized for animals and fungi, our understanding of the upstream regulators of TOR and its downstream targets is still fragmentary in photosynthetic organisms. In this study, we employed the rapamycin-sensitive green alga Chlamydomonas reinhardtii to elucidate the molecular cause of the amino acid accumulation that occurs after rapamycin-induced inhibition of TOR. Using different growth conditions and stable 13C- and 15N-isotope labeling, we show that this phenotype is accompanied by increased nitrogen (N) uptake, which is induced within minutes of TOR inhibition. Interestingly, this increased N influx is accompanied by increased activities of glutamine synthetase and glutamine oxoglutarate aminotransferase, the main N-assimilating enzymes, which are responsible for the rise in levels of several amino acids, which occurs within a few minutes. Accordingly, we conclude that even though translation initiation and autophagy have been reported to be the main downstream targets of TOR, the upregulation of de novo amino acid synthesis seems to be one of the earliest responses induced after the inhibition of TOR in Chlamydomonas.


Development of a procedure for measuring nitrogen by cold neutron prompt gamma-ray activation analysis.
An instrument for cold neutron prompt gamma-ray activation analysis (CNPGAA) has been used for the nondestructive determination of nitrogen. The samples were analyzed in an evacuated box to minimize background from neutron capture by atmospheric nitrogen. The system features lower background and lower detection limits than obtainable with the University of Maryland-National Institute of Standards and Technology (NIST) thermal neutron PGAA instrument. CNPGAA has been used to measure nitrogen in standard reference materials which included biological materials and soils; the results are in agreement with certified values. The detection limit for nitrogen in most biological and geological samples is near 1000 mg kg-1.


Resection of Large Urological Tumors With or Without Inferior Vena Cava Extension in Jehova's Witnesses.
Background: Renal and adrenal tumors with/without tumor thrombus in the inferior vena cava (IVC) pose a challenge to the surgeon due to the potential for massive hemorrhage and tumor thromboemboli. The situation would be more critical for Jehovah's Witness (JW) patients which refuse blood transfusion. A transplant-based (TB) approach to these tumors in JWs would result a safe surgical method, providing limited blood loss and perioperative complications. We report our experience using a TB surgical approach in JW harboring large adrenal/renal tumors with/without tumor thrombus trying to determine its usefulness in this setting. Patients and Methods: From 2003 to 2011, 7 patients underwent resection of renal/adrenal tumors with/without tumor thrombus in the IVC by means of a TB approach. Thrombus level was renal (n = 2), retrohepatic (n = 1), and suprahepatic (n = 1). The remaining 3 patients did not present thrombus. No pre-operative optimization or cell-saver were used. Estimated blood loss, perioperative complications (Clavien-Dindo and cause), hemoglobin/hematocrit loss, and length of stay were considered main outcomes. Results: The intervention was successfully completed without transfusion in all cases. Operative time and blood loss were 2.5 h (range: 1.83-5.75) and 150 cc (range: 100-750), respectively. No major post-operative complications were registered. However, minor complications were detected in 57% of the patients included. Median hemoglobin loss was 1.13 mg/dL, which translated a median hematocrit loss of 2.3%. Patients were discharged in a median of 7 days (range 5-20). Conclusions: A TB-surgical approach provides enhanced retroperitoneal exposure and optimal vascular control, thus limiting operative blood loss or major complication development, thus resulting useful in JWs.


Excess VO2 during ramp exercise is positively correlated to intercostal muscles deoxyhemoglobin levels above the gas exchange threshold in young trained cyclists.
We assessed respiratory muscles oxygenation responses during a ramp exercise to exhaustion and further explored their relationship with the non-linear increase of VO2 (VO2 excess) observed above the gas-exchange threshold. Ten male cyclists completed a ramp exercise to exhaustion on an electromagnetically braked cycle-ergometer with a rate of increment of 30Wmin(-1) with continuous monitoring of expired gases (breath-by-breath) and oxygenation status of intercostal muscles. Maximal inspiratory and expiratory pressure measurements were taken at rest and at exhaustion. The VO2 excess represents the difference between VO2max observed and VO2max expected using linear equation between the VO2 and the intensity before gas-exchange threshold. The deoxyhemoglobin remained unchanged until 60% of maximal aerobic power (MAP) and thereafter increased significantly by 37±18% and 40±22% at 80% and 100% of MAP, respectively. Additionally, the amplitude of deoxyhemoglobin increase between 60 and 100% of MAP positively correlated with the VO2 excess (r=0.69, p<0.05). Compared to exercise start, the oxygen tissue saturation index decreased from 80% of MAP (-4.8±3.2%, p<0.05) onwards. At exhaustion, maximal inspiratory and expiratory pressures declined by 7.8±16% and 12.6±10% (both p<0.05), respectively. In summary, our results suggest a significant contribution of respiratory muscles to the VO2 excess phenomenon.


[Antibodies directed to voltage-gated potassium channels in sera from acquired neuromyotonia and related disorders].
Anti-voltage-gated potassium channel (VGKC) antibodies were measured in sera from 21 patients with acquired neuromyotonia (Isaacs syndrome) and related disorders. Seventeen of 21 sera suppressed potassium currents of neuroblastoma cell line (NB-1) using the patch clamp method, and the finding is mostly correlated with myokymic discharge in electromyography. Regarding the pathophysiology of suppression of VGKC, we investigated the effects of sera from 2 ANM patients on channel kinetics using the patch clamp method. The activation and inactivation kinetics of the potassium current were not altered by patients' immunoglobulins. We also investigated the effect of patients' sera on different VGKC subtypes using hKv1.1 and 1.6 transfected CHO cells. The same patients' sera suppressed the expressed VGKCs. Our results suggest that anti-VGKC antibodies may be positive not only in patients with classical ANM (Isaacs syndrome) but also in patients with related disorders who did not fulfill the characteristic symptoms. These disorders may be categorized as potassium channelopathy of the peripheral nervous system. The pathophysiology of the suppression of VGKC by antibodies is not the direct effect on channel kinetic but due to increased degradation or reduced production of VGKC. Epitopes of Anti-VGKC antibodies are still unclear.


