A martius flap in the treatment of iatrogenic distal urogenital fistula.
Distal urogenital fistulas (DUF) are usually iatrogenic and are uncommon in Europe. They occur in the urethra or near the bladder neck, and can be caused by vaginal hysterectomy, para-urethral cyst surgery, or erosion of the bladder or urethra from tension-free slings or meshes. The psychological and physical health consequences of DUF are devastating because most patients consider themselves "healthy" before surgery. Incontinence can appear after successful DUF closure due to previously occult incontinence or urethral incompetence. Additional surgery for incontinence is sometimes necessary to achieve satisfactory outcome. A Martius flap was used in 23 patients between 2000 and 2015. Patient age range was 38-75 years (mean, 58.7). DUF was due to gynecologic surgery for benign disease (15 / 23; 65.2%), mesh / sling erosion (2 / 23; 8.7%), and malignancy (6 / 23; 26.1%). The follow-up period was one year. DUF was closed in 22 patients (95.6%). Satisfaction and complete dryness was achieved in 16 patients (69.6%) after the first procedure. Postoperative complications were: postoperative hematoma in 1 (4.4%), primary failure in 1 (4.4%), overactive bladder (OAB) syndrome in 3 (13.2%) and postoperative incontinence in 6 (26.4%) patients. A fascial sling was placed in patients with incontinence. All patients were dry after the secondary surgery. Anticholinergics were used for the treatment of OAB syndrome. Discomfort at the flap harvesting site was of minor importance. Finally, 22 out of 23 patients (95.6%) were satisfied. A Martius flap and additional fascial sling could be successfully used to optimize DUF treatment.


MINT and IntAct contribute to the Second BioCreative challenge: serving the text-mining community with high quality molecular interaction data.
In the absence of consolidated pipelines to archive biological data electronically, information dispersed in the literature must be captured by manual annotation. Unfortunately, manual annotation is time consuming and the coverage of published interaction data is therefore far from complete. The use of text-mining tools to identify relevant publications and to assist in the initial information extraction could help to improve the efficiency of the curation process and, as a consequence, the database coverage of data available in the literature. The 2006 BioCreative competition was aimed at evaluating text-mining procedures in comparison with manual annotation of protein-protein interactions. To aid the BioCreative protein-protein interaction task, IntAct and MINT (Molecular INTeraction) provided both the training and the test datasets. Data from both databases are comparable because they were curated according to the same standards. During the manual curation process, the major cause of data loss in mining the articles for information was ambiguity in the mapping of the gene names to stable UniProtKB database identifiers. It was also observed that most of the information about interactions was contained only within the full-text of the publication; hence, text mining of protein-protein interaction data will require the analysis of the full-text of the articles and cannot be restricted to the abstract. The development of text-mining tools to extract protein-protein interaction information may increase the literature coverage achieved by manual curation. To support the text-mining community, databases will highlight those sentences within the articles that describe the interactions. These will supply data-miners with a high quality dataset for algorithm development. Furthermore, the dictionary of terms created by the BioCreative competitors could enrich the synonym list of the PSI-MI (Proteomics Standards Initiative-Molecular Interactions) controlled vocabulary, which is used by both databases to annotate their data content.


An online non-meditative mindfulness intervention for people with ALS and their caregivers: a randomized controlled trial.
Objectives: Mindfulness-based interventions seem to be effective in promoting QOL of ALS patients and caregivers, but most require substantial time. In the Langerian approach, mindfulness can be easily promoted with mental tasks and short lectures. This study aims to explore the impact of an ALS-specific online Langerian mindfulness training program on QOL of ALS patients. Methods: We developed and tested with an Randomized Controlled Trial (RCT) a 5-week active learning mindfulness program. Participants were recruited from the ALS clinic at Penn State Health and online and were randomly assigned to either the mindfulness group or a wait-list control group. The primary outcome was the patient's QOL after the treatment. 3 and 6-month follow-ups, together with anxiety, depression, care burden, and physical function, assessed at all times for both patients and caregivers, were explored as secondary outcomes. Results: 47 ALS patients and 27 caregivers were recruited. Among the ALS patients, the experimental group reported higher levels of QOL at the end of the treatment (d = 0.54). Moreover, they showed lower values of depression, anxiety, and negative emotions, compared to the controls, over time. The caregivers from the mindfulness group reported lower scores of care burden, depression, and anxiety, with higher values of energy and emotional well-being over time. Conclusions: This small RCT provides preliminary evidence that this intervention leads to an increase of QOL and a reduction in psychological comorbidities in ALS patients and caregivers. Given the relatively short time commitment, it may be easily implemented by the ALS community.