Interaction between smoking, GSTM1 deletion and colorectal cancer: results from the GSEC study.
Cigarette smoking has inconsistently been associated with an increased risk of colorectal cancer. One of the enzymes responsible for the detoxification of the carcinogenic compounds present in tobacco smoke is glutathione S-transferase-mu (GST-mu). The gene that codes for this enzyme is GSTM1. In this study, we evaluated the associations and interaction between GSTM1 deletion, smoking behaviour and the development of colorectal cancer. We performed a pooled analysis within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). We selected six studies on colorectal cancer, including 1130 cases and 2519 controls, and restricted our analyses to Caucasians because the number of patients from other races was too limited. In addition we performed a meta-analysis including the studies from the GSEC database and other studies identified on MEDLINE on the same subject. The prevalence of the GSTM1 null genotype was within the range reported in other studies: 51.8% of the cases had the GSTM1 null genotype versus 56.6% of the controls. No significant association between the GSTM1 null genotype and colorectal cancer was found (odds ratio 0.92, 95% confidence interval 0.73-1.14). Our results suggest a possible positive association between lack of the GST-mu enzyme and colorectal cancer for non-smoking women (odds ratio 1.47, 95% confidence interval 0.80-2.70). There was no interaction between the effects of smoking and GSTM1 genotype on colorectal cancer risk in men and women (chi2=0.007, p=0.97). Our findings do not support an association between the GSTM1 null genotype and colorectal cancer. In addition, we did not find any modification of the smoking-induced colorectal cancer risk by GSTM1 genotype


Autistic artists give clues to cognition.
Certain autistic children whose linguistic ability is virtually nonexistent cart draw natural scenes from memory with astonishing accuracy. In particular their drawings display convincing perspective. In contrast, normal children of the same preschool age group and even untrained adults draw primitive schematics or symbols of objects which they can verbally identify. These are usually conceptual outlines devoid of detail. It is argued that the difference between autistic child artists and normal individuals is that autistic artists make no assumptions about what is to be seen in their environment. They have not formed mental representations of what is significant and consequently perceive all details as equally important. Equivalently, they do not impose visual or linguistic schema-a process necessary for rapid conceptualisation in a dynamic existence, especially when the information presented to the eye is incomplete.


Ce3+-ion, Surface Oxygen Vacancy, and Visible Light-induced Photocatalytic Dye Degradation and Photocapacitive Performance of CeO2-Graphene Nanostructures.
Cerium oxide nanoparticles (CeO2 NPs) were fabricated and grown on graphene sheets using a facile, low cost hydrothermal approach and subsequently characterized using different standard characterization techniques. X-ray photoelectron spectroscopy and electron paramagnetic resonance revealed the changes in surface states, composition, changes in Ce4+ to Ce3+ ratio, and other defects. Transmission electron microscopy (TEM) and high resolution TEM revealed that the fabricated CeO2 NPs to be spherical with particle size of ~10-12 nm. Combination of defects in CeO2 NPs with optimal amount of two-dimensional graphene sheets had a significant effect on the properties of the resulting hybrid CeO2-Graphene nanostructures, such as improved optical, photocatalytic, and photocapacitive performance. The excellent photocatalytic degradation performances were examined by monitoring their ability to degrade Congo red ~94.5% and methylene blue dye ~98% under visible light irradiation. The photoelectrode performance had a maximum photocapacitance of 177.54 Fg-1 and exhibited regular capacitive behavior. Therefore, the Ce3+-ion, surface-oxygen-vacancies, and defects-induced behavior can be attributed to the suppression of the recombination of photo-generated electron-hole pairs due to the rapid charge transfer between the CeO2 NPs and graphene sheets. These findings will have a profound effect on the use of CeO2-Graphene nanostructures for future energy and environment-related applications.


The current status of femoropopliteal bypass grafting.
Results of saphenous vein bypass grafts for femoral occlusive disease justify their use in the management of patients with threatened limb loss and in selected patients with intermittent claudication. Early results with PTFE and umbilical vein grafts indicate that successful bypass is feasible in patients with absent or inadequate saphenous veins. Currently, however, long-term follow-up with these new grafts is lacking and continued use of saphenous vein grafts whenever possible is preferred.


Developmental correlates of midfacial components in a normal and cleft lip and palate human fetal sample.
Midfacial hypoplasia in patients with complete clefts of the lip and palate is considered to be the result of congenital dysmorphogenesis combined with surgical effects. The present study describes congenital correlates of midfacial hypoplasia by examining the relationships between premaxillary size and a number of adjacent oronasal capsular components in a sample of second trimester normal and complete cleft fetal specimens. Midfacial relationships from previously published data from 3-D computer reconstructions of histologic material were assessed by multiple regression and path analyses. Stepwise multiple regression analysis revealed that the combination of age (body size) and nasal septal length were the best predictor variables of premaxillary length and accounted for 90 percent and 93 percent (p less than .01) of the variance in normal and cleft fetal specimens, respectively. Tongue length was seen to slightly increase the R2 values in the cleft, but not the normal sample. Path analysis results revealed that with body size held constant, nasal capsule volume explained only 3 percent of premaxillary variance, while septal length accounted for approximately 45 percent of the variance (p less than .05). Results show that the relationships of the midfacial components in the cleft fetal sample closely followed normal second-trimester midfacial growth patterns and suggest that the septal-traction model may be a more parsimonious and primary explanatory mechanism of early midfacial growth than the functional matrix model in both normal and complete cleft fetal specimens.


Reduction and s-carboxymethylation of proteins: large-scale method.
INTRODUCTIONIntact interchain and/or intrachain disulfide linkage in a protein can present problems during proteolytic or chemical fragmentation procedures. Disulfide bonds are commonly cleaved by reducing cystine to yield cysteine residues. However, cysteine residues are highly reactive, which can complicate sequence work. In this protocol, the intact protein (>1 mg) is reduced and then S-alkylated with iodoacetic acid (or iodoacetamide). The resulting cysteine derivative S-carboxymethylcysteine (or S-carboximadomethylcysteine) is easily detectable during chemical sequencing.


Hepatic uptake of gluconeogenic substrates in late-pregnant and mid-lactating rats.
Lactate uptake by liver is markedly increased in late-pregnant and mid-lactating rats without concomitant changes in its availability. Glycerol contribution to the liver 3-C unit uptake is only significant at term gestation (50% of lactate uptake) but almost negligible at mid-lactation (10% of lactate uptake). Pyruvate is only taken up by the liver of 15-day lactating rats. As a general trend, the livers of either pregnant or lactating rats are provided with an enhanced capacity to take up gluconeogenic substrates.


Reevaluating nutrition as a risk factor for cardio-metabolic diseases.
The consumption of saturated fats is considered a risk factor for cardiovascular diseases. Review published papers on the role of macro-nutrient intake in cardiovascular risk. Recent reports from the PURE study and several previous meta-analyses, show that the consumption of total saturated and unsaturated fat is not associated with risk of acute myocardial infarction or mortality due to cardiovascular disease. High carbohydrate intake was associated with the highest risk of total and cardiovascular mortality, while total fat consumption or of its different types was associated with a lower risk of mortality. A high consumption of fruits, vegetables and legumes was associated with lower risk of total mortality and non-cardiovascular mortality. The consumption of 100 g of legumes, two or three times a week, ameliorated deficiencies of the nutrients contained in these foods and was associated with a reduction in the risk of developing chronic non-communicable diseases. A healthy diet should be balanced and varied, be composed of a proportion of complex carbohydrates rich in fibber between 50-55% of the daily energy consumed, of saturated and unsaturated fat (25-30%), animal and vegetable protein (including legumes) between 15-25%, vitamins, minerals and water. These nutrients are abundantly present in fruits, vegetables, cereals, legumes, milk and its derivatives, eggs and meats, so public policies should promote the availability and access to these nutrients within primary prevention programs to reduce the growing prevalence of cardio-metabolic diseases.


A surgical approach to iatrogenic vascular injuries in pediatric cases.
Surgical intervention is mandatory in many children who present with vascular trauma or in complicated cases after medical interventions. In this study, surgical interventions applied after vascular injuries in children were analyzed. Between January 2002 and December 2012, 17 patients (aged under 18) who were admitted to the emergency room with vascular injuries were retrospectively analyzed. The data was collected through hospital records. Preoperative and postoperative data of the patients were recorded and analyzed. Of the total, 11 patients were female (64.7%) and 6 patients were male (35.3%) with a range of 4-192 months. In total, 14 (82.3%) injuries were due to angiographic interventions, 1 (5.9%) was due to external trauma, 1 (5.9%) was due to preoperative trauma, and 1 (5.9%) was due to a catheterization complication in the intensive care unit. Additionally, 11 (64.7%) injuries were located in the right femoral artery, 3 (17.6%) were located in the left femoral artery, 2 (11.8%) were located in the left brachial artery, and 1 (5.9%) was located in the left external iliac vein. Also, 5 (29.4%) patients were managed under local anesthesia and 12 (70.6%) patients were managed under general anesthesia. With respect to treatment, 15 (88.2%) injuries were repaired with primary sutures, 1 (5.9%) injury was repaired with an end-to-end anastomosis, and 1 (5.9%) injury was repaired with a saphenous vein graft interposition. In addition, 16 (94.1%) patients underwent a thrombectomy prior to the repair. The total hospital stay was calculated as 2.7±1.4 days. The intensive care unit stay was calculated as 1.1±0.4 days. There was no mortality, a loss of an injured extremity, or an infection. No other complication was detected. Iatrogenic interventional procedures seem to be responsible for the majority of pediatric vascular injuries. The results of surgical repairs in these injuries are successful and efficient.


Model-Free Measurement of the Pair Potential in Colloidal Fluids Using Optical Microscopy.
We report a straightforward, model-free approach for measuring pair potentials from particle-coordinate data, based on enforcing consistency between the pair distribution function measured separately by the distance-histogram and test-particle insertion routes. We demonstrate the method's accuracy and versatility in simulations of simple fluids, before applying it to an experimental system composed of superparamagnetic colloidal particles. The method will enable experimental investigations into many-body interactions and allow for effective coarse graining of interactions from simulations.


Single oral dose treatment of uncomplicated urinary tract infection in women.
A single oral dose of an antimicrobial agent is as effective as a conventional 3-day course for the treatment of uncomplicated lower urinary tract infections. A case history of a young woman with recurrent cystitis is presented to demonstrate this approach to the management of a common clinical problem. The place of antimicrobial prophylaxis is also discussed.


Aging alters circadian and light-induced expression of clock genes in golden hamsters.
Aging alters numerous aspects of circadian biology, including the amplitude of rhythms generated by the suprachiasmatic nuclei (SCN) of the hypothalamus, the site of the central circadian pacemaker in mammals, and the response of the pacemaker to environmental stimuli such as light. Although previous studies have described molecular correlates of these behavioral changes, to date only 1 study in rats has attempted to determine if there are age-related changes in the expression of genes that comprise the circadian clock itself. We used in situ hybridization to examine the effects of age on the circadian pattern of expression of a subset of the genes that comprise the molecular machinery of the circadian clock in golden hamsters. Here we report that age alters the 24-h expression profile of Clock and its binding partner Bmal1 in the hamster SCN. There is no effect of age on the 24-h profile of either Per1 or Per2 when hamsters are housed in constant darkness. We also found that light pulses, which induce smaller phase shifts in old animals than in young, lead to decreased induction of Per1, but not of Per2, in the SCN of old hamsters.


Development and validation of an arrhythmia-specific scale in tachycardia and arrhythmia with focus on health-related quality of life.
Arrhythmias can cause a profoundly negative impact on a person's daily life, leading to impaired health-related quality of life (HRQOL). Assessment of HRQOL can provide valuable information before, during, and after healthcare interventions for arrhythmias. The aim was to develop and validate a disease-specific scale evaluating HRQOL in patients with different forms of arrhythmia. The Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA HRQOL) was developed from a literature review, patient interviews, and expert panel evaluations. This version was then psychometrically evaluated in patients treated with radiofrequency catheter ablation because of different forms of arrhythmias and patients who sought emergency care because of atrial fibrillation. Construct validity was evaluated with item-total correlations, confirmatory factor analyses, and convergent and discriminant validity. Internal consistency was evaluated using Cronbach's α. All items reached the expected level of item-total correlations of greater than 0.3 for the total scale. The content validity index was sufficient for all items, as was the total scale (0.86-1.0). The 2-factor confirmatory factor analysis model that included the physical and mental factors showed a better fit between model and data than the 1-factor model did (P < .001). Convergent and discriminant validities were evaluated in the correlation analyses between the ASTA HRQOL subscales and SF-36 physical and mental dimensions. A strong correlation was found between the hypothesized physical and mental scales. Internal consistency was satisfactory with a lower bound confidence interval (95%) for Cronbach's α .70 or greater for all the ASTA HRQOL scales. The ASTA HRQOL questionnaire can be a valuable contribution to HRQOL assessments in patients with different forms of arrhythmia. Until there is more evidence regarding validity and reliability, using both the total and subscale scores is recommended.


Transverse anisotropy in the deformation of the muscle during dynamic contractions.
When pennate muscle fibres shorten, the transverse deformation of fibres results in an increase in pennation angle of fascicles (bundles of fibres) and transverse deformation of muscle belly. Transverse shape changes of a muscle can influence force generation. Recent modelling studies predicted asymmetrical transverse deformations in the muscle fascicles in the gastrocnemii. However, these predictions have not been tested experimentally. As muscle is a 3D entity, it is important to explore the structural changes in a 3D perspective to enhance our understanding of the underlying structural mechanisms that have functional implications. The medial and lateral gastrocnemius muscles from 12 subjects were imaged during plantarflexion movements on a dynamometer. The muscle belly was simultaneously scanned from two orthogonal directions using two ultrasound probes. Fascicle deformations were measured from the two orthogonal ultrasound scans to provide 3D information of muscle geometry. Whilst transverse deformations in the medial gastrocnemius were similar from the two directions, the data for the lateral gastrocnemius confirm that transverse anisotropy can occur in the muscle fascicles. As the lateral gastrocnemius fascicle length shortened, the pennation angle increased and the fascicles bulged transversally in one direction (closest to the typical 2D scanning plane) while thinning in the other orthogonal direction. We suggest that the transverse deformation of the muscle fascicles depends on the stiffness of the aponeuroses, properties of connective tissue structures surrounding muscle, and compressive forces both internal and external to the muscle. These results highlight that muscle fascicles do not bulge uniformly and the implications for this behaviour on muscle function remain largely unexplored.