Estimating the position and orientation of a mobile robot with respect to a trajectory using omnidirectional imaging and global appearance.
Along the past years, mobile robots have proliferated both in domestic and in industrial environments to solve some tasks such as cleaning, assistance, or material transportation. One of their advantages is the ability to operate in wide areas without the necessity of introducing changes into the existing infrastructure. Thanks to the sensors they may be equipped with and their processing systems, mobile robots constitute a versatile alternative to solve a wide range of applications. When designing the control system of a mobile robot so that it carries out a task autonomously in an unknown environment, it is expected to take decisions about its localization in the environment and about the trajectory that it has to follow in order to arrive to the target points. More concisely, the robot has to find a relatively good solution to two crucial problems: building a model of the environment, and estimating the position of the robot within this model. In this work, we propose a framework to solve these problems using only visual information. The mobile robot is equipped with a catadioptric vision sensor that provides omnidirectional images from the environment. First, the robot goes along the trajectories to include in the model and uses the visual information captured to build this model. After that, the robot is able to estimate its position and orientation with respect to the trajectory. Among the possible approaches to solve these problems, global appearance techniques are used in this work. They have emerged recently as a robust and efficient alternative compared to landmark extraction techniques. A global description method based on Radon Transform is used to design mapping and localization algorithms and a set of images captured by a mobile robot in a real environment, under realistic operation conditions, is used to test the performance of these algorithms.


Reducing Fluoroscopic Radiation Exposure During Endomyocardial Biopsy in Pediatric Transplant Recipients.
Endomyocardial biopsy (EMB) with fluoroscopy is used for rejection surveillance in pediatric heart transplantation. Lowering frame rate may reduce radiation, but decreases temporal resolution and image quality. We undertook a quality initiative reducing frame rate from 10 frames per second (FPS) to 5 FPS. To assess whether lowering frame rate can reduce radiation exposure without compromising safety, data on EMBs from 9/2009 to 4/2013 without angiography or intervention were reviewed. Effective dose was calculated from dose area product (DAP) and fluoroscopy time. Complications were reviewed. Independent t test compared pre- and post-data and a general linear model were used to control for confounders. Paired t test of most proximate data was used for pts with EMB before and after our change. Eighty-six patients had 543 EMB. After adjusting for weight, attending, and presence of a fellow, the lower FPS group had a 60.3% reduction in DAP (p < 0.0001) and 53.8% drop in effective dose (p < 0.0001). Fluoroscopy time did not differ. Twenty-eight pts had EMBs both before and after the FPS change. Pair-wise analysis of this group demonstrated a 33% reduction in DAP (p < 0.05) and 37% drop in effective dose (p < 0.01), without difference in fluoroscopy time. No patient had an increase in TR > 1 grade by ECHO. There were no deaths or perforations. Lowering the frame rate reduces radiation exposure by >50% without compromising safety. Efforts to further minimize radiation exposure of this vulnerable population should be considered.


Efficacy of recombinant human C1 esterase inhibitor for the treatment of severe hereditary angioedema attacks.
Severe attacks of hereditary angioedema (HAE) are debilitating and potentially life threatening, and can increase anxiety and the use of medical resources. This post hoc assessment evaluated recombinant human C1 esterase inhibitor (rhC1-INH) used to treat acute severe HAE attacks. In a double-blind, randomized-controlled trial (RCT), patients with an HAE attack (baseline visual analog scale score of ≥50 mm, with severe attacks defined as ≥75 mm) were randomly assigned to receive rhC1-INH (50 IU/kg for patients who weighed <84 kg; 4200 IU for patients who weighed ≥84 kg) or placebo. Also, in an open-label extension (OLE) study of rhC1-INH, oropharyngeal-laryngeal attacks were analyzed. Rescue therapy with rhC1-INH 50 IU/kg (≤4200 IU) was permitted after 4 hours or for life-threatening symptoms (in the RCT) or after 1 hour (in the OLE study). The primary end point measured the time to the beginning of symptom relief by using the Treatment Effects Questionnaire. Of 75 adults in the RCT, 43 had severe attacks and received either rhC1-INH (n = 24) or placebo (n = 19). The median (95% confidence interval) time to the onset of symptom relief totaled 90.0 minutes (95% confidence interval, 47.0-120.0 minutes) versus 334.0 minutes (95% confidence interval, 105.0 to not calculable minutes; hazard ratio, 2.5; p = 0.02), for rhC1-INH and placebo, respectively. Open-label rhC1-INH rescue therapy was administered to 1 of 24 in the rhC1-INH group (4.2%) and 10 of 19 in the placebo group (52.6%). During the OLE study, the median onset of symptom relief with rhC1-INH for eight oropharyngeal-laryngeal HAE attacks was 69.0 minutes (95% confidence interval, 59.0-91.0 minutes). In the current study, rhC1-INH was efficacious in resolving severe HAE attacks, including oropharyngeal-laryngeal attacks. The rhC1-INH rescue treatment rapidly improved symptoms for patients who received placebo and who experienced worsening or sustained symptoms.