Comparative efficacy, speed, and adverse effects of three PTSD treatments: exposure therapy, EMDR, and relaxation training.
The authors examined the efficacy, speed, and incidence of symptom worsening for 3 treatments of posttraumatic stress disorder (PTSD): prolonged exposure, relaxation training, or eye movement desensitization and reprocessing (EMDR; N = 60). Treaments did not differ in attrition, in the incidence of symptom worsening, or in their effects on numbing and hyperarousal symptoms. Compared with EMDR and relaxation training, exposure therapy (a) produced significantly larger reductions in avoidance and reexperiencing symptoms, (b) tended to be faster at reducing avoidance, and (c) tended to yield a greater proportion of participants who no longer met criteria for PTSD after treatment. EMDR and relaxation did not differ from one another in speed or efficacy.


The Product of Yersinia pseudotuberculosis mcc Operon Is a Peptide-Cytidine Antibiotic Activated Inside Producing Cells by the TldD/E Protease.
Microcin C is a heptapeptide-adenylate antibiotic produced by some strains of Escherichia coli. Its peptide part is responsible for facilitated transport inside sensitive cells where it is proteolyzed with release of a toxic warhead-a nonhydrolyzable aspartamidyl-adenylate, which inhibits aspartyl-tRNA synthetase. Recently, a microcin C homologue from Bacillus amyloliquefaciens containing a longer peptide part modified with carboxymethyl-cytosine instead of adenosine was described, but no biological activity of this compound was revealed. Here, we characterize modified peptide-cytidylate from Yersinia pseudotuberculosis. As reported for B. amyloliquefaciens homologue, the initially synthesized compound contains a long peptide that is biologically inactive. This compound is subjected to endoproteolytic processing inside producing cells by the evolutionary conserved TldD/E protease. As a result, an 11-amino acid long peptide with C-terminal modified cytosine residue is produced. This compound is exported outside the producing cell and is bioactive, inhibiting sensitive cells in the same way as E. coli microcin C. Proteolytic processing inside producing cells is a novel strategy of peptide-nucleotide antibiotics biosynthesis that may help control production levels and avoid toxicity to the producer.


Patterns for RANTES secretion and intercellular adhesion molecule 1 expression mediate transepithelial T cell traffic based on analyses in vitro and in vivo.
Immune cell migration into and through mucosal barrier sites in general and airway sites in particular is a critical feature of immune and inflammatory responses, but the determinants of transepithelial (unlike transendothelial) immune cell traffic are poorly defined. Accordingly, we used primary culture airway epithelial cells and peripheral blood mononuclear cells to develop a cell monolayer system that allows for apical-to-basal and basal-to-apical T cell transmigration that can be monitored with quantitative immunofluorescence flow cytometry. In this system, T cell adhesion and subsequent transmigration were blocked in both directions by monoclonal antibodies (mAbs) against lymphocyte function-associated antigen 1 (LFA-1) or intercellular adhesion molecule 1 (ICAM-1) (induced by interferon gamma [IFN-gamma] treatment of epithelial cells). The total number of adherent plus transmigrated T cells was also similar in both directions, and this pattern fit with uniform presentation of ICAM-1 along the apical and basolateral cell surfaces. However, the relative number of transmigrated to adherent T cells (i.e., the efficiency of transmigration) was increased in the basal-to-apical relative to the apical-to-basal direction, so an additional mechanism was needed to mediate directional movement towards the apical surface. Screening for epithelial-derived beta-chemokines indicated that IFN-gamma treatment caused selective expression of RANTES (regulated upon activation, normal T cell expressed and secreted), and the functional significance of this finding was demonstrated by inhibition of epithelial-T cell adhesion and transepithelial migration by anti-RANTES mAbs. In addition, we found that epithelial (but not endothelial) cells preferentially secreted RANTES through the apical cell surface thereby establishing a chemical gradient for chemotaxis across the epithelium to a site where they may be retained by high levels of RANTES and apical ICAM-1. These patterns for epithelial presentation of ICAM-1 and secretion of RANTES appear preserved in airway epithelial tissue studied either ex vivo with expression induced by IFN-gamma treatment or in vivo with endogenous expression induced by inflammatory disease (i.e., asthma). Taken together, the results define how the patterns for uniform presentation of ICAM-1 along the cell surface and specific apical sorting of RANTES may serve to mediate the level and directionality of T cell traffic through epithelium (distinct from endothelium) and provide a basis for how this process is precisely coordinated to route immune cells to the mucosal surface and maintain them there under normal and stimulated conditions.


Vision Outcomes for Pediatric Patients With Optic Pathway Gliomas Associated With Neurofibromatosis Type I: A Systematic Review of the Clinical Evidence.
Children with neurofibromatosis type I (NF1) have a higher predisposition for low-grade astrocytomas of the optic pathway, commonly referred to as optic pathway gliomas (OPGs). OPGs can result in visual deterioration. Treatment outcomes in OPG-NF1 management are often reported around tumor stabilization. We sought to compare vision outcomes associated with different OPG treatment strategies to inform about this important functional metric. A meta-analysis exploring the different modalities to treat children with OPG-NF1 was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using multiple databases. Of the 113 articles identified in the search, 23 full text articles, representing 564 patients, were included for review. These articles included retrospective, prospective, and randomized controlled studies on observation (n=9), chemotherapy (n=19), radiation therapy (n=6), and surgery (n=7). Of the patients undergoing observation, 87% (60/69) demonstrated stable acuity. In the chemotherapy studies, 27.3% (72/264) demonstrated improved acuity/visual field and/or visual-evoked potential amplitudes, 39.4% (104/264) stable acuity, and 33.3% (88/264) deterioration. Both the radiation and surgical treatments reported worsening acuity at 90.9% (10/11) and 73.3% (11/15), respectively. Causal associations are not known. Indications for and timing of treatment choice warrant larger scale study to provide further understanding.