Dunn View Alpha Angle More Useful Than Femoral Head-Neck Offset to Predict Acetabular Cartilage Damage in Patients With Femoroacetabular Impingement Syndrome Undergoing Hip Arthroscopy.
To identify radiographic measurements and demographics that are predictive of acetabular cartilage damage in patients with femoroacetabular impingement syndrome (FAIS) undergoing hip arthroscopy. More specifically, to compare the predictive value of alpha angle and femoral head-neck offset, as measured on Dunn view radiographs, in determining the preoperative likelihood and severity of acetabular cartilage damage. Patients were included if they underwent primary hip arthroscopy for FAIS between February 2008 and June 2020. Exclusion criteria were prior ipsilateral hip conditions, Tönnis grade of osteoarthritis >1, unwilling to participate, missing intraoperative, demographic or radiographic variables of interest, and lateral center-edge angle (LCEA) >40° or ≤25°. Fourteen variables were assessed in a bivariate comparison and analyzed in a multivariate logistic model. The Acetabular Labrum Articular Disruption (ALAD) and Outerbridge (OB) classifications were used to define acetabular cartilage defects. Those without damage or those with mild acetabular cartilage damage belonged to the ALAD/OB ≤2 group and those with severe damage belonged to the ALAD/OB ≥ 3 group. A total of 1485 patients were analyzed, including 1038 patients with ALAD/OB ≤2 and 447 patients with ALAD/OB ≥3. There was a greater proportion of males in the ALAD/OB ≥3 group (64.21% vs 25.82%; P <.001). The multivariate logistic regression selected age, sex, anterior center-edge angle (ACEA), and alpha angle. Every additional degree in the alpha angle was associated with a 6% increase in the odds of severe acetabular cartilage damage (odds ratio [OR], 1.06 [95% confidence interval [CI], 0.12-8.11]). The multivariate analysis did not identify femoral head-neck offset as a predictor. The odds of severe acetabular cartilage damage were 3.73 times higher in males than females (OR, 3.73 [95% CI, 0.01-1705.96]). Higher age was found to increase the likelihood of ALAD/OB ≥3 (OR, 1.04 [95% CI, 0.13-7.75]). In a multivariate analysis, factors identified as preoperative predictors of acetabular cartilage damage in patients with FAIS were age, sex, ACEA, and alpha angle. Femoral head-neck offset was not predictive, suggesting that Dunn view alpha angle may take precedence as a predictor of acetabular cartilage damage. Level III, cohort study.


Left-Biased Spermatogenic Failure in 129/SvJ Dnd1Ter/+ Mice Correlates with Differences in Vascular Architecture, Oxygen Availability, and Metabolites.
Homozygosity for the Ter mutation in the RNA-binding protein Dead end 1 (Dnd1(Ter/Ter)) sensitizes germ cells to degeneration in all mouse strains. In 129/SvJ mice, approximately 10% of Dnd1(Ter/+) heterozygotes develop spermatogenic failure, and 95% of unilateral cases occur in the left testis. The first differences between right and left testes were detected at Postnatal Day 15 when many more spermatogonial stem cells (SSCs) were undergoing apoptosis in the left testis compared to the right. As we detected no significant left/right differences in the molecular pathway associated with body axis asymmetry or in the expression of signals known to promote proliferation, differentiation, and survival of germ cells, we investigated whether physiological differences might account for asymmetry of the degeneration phenotype. We show that left/right differences in vascular architecture are associated with a decrease in hemoglobin saturation and increased levels of HIF-1alpha in the left testis compared to the right. In Dnd1 heterozygotes, lower oxygen availability was associated with metabolic differences, including lower levels of ATP and NADH in the left testis. These experiments suggest a dependence on oxygen availability and metabolic substrates for SSC survival and suggest that Dnd1(Ter/+) SSCs may act as efficient sensors to detect subtle environmental changes that alter SSC fate.


A randomized, controlled trial of an intervention promoting cataract surgery acceptance in rural China: the Guangzhou Uptake of Surgery Trial (GUSTO).
To evaluate an educational intervention promoting acceptance of cataract surgery in rural China using a randomized controlled design. Patients aged 50 years or older with presenting visual acuity (PVA) less than 6/18 in one or both eyes due to cataract were recruited from 26 screening sessions (13 intervention, 13 control) conducted by five rural hospitals in Guangdong, China. At intervention sessions, subjects were shown a 5-minute informational video, and counseled about cataract, surgery, and surgical cost. During screening, all subjects answered questionnaires on knowledge and attitudes about cataract, their finances, and transportation, and were referred for definitive examination if eligible. Study outcomes were acceptance of surgery (principal outcome) and hospital follow-up. Subjects in the intervention group were younger than controls (P = 0.01), but the groups did not otherwise differ. Among 212 intervention patients and 222 controls, no differences in knowledge and attitude regarding cataract were found. Surgery was accepted by 31.1% of intervention patients and 34.2% of controls (P > 0.50). Predictors of acceptance included younger age, worse logMAR PVA, knowing that cataract can be treated surgically only, greater anticipated loss in income from hospitalization, and greater house floor space per person. Membership in the intervention group was not associated with accepting surgery (odds ratio [OR] = 1.11, 95% confidence interval [CI] 0.67-1.84) or hospital follow-up (OR = 1.03, 95% CI = 0.63-1.67). Educational interventions that successfully impart the knowledge that cataract can be only treated surgically may be more effective in increasing uptake in this setting. (ClinicalTrials.gov number, NCT01123928.).