Treatment Minimization in Older Patients With Early-Stage Breast Cancer.
The management of early-stage breast cancer in older patients is complex and requires a careful balance of the risk of cancer death with the competing risks of comorbidities and treatment-related toxicity in women with largely favorable disease. As the US population continues to age, oncologists will increasingly encounter this clinical challenge. Several strategies involving each core component of breast cancer therapy have been investigated to minimize treatment in these patients while still maintaining acceptable outcomes. These include omission of primary tumor resection, surgical axillary evaluation, systemic chemotherapy, and/or radiotherapy, as well as reduction in radiotherapy treatment volume (partial breast irradiation) or total treatment time (hypofractionation). We review these strategies and the literature supporting their use, as well as future directions for treatment minimization.


Mycobacterium tuberculosis complex enhances susceptibility of CD4 T cells to HIV through a TLR2-mediated pathway.
Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex) could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs) collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC(2)155, and stimulated CD4+ cells were infected with R5-and X4-tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01). Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4-tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition.


Development of calf diarrhoea vaccines.
Rotavirus and enterotoxigenic E. coli were found to cause approximately three-quarters of the total number of outbreaks of diarrhoea in young calves. Vaccinating pregnant cows with a combined vaccine of K99 antigen from E. coli and inactivated calf rotavirus stimulated secretion of specific antibodies in colostrum and milk. Calves born to vaccinated cows were completely protected against experimental enterotoxigenic colibacillosis. The efficacy of the rotavirus component is being investigated in field trials from which the early results look promising.


The development of necroptosis: what we can learn.
Necroptosis is a new type of programmed cell death discovered in recent years, playing an important role in various diseases. Since it was conceptualized in 2005, research on necroptosis has developed rapidly. However, few bibliometric analyses have provided a comprehensive overview of the field. This study aimed to employ a bibliometric analysis to assess necroptosis research's current status and hotspot, highlight landmark findings, and orientate future research. A total of 3993 publications from the WoSCC were collected for this study. Multiple tools were used for bibliometric analysis and data visualization, including an online website, VOSviewer, CiteSpace, and HistCite. Publications related to necroptosis have increased significantly annually, especially in the last 5 years. Globally, the USA and Harvard University are the most outstanding countries and institutions in this field, respectively. The academic groups managed by Peter Vandenabeele and Junying Yuan both have permanent and intensive research on necroptosis. Cell Death and Differentiation is the most vital journal in this field. The molecular mechanisms of necroptosis and its role in disease are the focus of current research, while the crosstalk between programmed cell death is an emerging direction in the field. The "reactive oxygen species", "innate immunity", and "programmed cell death" may be potential research hotspots. Our results present a comprehensive knowledge map and explore research trends. Researchers and funding agencies on necroptosis can obtain helpful references from our study.


DPAC: A Tool for Differential Poly(A)-Cluster Usage from Poly(A)-Targeted RNAseq Data.
Poly(A)-tail targeted RNAseq approaches, such as 3'READS, PAS-Seq and Poly(A)-ClickSeq, are becoming popular alternatives to random-primed RNAseq to focus sequencing reads just to the 3' ends of polyadenylated RNAs to identify poly(A)-sites and characterize changes in their usage. Additionally, we and others have demonstrated that these approaches perform similarly to other RNAseq strategies for differential gene expression analysis, while saving on the volume of sequencing data required and providing a simpler library synthesis strategy. Here, we present DPAC ( D ifferential P oly( A )- C lustering); a streamlined pipeline for the preprocessing of poly(A)-tail targeted RNAseq data, mapping of poly(A)-sites, poly(A)-site clustering and annotation, and determination of differential poly(A)-cluster usage using DESeq2. Changes in poly(A)-cluster usage is simultaneously used to report differential gene expression, differential terminal exon usage and alternative polyadenylation (APA).


Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links.
Fibrosis is a pathological state characterized by excessive deposition of the extracellular matrix components leading to impaired tissue function in the affected organ. It results in scarring of the affected tissue akin to an over-healing wound as a consequence of chronic inflammation and repair in response to injury. Persistent trauma of susceptible oral mucosa due to habitual chewing of betel quid resulting in zealous healing of the mucosal tissue is one plausible explanation for the onset of oral submucous fibrosis (OSF). The irreversibility and resistance of collagen to degradation and its high potential to undergo malignant change are a major reason for morbidity in OSF. Hence, early diagnosis and timely treatment are crucial to prevent the progression of OSF to malignancy. This review focuses on the mechanistic insight into the role of collagen cross-links in advancing fibrosis and possible therapeutic targets that bring about a reversal of fibrosis. These options may be beneficial if attempted as a specific therapeutic modality in OSF as is in organ fibrosis. The upregulation of lysyl oxidase and lysyl hydroxylase has been shown to exhibit the higher levels of the hydroxylysine aldehyde-derived cross-links in fibrosis and tumor stroma promoting the tumor cell survival, resistance, and invasion. The in silico analysis highlights the potential drugs that may target the genes regulating collagen crosslinking.


Overweight, obesity and risk of work disability: a cohort study of construction workers in Germany.
Although obesity and permanent work disability impose a great burden on the individual and are very costly for society, data on the impact of being overweight on occupational disability are sparse, especially in men who work hard physically. The aim of this study was to investigate the association of body mass index (BMI) with work disability among construction workers. The association between BMI and work disability was examined during a mean follow-up period of 10.8 years in a cohort of 16,875 male construction workers in Württemberg, Germany, who participated in routine occupational health examinations from 1986 to 1992. Hazard ratios were calculated with normal weight (20.0-22.4 kg/m(2)) as reference using the Cox proportional hazards model, after adjustment for potential confounding factors. Overall, a U-shaped association of BMI with all-cause work disability (total number = 3064 cases) was observed, with the lowest risk of disabilities at BMI levels between 25 and 27.4 kg/m(2). Strong positive associations were observed between BMI and work disability due to osteoarthritis or cardiovascular diseases, whereas BMI was inversely related to work disability due to cancer, even after exclusion of the first 3 years of follow-up. Moderate overweight is not associated with increased risk of work disability among construction workers, but obesity increases the risk of work disability due to osteoarthritis and cardiovascular disease.


Brain Signatures of New (Pseudo-) Words: Visual Repetition in Associative and Non-associative Contexts.
The contribution of two different training contexts to online, gradual lexical acquisition was investigated by event-related potentials (ERPs) elicited by new, word-like stimuli. Pseudowords were repeatedly preceded by a picture representing a well-known object (semantic-associative training context) or by a hash mark (non-associative training context). The two training styles revealed differential effects of repetition in both behavioral and ERPs data. Repetition of pseudowords not associated with any stimulus gradually enhanced the late positive component (LPC) as well as speeded lexical categorization of these stimuli, suggesting the formation of episodic memory traces. However, repetition under the semantic-associative context caused higher reduction in N400 component and categorization latencies. This result suggests the facilitation in the lexico-semantic processing of pseudowords as a consequence of their progressive associations to picture-concepts, going beyond the visual memory trace that is generated under the non-associative context.