Longitudinal Treatment Patterns and Associated Outcomes in Patients With Newly Diagnosed Systemic Lupus Erythematosus.
The treatment of systemic lupus erythematosus (SLE) is complex, with a wide range of drugs commonly prescribed. The aims of this study were to identify longitudinal treatment patterns in patients with incident SLE and to estimate the associations of treatment patterns with clinical and economic outcomes. This retrospective, observational cohort study used a US managed care claims database to identify patients with newly diagnosed SLE and 4-year treatment follow-up. Patients were aged ≥ 18 years, with continuous medical and pharmacy benefits for 12 months before and 48 months after the index date (first medical claim with a diagnosis of SLE). Longitudinal treatment patterns were grouped using a k-means cluster analysis. Therapies were included in the cluster analysis if the mean number of prescriptions in each year was ≥ 0.05. Clinical and economic outcomes were compared across clusters using multivariate regression analyses. Data from 1611 patients with incident SLE were analyzed (91.4% women; mean [SD] age, 44.5 [9.5] years; 56.2% managed primarily by a specialist). Hydroxychloroquine and corticosteroids were the most commonly prescribed therapies; methotrexate, azathioprine, and mycophenolate mofetil also met the criteria for inclusion in the cluster analysis. Ten treatment clusters were identified; the most common was minimally treated patients (42.8%). Hydroxychloroquine monotherapy, corticosteroid monotherapy, and corticosteroid/hydroxychloroquine combination therapy were received by 34.0%, 11.2%, and 7.8% of patients, respectively. Methotrexate or azathioprine with a corticosteroid/hydroxychloroquine were received by 4.2% of patients. Changes in therapy, except discontinuations, were rare. Compared with the minimally treated cluster, those that received corticosteroid monotherapy (mean dose, >12.0 mg/d) had poorer clinical and economic outcomes; the hydroxychloroquine-monotherapy cluster had similar or better outcomes; and patients who received a corticosteroid/hydroxychloroquine with or without methotrexate or azathioprine demonstrated outcomes that were poorer but that appeared better than those with corticosteroid monotherapy. SLE-related visits with a nonspecialist were common (~45%) and remained unchanged over time despite better clinical and economic outcomes associated with specialist visits. This study utilized cluster analysis, an unsupervised machine-learning method, to systematically discern treatment patterns over 4 years and to estimate outcomes associated with the identified treatment patterns. The results suggest that minimal treatment is the most common approach in patients with newly diagnosed SLE. Clinical and economic outcomes are poorest with corticosteroid monotherapy but may improve with the addition of hydroxychloroquine and/or an immunosuppressive agent. A large proportion of SLE care is provided by nonspecialists despite the potential benefits of involving a specialist.


Fabibacter misakiensis sp. nov., a marine bacterium isolated from coastal surface water.
A slightly curved-rod-shaped, pink-pigmented, Gram-stain-negative, aerobic bacterial strain with gliding motility, designated SK-8T, was isolated from coastal surface water of Misaki, Japan. Phylogenetic trees generated using 16S rRNA gene sequences revealed that strain SK-8T belonged to the genus Fabibacter and showed 96.0 % sequence similarity to the type strain of the most closely related species, Fabibacter pacificus DY53T. The novel isolate was phenotypically and physiologically different from previously described strains. The major cellular fatty acids were iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH. Major polar lipids were phosphatidylethanolamine, two aminophospholipids and an unidentified phospholipid. The DNA G+C content was 39.1 mol% and MK-7 was the only predominant isoprenoid quinone. On the basis of this taxonomic study employing a polyphasic approach, it was suggested that strain SK-8T represents a novel species of the genus Fabibacter, with the newly proposed name Fabibacter misakiensis sp. nov. The type strain is SK-8T ( = NBRC 110216T = KCTC 32969T).


Complete nucleotide sequence of a type 4 hepatitis C virus variant, the predominant genotype in the Middle East.
Hepatitis C virus (HCV) type 4 is the predominant genotype found throughout the Middle East and parts of Africa, often in association with high population prevalence as in Egypt. To investigate more fully its evolutionary relationship with other genotypes of HCV, and to study its overall genome organization, we have determined the entire sequence encompassing the coding region of the genotype 4a isolate ED43, obtained from an HCV-infected individual from Egypt. The sequence of ED43 contained a single open reading frame encoding a polyprotein of 3008 amino acids (aa), smaller than that reported for other HCV genotypes which vary from 3010 aa to 3037 aa. The nucleotide and amino acid sequences were compared with the full-length sequences already reported for genotypes 1a, 1b, 1c, 2a, 2b, 2c, 3a, 3b and those of isolates JKO49 and JKO46 described as types 10a and 11a. The differences in length of the polyprotein originated in variable regions in the E2 and NS5A genes. The complete sequence of ED43 confirmed the classification of type 4 as a separate major genotype.


Anal Carcinoma, Version 2.2012: featured updates to the NCCN guidelines.
The workup and management of squamous cell anal carcinoma, which represents the most common histologic form of the disease, are addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma. These NCCN Guidelines Insights provide a summary of major discussion points of the 2012 NCCN Anal Carcinoma Panel meeting. In summary, the panel made 4 significant changes to the 2012 NCCN Guidelines for Anal Carcinoma: 1) local radiation therapy was added as an option for the treatment of patients with metastatic disease; 2) multifield technique is now preferred over anteroposterior-posteroanterior (AP-PA) technique for radiation delivery and the AP-PA technique is no longer recommended as the standard of care; 3) PET/CT should now be considered for radiation therapy planning; and 4) a section on risk reduction was added to the discussion section. In addition, the panel discussed the use of PET/CT for the workup of anal canal cancer and decided to maintain the recommendation that it can be considered in this setting. They also discussed the use of PET/CT for the workup of anal margin cancer and for the assessment of treatment response. They reaffirmed their recommendation that PET/CT is not appropriate in these settings.


Basaloid squamous cell carcinoma of oral cavity with incongruent clinical course.
Basaloid squamous cell carcinoma (BSCC) is a rare variant of SCC having a marked predilection for the upper aerodigestive tract. It is regarded as a high-grade tumour with increased propensity for metastasis to distant sites. The histological hallmark of BSCC is its dimorphic pattern of presentation with a characteristic basal cell component associated with squamous component. We report two cases of BSCC on the buccal mucosa and gingiva, respectively, with the former presenting as a primary lesion in a patient without a positive history of tobacco and alcohol use and the latter present as a seemingly metachronous development from carcinoma lung. The proliferative index of the two diverse yet similar entities was assessed by Ki-67 labelling index (LI) and the association of human papillomavirus (HPV) was detected with p16 monoclonal antibody. The intrinsically aggressive behaviour of BSCC and its association with HPV is highlighted.


MP2RAGEME: T1 , T2* , and QSM mapping in one sequence at 7 tesla.
Quantitative magnetic resonance imaging generates images of meaningful physical or chemical variables measured in physical units that allow quantitative comparisons between tissue regions and among subjects scanned at the same or different sites. Here, we show that we can acquire quantitative T1 , T2* , and quantitative susceptibility mapping (QSM) information in a single acquisition, using a multi-echo (ME) extension of the second gradient-echo image of the MP2RAGE sequence. This combination is called MP2RAGE ME, or MP2RAGEME. The simultaneous acquisition results in large time savings, perfectly coregistered data, and minimal image quality differences compared to separately acquired data. Following a correction for residual transmit B1+ -sensitivity, quantitative T1 , T2* , and QSM values were in excellent agreement with those obtained from separately acquired, also B1+ -corrected, MP2RAGE data and ME gradient echo data. The quantitative values from reference regions of interests were also in very good correspondence with literature values. From the MP2RAGEME data, we further derived a multiparametric cortical parcellation, as well as a combined arterial and venous map. In sum, our MP2RAGEME sequence has the benefit in large time savings, perfectly coregistered data and minor image quality differences.


Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma.
Glioma stem cells (GSCs), a subpopulation of tumor cells, contribute to tumor heterogeneity and therapy resistance. Gene expression profiling classified glioblastoma (GBM) and GSCs into four transcriptomically-defined subtypes. Here, we determined the DNA methylation signatures in transcriptomically pre-classified GSC and GBM bulk tumors subtypes. We hypothesized that these DNA methylation signatures correlate with gene expression and are uniquely associated either with only GSCs or only GBM bulk tumors. Additional methylation signatures may be commonly associated with both GSCs and GBM bulk tumors, i.e., common to non-stem-like and stem-like tumor cell populations and correlating with the clinical prognosis of glioma patients. We analyzed Illumina 450K methylation array and expression data from a panel of 23 patient-derived GSCs. We referenced these results with The Cancer Genome Atlas (TCGA) GBM datasets to generate methylomic and transcriptomic signatures for GSCs and GBM bulk tumors of each transcriptomically pre-defined tumor subtype. Survival analyses were carried out for these signature genes using publicly available datasets, including from TCGA. We report that DNA methylation signatures in proneural and mesenchymal tumor subtypes are either unique to GSCs, unique to GBM bulk tumors, or common to both. Further, dysregulated DNA methylation correlates with gene expression and clinical prognoses. Additionally, many previously identified transcriptionally-regulated markers are also dysregulated due to DNA methylation. The subtype-specific DNA methylation signatures described in this study could be useful for refining GBM sub-classification, improving prognostic accuracy, and making therapeutic decisions.