Estimating renal function in lupus nephritis: comparison of the Modification of Diet in Renal Disease and Cockcroft Gault equations.
Estimates of renal function are widely used in clinical practice and research. We assessed the performance of the Cockcroft-Gault (CG) and the Modification of Diet in Renal Disease (MDRD) equations in lupus nephritis patients. Data from ninety-seven lupus nephritis patients in the Hopkins Lupus Cohort were reviewed. Two renal function estimates, the CG and the MDRD, were compared with the 24 h creatinine clearance (CrCl). In the entire group of patients, the CG and MDRD equations had good global agreement with CrCl (R-square = 0.91 and 0.69, respectively). On average the CG equation overestimated CrCl by 2.36 mL/min/1.73 m(2), whereas the MDRD equation underestimated CrCl by 5.85 mL/min/1.73 m(2), P = 0.0004. The CG equation had greater accuracy (mean squared error) than the MDRD equation (14.93 versus 28.47 mL/min/1.73 m(2), P = 0.002) when predicting CrCl. Although both equations lacked precision (standard deviation of the difference scores) in patients with CrCl > or = 60 mL/min/1.73 m(2), the CG equation was more precise than the MDRD equation in this group, (15.68 versus 29.58 mL/min/1.73 m(2), P = 0.003). In lupus nephritis patients, the CG equation was superior to the MDRD equation as an estimate of CrCl. However, both equations lacked precision in patients with CrCl > or = 60 mL/min/1.73 m(2).


"Glucose and ethanol-dependent transcriptional regulation of the astaxanthin biosynthesis pathway in Xanthophyllomyces dendrorhous".
The yeast Xanthophyllomyces dendrorhous is one of the most promising and economically attractive natural sources of astaxanthin. The biosynthesis of this valuable carotenoid is a complex process for which the regulatory mechanisms remain mostly unknown. Several studies have shown a strong correlation between the carbon source present in the medium and the amount of pigments synthesized. Carotenoid production is especially low when high glucose concentrations are used in the medium, while a significant increase is observed with non-fermentable carbon sources. However, the molecular basis of this phenomenon has not been established. In this work, we showed that glucose caused transcriptional repression of the three genes involved in the synthesis of astaxanthin from geranylgeranyl pyrophosphate in X. dendrorhous, which correlates with a complete inhibition of pigment synthesis. Strikingly, this regulatory response was completely altered in mutant strains that are incapable of synthesizing astaxanthin. However, we found that addition of ethanol caused the induction of crtYB and crtS gene expression and promoted de novo synthesis of carotenoids. The induction of carotenogenesis was noticeable as early as 24 h after ethanol addition. For the first time, we demonstrated that carbon source-dependent regulation of astaxanthin biosynthesis in X. dendrorhous involves changes at the transcriptional level. Such regulatory mechanism provides an explanation for the strong and early inhibitory effect of glucose on the biosynthesis of this carotenoid.


The double burden.
One third of the world's population is latently infected with Mycobacterium tuberculosis, and with the lifestyle changes succeeding the on-going urbanization, populations already burdened by tuberculosis are experiencing a dramatic increase in chronic diseases, with diabetes being a serious challenge. Tuberculosis and diabetes are not only becoming co-existing diseases. In fact, the diseases interact, and there is evidence to suggest that especially diabetes disease increases the susceptibility for developing active tuberculosis disease. Furthermore, it is plausible that tuberculosis leads to, either transient or permanent, impairment of the glucose metabolism, which ultimately will turn into diabetes. A number of studies from the Americas, Europe, Asia, and, most lately, from sub-Saharan Africa have reported strong association between tuberculosis and diabetes; on average, the estimated risk of active tuberculosis is thrice as high among people with diabetes. The study from sub-Saharan Africa was conducted in Tanzania and is the basis of this thesis. Based on available evidence on the association between tuberculosis and diabetes, the primary aim of the study was to assess the role of diabetes for tuberculosis risk, manifestations, treatment outcomes and survival in a Tanzanian population of tuberculosis patients and non-tuberculosis neighbourhood controls. The study was conducted in Mwanza City in northern Tanzania, with a population exceeding half a million inhabitants, with tuberculosis and HIV being common infections in the region, but with little knowledge about the prevalence of diabetes. We recruited newly diagnosed pulmonary tuberculosis patients from spring 2006 and continuously till the fall 2009, with all participating in a nutritional intervention running in parallel with the medical tuberculosis treatment. All participants underwent diabetes and HIV testing as well as a series of measurements such as anthropometric, clinical and paraclinical parameters. The population was followed up during treatment (2 and 5 months) to assess treatment outcome as well as after one year to assess their survival status. Based on data from 1,250 tuberculosis patients and 350 neighbourhood controls, we found that 38 and 21%, respectively, had impaired glycaemia, and that the prevalence of diabetes was 17 and 9% among tuberculosis patients and controls, respectively. This difference in prevalence between patients and controls was equivalent to an adjusted odds ratio of more than four, indicating a strong association between tuberculosis and diabetes. Furthermore, we found that diabetes was associated with tuberculosis among both participants with or without HIV co-infection. Despite the strong association, diabetes had only moderate clinical implications when the tuberculosis patients initiated the tuberculosis treatment; the patients with diabetes co-morbidity had a minor elevation in the immune response and more frequently reported to have fever. Furthermore, diabetes did not seem to delay time to sputum conversion during treatment. Nevertheless, diabetes co-morbidity led to impaired treatment outcome with slower recovery of weight and haemoglobin and a more than four times higher mortality rate within the initial phase of tuberculosis treatment. In conclusion, in the African region, the double burden of tuberculosis and diabetes is becoming a major health problem. Although the tuberculosis incidence has stabilized during the last decade, the increasing incidence of diabetes will possibly interfere with tuberculosis control and may, consequently, make the tuberculosis incidence increase again. Future research strategies should focus on enhanced diagnostic tools to identify tuberculosis patients with diabetes co-morbidity, and on the role of disease-disease, drug-disease and drug-drug interactions between tuberculosis and diabetes diseases and treatments.


Assessing the influence of a passive, upper extremity exoskeletal vest for tasks requiring arm elevation: Part I - "Expected" effects on discomfort, shoulder muscle activity, and work task performance.
Use of exoskeletal vests (designed to support overhead work) can be an effective intervention approach for tasks involving arm elevation, yet little is known on the potential beneficial impacts of their use on physical demands and task performance. This laboratory study (n = 12) evaluated the effects of a prototype exoskeletal vest during simulated repetitive overhead drilling and light assembly tasks. Anticipated or expected benefits were assessed, in terms of perceived discomfort, shoulder muscle activity, and task performance. Using the exoskeletal vest did not substantially influence perceived discomfort, but did decrease normalized shoulder muscle activity levels (e.g., ≤ 45% reduction in peak activity). Drilling task completion time decreased by nearly 20% with the vest, but the number of errors increased. Overall, exoskeletal vest use has the potential to be a new intervention for work requiring arm elevation; however, additional investigations are needed regarding potential unexpected or adverse influences (see Part II).