Exercise for diabetic pregnant women.
Diabetes in pregnancy may result in unfavourable maternal and neonatal outcomes. Exercise was proposed as an additional strategy to improve glycaemic control. The effect of exercise during pregnancies complicated by diabetes needs to be assessed. To evaluate the effect of exercise programs, alone or in conjunction with other therapies, compared to no specific program or to other therapies, in pregnant women with diabetes on perinatal and maternal morbidity and on the frequency of prescription of insulin to control glycaemia. To compare the effectiveness of different types of exercise programs on perinatal and maternal morbidity. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2005). All known randomised controlled trials evaluating the effect of exercise in diabetic pregnant women on perinatal outcome and maternal morbidity. We evaluated relevant studies for meeting the inclusion criteria and methodological quality. Three review authors abstracted the data. For all data analyses, we entered data based on the principle of intention to treat. We calculated relative risks and 95% confidence intervals for dichotomous data. Four trials, involving 114 pregnant women with gestational diabetes, were included in the review. None included pregnant women with type 1 or type 2 diabetes. Women were recruited during the third trimester and the intervention was performed for about six weeks. The programs generally consisted in exercising three times a week for 20 to 45 minutes. We found no significant difference between exercise and the other regimen in all the outcomes evaluated. There is insufficient evidence to recommend, or advise against, diabetic pregnant women to enrol in exercise programs. Further trials, with larger sample size, involving women with gestational diabetes, and possibly type 1 and 2 diabetes, are needed to evaluate this intervention.


The groin flap in reparative surgery of the hand.
The historical literature of the use of axial vascular pattern flaps from the hypogastric and iliofemoral regions in reparative surgery of the hand is concisely reviewed. Thirty-six iliofemoral (groin) flaps were utilized for delayed primary resurfacing and secondary reconstruction of defects of the hand and forearm. Two flaps (6 percent) were complicated by partial necrosis. We caution against the immediate resurfacing (within 24 hours of injury) of acute crushed hand wounds by distant flaps. The immediate application of a healthy flap on a soiled or crushed wound invites complications of local tissue necrosis, infection, and subsequent loss of the flap. When distant flaps are indicated for coverage of acute hand wounds, delayed primary coverage following complete removal of all nonviable tissue is a safe and reliable regimen. It is advantageous to design the serviceable portion of the flap on the distal area of the vascular territory of the groin flap. Thoughtful yet "radical" defatting can be performed on the lateral portion of the groin flap territory. Constructed in this way, the long medial base of the groin flap allows freedom for movement at the wrist and metacarpophalangeal and interphalangeal joints, thus decreasing edema and stiffness. In the management of soft-tissue defects in the hand requiring distant flap coverage, we choose to utilize the conventional groin flap in preference to the microvascular free flap when both techniques will deliver equal results.


Normotriglyceridemic abetalipoproteinemia. absence of the B-100 apolipoprotein.
In the two genetic forms of abetalipoproteinemia described previously, recessive abetalipoproteinemia and homozygous hypobetalipoproteinemia, all lipoproteins that normally contain apolipoprotein B are absent from plasma. We describe here a new disorder in which normal low density and very low density lipoproteins are absent, but in which triglycerides are absorbed from the intestine and chylomicrons are present in plasma. The underlying molecular defect appears to be selective deletion of the hepatogenous B-100 apolipoprotein. The B-48 apolipoprotein found in chylomicrons is spared. These findings suggest that the two species of apolipoprotein B are under separate genetic control and that low density lipoproteins are not normally derived from chylomicrons.