Pulmonary transcriptomic responses indicate a dual role of inflammation in pneumonia development and viral clearance during 2009 pandemic influenza infection.
The interaction between influenza virus and the host response to infection clearly plays an important role in determining the outcome of infection. While much is known on the participation of inflammation on the pathogenesis of severe A (H1N1) pandemic 09-influenza virus, its role in the course of non-fatal pneumonia has not been fully addressed. A systems biology approach was used to define gene expression profiles, histology and viral dynamics in the lungs of healthy immune-competent mice with pneumonia caused by a human influenza A (H1N1) pdm09 virus, which successfully resolved the infection. Viral infection activated a marked pro-inflammatory response at the lung level paralleling the emergence of histological changes. Cellular immune response and cytokine signaling were the two signaling pathway categories more representative of our analysis. This transcriptome response was associated to viral clearance, and its resolution was accompanied by resolution of histopathology. These findings suggest a dual role of pulmonary inflammation in viral clearance and development of pneumonia during non-fatal infection caused by the 2009 pandemic influenza virus. Understanding the dynamics of the host's transcriptomic and virological changes over the course of the infection caused by A (H1N1) pdm09 virus may help identifying the immune response profiles associated with an effective response against influenza virus.


It's a Process: Reactions to HIV Diagnosis and Engagement in HIV Care among High-Risk Heterosexuals.
After HIV diagnosis, heterosexuals in high-poverty urban areas evidence delays in linkage to care and antiretroviral therapy initiation compared to other groups. Yet barriers to/facilitators of HIV care among these high-risk heterosexuals are understudied. Under the theory of triadic influence, putative barriers to HIV care engagement include individual/attitudinal-level (e.g., fear, medical distrust), social-level (e.g., stigma), and structural-level influences (e.g., poor access). Participants were African-American/Black and Hispanic adults found newly diagnosed with HIV (N = 25) as part of a community-based HIV testing study with heterosexuals in a high-poverty, high-HIV-incidence urban area. A sequential explanatory mixed-methods design was used. We described linkage to HIV care and clinical outcomes [CD4 counts, viral load (VL) levels] over 1 year, and then addressed qualitative research questions about the experience of receiving a new HIV diagnosis, its effects on timely engagement in HIV care, and other barriers and facilitators. Participants were assessed five times, receiving a structured interview battery, laboratory tests, data extraction from the medical record, a post-test counseling session, and in-person/phone contacts to foster linkage to care. Participants were randomly selected for qualitative interviews (N = 15/25) that were recorded and transcribed, then analyzed using systematic content analysis. Participants were 50 years old, on average (SD = 7.2 years), mostly male (80%), primarily African-American/Black (88%), and low socioeconomic status. At the first follow-up, rates of engagement in care were high (78%), but viral suppression was modest (39%). Rates improved by the final follow-up (96% engaged, 62% virally suppressed). Two-thirds (69%) were adequately retained in care over 1 year. Qualitative results revealed multi-faceted responses to receiving an HIV diagnosis. Problems accepting and internalizing one's HIV status were common. Reaching acceptance of one's HIV-infected status was frequently a protracted and circuitous process, but acceptance is vital for engagement in HIV care. Fear of stigma and loss of important relationships were potent barriers to acceptance. Thus, partially as a result of difficulties accepting HIV status, delays in achieving an undetectable VL are common in this population, with serious potential negative consequences for individual and public health. Interventions to foster acceptance of HIV status are needed.


Electrolyte and Additive Engineering for Zn Anode Interfacial Regulation in Aqueous Zinc Batteries.
Aqueous Zn-metal batteries (AZMBs) have gained great interest due to their low cost, eco-friendliness, and inherent safety, which serve as a promising complement to the existing metal-based batteries, e.g., lithium-metal batteries and sodium-metal batteries. Although the utilization of aqueous electrolytes and Zn metal anode in AZMBs ensures their improved safety over other metal batteries meanwhile guaranteeing their decent energy density at the cell level, plenty of challenges involved with metallic Zn anode still await to be addressed, including dendrite growth, hydrogen evolution reaction, and zinc corrosion and passivation. In the past years, several attempts have been adopted to address these problems, among which engineering the aqueous electrolytes and additives is regarded as a facile and promising approach. In this review, a comprehensive summary of aqueous electrolytes and electrolyte additives will be given based on the recent literature, aiming at providing a fundamental understanding of the challenges associated with the metallic Zn anode in aqueous electrolytes, meanwhile offering a guideline for the electrolytes and additives engineering strategies toward stable AZMBs in the future.


Biochemical map of polypeptides specified by foot-and-mouth disease virus.
Pulse-chase labeling of foot-and-mouth disease virus-infected bovine kidney cells revealed stable and unstable viral-specific polypeptides. To identify precursor-product relationships among these polypeptides, antisera against a number of structural and nonstructural viral-specific polypeptides were used. Cell-free translations programmed with foot-and-mouth disease virion RNA or foot-and-mouth disease virus-infected bovine kidney cell lysates, which were shown to contain almost identical polypeptides, were immunoprecipitated with the various antisera. To further establish identity, some proteins were compared by partial protease digestion. Evidence for a membrane association of the polypeptides coded for by the middle genome region is also presented. A biochemical map of the foot-and-mouth disease virus genome was established from the above information.


Combination of cell signaling molecules can facilitate MYOD1-mediated myogenic transdifferentiation of pig fibroblasts.
Myogenic transdifferentiation can be accomplished through ectopic MYOD1 expression, which is facilitated by various signaling pathways associated with myogenesis. In this study, we attempted to transdifferentiate pig embryonic fibroblasts (PEFs) myogenically into skeletal muscle through overexpression of the pig MYOD1 gene and modulation of the FGF, TGF-β, WNT, and cAMP signaling pathways. The MYOD1 overexpression vector was constructed based on comparative sequence analysis, demonstrating that pig MYOD1 has evolutionarily conserved domains across various species. Although forced MYOD1 expression through these vectors triggered the expression of endogenous muscle markers, transdifferentiated muscle cells from fibroblasts were not observed. Therefore, various signaling molecules, including FGF2, SB431542, CHIR99021, and forskolin, along with MYOD1 overexpression were applied to enhance the myogenic reprogramming. The modified conditions led to the derivation of myotubes and activation of muscle markers in PEFs, as determined by qPCR and immunostaining. Notably, a sarcomere-like structure was observed, indicating that terminally differentiated skeletal muscle could be obtained from transdifferentiated cells. In summary, we established a protocol for reprogramming MYOD1-overexpressing PEFs into the mature skeletal muscle using signaling molecules. Our myogenic reprogramming can be used as a cell source for muscle disease models in regenerative medicine and the production of cultured meat in cellular agriculture.