The effects of clinical practice guidelines on patient outcomes in primary care: a systematic review.
To assess the evidence for the effectiveness of clinical practice guidelines (CPGs) in improving patient outcomes in primary care. A search of the MEDLINE, HEALTHPLAN, CINAHL and FAMLI databases was conducted to identify studies published between Jan. 1, 1980, and Dec. 31, 1995, concerning the use of guidelines in primary medical care. The keywords used in the search were "clinical guidelines," "primary care," "clinical care," "intervention," "randomized controlled trial" and "effectiveness." Studies of the use of CPGs were selected if they involved a randomized experimental or quasi-experimental method, concerned primary care, were related to clinical care and examined patient outcomes. Of 91 trials of CPGs identified through the search, 13 met the criteria for inclusion in the critical appraisal. The following data were extracted, when possible, from the 13 trials: country and setting, number of physicians, number of patients (and the proportion followed to completion), length of follow-up, study method (including random assignment method), type of intervention, medical condition treated and effect on patient outcomes (including clinical and statistical significance, with confidence intervals). The most common conditions studied were hypertension (7 studies), asthma (2 studies) and cigarette smoking (2 studies). Four of the studies followed nationally developed guidelines, and 9 used locally developed guidelines. Six studies involved computerized or automated reminder systems, whereas the others relied on small-group workshops and education sessions. Only 5 of the 13 trials (38%) produced statistically significant results. There is very little evidence that the use of CPGs improves patient outcomes in primary medical care, but most studies published to date have used older guidelines and methods, which may have been insensitive to small changes in outcomes. Research is needed to determine whether the newer, evidence-based CPGs have an effect on patient outcomes.


Périgord black truffle genome uncovers evolutionary origins and mechanisms of symbiosis.
The Périgord black truffle (Tuber melanosporum Vittad.) and the Piedmont white truffle dominate today's truffle market. The hypogeous fruiting body of T. melanosporum is a gastronomic delicacy produced by an ectomycorrhizal symbiont endemic to calcareous soils in southern Europe. The worldwide demand for this truffle has fuelled intense efforts at cultivation. Identification of processes that condition and trigger fruit body and symbiosis formation, ultimately leading to efficient crop production, will be facilitated by a thorough analysis of truffle genomic traits. In the ectomycorrhizal Laccaria bicolor, the expansion of gene families may have acted as a 'symbiosis toolbox'. This feature may however reflect evolution of this particular taxon and not a general trait shared by all ectomycorrhizal species. To get a better understanding of the biology and evolution of the ectomycorrhizal symbiosis, we report here the sequence of the haploid genome of T. melanosporum, which at approximately 125 megabases is the largest and most complex fungal genome sequenced so far. This expansion results from a proliferation of transposable elements accounting for approximately 58% of the genome. In contrast, this genome only contains approximately 7,500 protein-coding genes with very rare multigene families. It lacks large sets of carbohydrate cleaving enzymes, but a few of them involved in degradation of plant cell walls are induced in symbiotic tissues. The latter feature and the upregulation of genes encoding for lipases and multicopper oxidases suggest that T. melanosporum degrades its host cell walls during colonization. Symbiosis induces an increased expression of carbohydrate and amino acid transporters in both L. bicolor and T. melanosporum, but the comparison of genomic traits in the two ectomycorrhizal fungi showed that genetic predispositions for symbiosis-'the symbiosis toolbox'-evolved along different ways in ascomycetes and basidiomycetes.


The response to sex steroid hormones and vitamin D of cultured osteoblasts derived from ovariectomized mice with and without 17beta-estradiol pretreatment.
This study investigated whether 17beta-estradiol (E2) may have different effects on osteoblasts derived from estrogen-deficient ovariectomized (OVX) mice compared to sham-operated normal animals. We studied the specific effects of 17beta-estradiol on the differentiation and function of cultured osteoblasts derived from these groups of animals, with or without estrogen replacement treatment. One-month-old mice were ovariectomized or sham-operated, and treated (every second day) for 4 weeks with 0.5 mg/kg 17beta-estradiol or with vehicle alone. At the end of the experiment, bones were removed for primary osteoblast cultures or for morphological and chemical evaluation. In cells from untreated OVX animals, alkaline phosphatase (ALP) specific activity was reduced, while collagen production and mineralization were unchanged when compared to cells from controls. In vivo estrogen pretreatment of the OVX mice elevated ALP activity and mineralization of the cells, while collagen production was reduced. The addition of 17beta-estradiol to the culture medium increased ALP activity, collagen production, and mineralization by all cultured osteoblasts, except in those derived from sham-operated, estrogen-pretreated mice, where these features remained unchanged. Osteocalcin production was unchanged. Addition of testosterone or 1,25(OH)2D3 to the culture medium induced changes that differed among the groups depending on the source of the cultured cells. It seems that ovariectomy in mice prior to culture affected the phenotype of the cultured osteoblasts and their response to estradiol, testosterone, and 1,25(OH)2D3, depending on whether animals were pretreated with estradiol or not. These results imply that the animal's estrogen status prior to culture can influence the response to estrogens; this finding may have important implications for hormone replacement therapy (HRT) in postmenopausal women.