Flow Diversion of Posterior Circulation Cerebral Aneurysms: A Single-Institution Series of 59 Cases.
Posterior circulation cerebral aneurysms are at higher risk of rupture and are more symptomatic than those in the anterior circulation. Existing treatments carry significant morbidity. Early reports of flow diversion for posterior circulation aneurysms have suggested high complication and low occlusion rates. To report safety and efficacy of flow diversion with the pipeline embolization device (ev3, Medtronic Inc, Dublin, Ireland) for aneurysms located throughout the posterior circulation. A prospective, institutional review board-approved database was analyzed for all patients with posterior circulation aneurysms treated by flow diversion at our institution. Fifty-nine embolization procedures were performed on 55 patients. Average aneurysm size was 9.4 mm. Morphology was saccular (45%), fusiform (29%), or dissecting/pseudo-aneurysms (25%). Sixty-two percent of aneurysms arose along the vertebral artery. There were 7 mid-basilar (13%) and 7 basilar apex (13%) aneurysms. Procedural success was 98%; 1 Pipeline embolization device was placed in 85%; and coiling was performed in 17% of cases. There were 5 major complications (8%), all strokes. Patients with major stroke had modified Rankin Scale score at last follow-up of 1, 3, 4, 6, and 6 (2 mortalities). There were zero intracerebral or subarachnoid hemorrhages. No variable predicted complications on univariate or multivariate analysis. Follow-up digital subtraction angiography was performed for 43 patients (78%). Complete occlusion was 68% at 6 mo and 78% at 12 mo. Average follow-up was 11.8 mo. Fusiform or dissecting morphology and large or giant aneurysm size were predictors of aneurysm persistence at 6 mo on multivariate logistic regression. This is a large single-institution series of Pipeline (Medtronic Inc) for posterior circulation aneurysms and demonstrates acceptable safety and effectiveness in these challenging cases.


Patellar tilt correlates with vastus lateralis: vastus medialis activation ratio in maltracking patellofemoral pain patients.
Patellofemoral (PF) pain is a common ailment of the lower extremity. A theorized cause for pain is patellar maltracking due to vasti muscle activation imbalance, represented as large vastus lateralis:vastus medialis (VL:VM) activation ratios. However, evidence relating vasti muscle activation imbalance to patellar maltracking is limited. The purpose of this study was to investigate the relationship between VL:VM activation ratio and patellar tracking measures, patellar tilt and bisect offset, in PF pain subjects and pain-free controls. We evaluated VL:VM activation ratio and VM activation delay relative to VL activation in 39 PF pain subjects and 15 pain-free controls during walking. We classified the PF pain subjects into normal tracking and maltracking groups based on patellar tilt and bisect offset measured from weight-bearing magnetic resonance imaging. Patellar tilt correlated with VL:VM activation ratio only in PF pain subjects classified as maltrackers. This suggests that a clinical intervention targeting vasti muscle activation imbalance may be effective only in PF pain subjects classified as maltrackers.


Cardiogenetics: the role of genetic testing for inherited arrhythmia syndromes and sudden death.
There have been remarkable advances in our knowledge of the underlying heritability of cardiac arrhythmias. Long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive cardiac conduction disease and the short QT syndrome comprise the inherited arrhythmia syndromes (IASs). Pathogenic variants in cardiac ion channel and calcium handling protein genes lead to these conditions, usually in the absence of overt structural cardiac disease. Diagnosis is contingent on the ECG phenotype but genetic testing may help to confirm the diagnosis and provide information on the mechanism of arrhythmogenesis that may guide treatment and provide prognostic information in relation to the risk of sudden arrhythmic death. Clinical genetic testing uses 'panels' of genes that are the likely culprits for the IASs being investigated. An International Consortium (Clinical Genome Resource) has curated gene panels based on genetic and experimental evidence of causation of inherited conditions and that have a role in clinical genetic testing. A 'single gene' or monogenic basis for IASs exists but in future, missing heritability and incomplete penetrance will be uncovered by association of common variants through genome-wide association studies. Novel rare variants will also be detected through whole-genome sequencing. The formulation of polygenic risk scores will likely help to predict phenotypic expression and response to treatments/risk stratification and move genetic testing very much to the fore of the diagnostic process.


YAHA: fast and flexible long-read alignment with optimal breakpoint detection.
With improved short-read assembly algorithms and the recent development of long-read sequencers, split mapping will soon be the preferred method for structural variant (SV) detection. Yet, current alignment tools are not well suited for this. We present YAHA, a fast and flexible hash-based aligner. YAHA is as fast and accurate as BWA-SW at finding the single best alignment per query and is dramatically faster and more sensitive than both SSAHA2 and MegaBLAST at finding all possible alignments. Unlike other aligners that report all, or one, alignment per query, or that use simple heuristics to select alignments, YAHA uses a directed acyclic graph to find the optimal set of alignments that cover a query using a biologically relevant breakpoint penalty. YAHA can also report multiple mappings per defined segment of the query. We show that YAHA detects more breakpoints in less time than BWA-SW across all SV classes, and especially excels at complex SVs comprising multiple breakpoints. YAHA is currently supported on 64-bit Linux systems. Binaries and sample data are freely available for download from http://faculty.virginia.edu/irahall/YAHA. email@example.com.


Predicting Long-Term Stability of an Oral Delivered Antibody Drug Product with Accelerated Stability Assessment Program Modeling.
The oral delivery of protein therapeutics offers numerous advantages for patients but also presents significant challenges in terms of development. Currently, there is limited knowledge available regarding the stability and shelf life of orally delivered protein therapeutics. In this study, a comprehensive assessment of the stability of an orally delivered solid dosage variable domain of heavy-chain antibody (VHH antibody) drug product was conducted. Four stability related quality attributes that undergo change as a result of thermal and humidity stress were identified. Subsequently, these attributes were modeled using an accelerated stability approach facilitated by ASAPprime software. To the best of our knowledge, this is the first time that this approach has been reported for an antibody drug product. We observed overall good model quality and accurate predictions regarding the protein stability during storage. Notably, we discovered that protein aggregation, formed through a degradation pathway, requires additional adjustments to the modeling method. In summary, the ASAP approach demonstrated promising results in predicting the stability of this complex solid-state protein formulation. This study sheds light on the stability and shelf life of orally delivered protein therapeutics, addressing an important knowledge gap in the field.