Multiplex protein detection on circulating tumor cells from liquid biopsies using imaging mass cytometry.
Molecular analysis of circulating and disseminated tumor cells (CTCs/DTCs) has great potential as a means for continuous evaluation of prognosis and treatment efficacy in near-real time through minimally invasive liquid biopsies. To realize this potential, however, methods for molecular analysis of these rare cells must be developed and validated. Here, we describe the integration of imaging mass cytometry (IMC) using metal-labeled antibodies as implemented on the Fluidigm Hyperion Imaging System into the workflow of the previously established High Definition Single Cell Analysis (HD-SCA) assay for liquid biopsies, along with methods for image analysis and signal normalization. Using liquid biopsies from a metastatic prostate cancer case, we demonstrate that IMC can extend the reach of CTC characterization to include dozens of protein biomarkers, with the potential to understand a range of biological properties that could affect therapeutic response, metastasis and immune surveillance when coupled with simultaneous phenotyping of thousands of leukocytes.


Lichenoid Drug Eruption following Intravenous Application of Orally Formulated Diamorphine, a Semisynthetic Heroin.
Lichen planus is a common skin disorder of unknown etiology. Most cases are idiopathic, but substances such as gold, antimalarials, penicillamine, thiazide diuretics, β-blockers, arsenic and nonsteroidal anti-inflammatory drugs have been implicated as trigger factors. We report the case of a lichenoid eruption in a male drug addict who administered oral heroin (diamorphine) intravenously. Diamorphine was stopped immediately. Following topical steroids, phototherapy and oral acitretin, the lesions gradually disappeared. A lymphocyte transformation test was negative for pure morphine and codeine. A coincidental association between the intravenous application of orally formulated semisynthetic heroin and the lichenoid eruption cannot be completely ruled out. However, the diagnosis of a lichenoid drug eruption is favoured over idiopathic lichen planus because of the clear chronological correlation between drug use and appearance as well as drug withdrawal and disappearance of the skin lesions, and because of a flare-up following repeated intravenous application of diamorphine.


'Parabolic' trapped modes and steered Dirac cones in platonic crystals.
This paper discusses the properties of flexural waves governed by the biharmonic operator, and propagating in a thin plate pinned at doubly periodic sets of points. The emphases are on the design of dispersion surfaces having the Dirac cone topology, and on the related topic of trapped modes in plates for a finite set (cluster) of pinned points. The Dirac cone topologies we exhibit have at least two cones touching at a point in the reciprocal lattice, augmented by another band passing through the point. We show that these Dirac cones can be steered along symmetry lines in the Brillouin zone by varying the aspect ratio of rectangular lattices of pins, and that, as the cones are moved, the involved band surfaces tilt. We link Dirac points with a parabolic profile in their neighbourhood, and the characteristic of this parabolic profile decides the direction of propagation of the trapped mode in finite clusters.


Forensic Mitochondrial DNA Analysis: Current Practice and Future Potential.
Current practices for performing forensic mitochondrial DNA (mtDNA) sequence analysis, as employed in public and private laboratories across the United States, have changed remarkably little over the past 20 years. Alternative approaches have been developed and proposed, and new technologies have emerged, but the core methods have remained relatively unchanged. Once DNA has been recovered from biological material (for example, from older skeletal remains and hair shafts), segments of the mtDNA control region are amplified using a variety of approaches, dictated by the quality of the sample being tested. The amplified mtDNA products are subjected to Sanger-based sequencing and data interpretation is performed using one of many available software packages. These relatively simple methods, at least in retrospect, have remained robust, and have stood the test of time. However, alternative methods for mtDNA analysis remain viable options (for example, linear array assays and dHPLC), and should be revisited as the desire to streamline the testing process, interpret heteroplasmy, and deconvolute mixed mtDNA profiles intensifies. Therefore, it is important to periodically reassess the alternative methods available to the mtDNA practitioner, and to evaluate newer technologies being put forth by the scientific community, for example, next-generation sequencing. Although the basic mitochondrial DNA protocols and practices of public and private laboratories are similar, an overview of the current practices of forensic mtDNA analysis is provided, helping to frame the path forward.


Inflammation: a driving force speeds cancer metastasis.
It has been increasingly recognized that tumor microenvironment plays an important role in carcinogenesis. Inflammatory component is present and contributes to tumor proliferation, angiogenesis, metastasis and resistance to hormonal and chemotherapy. This review highlights the role of inflammation in the tumor metastasis. We focus on the function of proinflammatory factors, particularly cytokines during tumor metastasis. Understanding of the mechanisms by which inflammation contributes to metastasis will lead to innovative approach for treating cancer. How tumor spread remains an enigma and has received great attention in recent years, as metastasis is the major cause of cancer mortality. The complex and highly selective metastatic cascade not only depends on the intrinsic properties of tumor cells but also the microenvironment that they derive from. An inflammatory milieu consisting of infiltrated immune cells and their secretory cytokines, chemokines and growth factors contribute significantly to the invasive and metastatic traits of cancer cells. Here, we review new insights into the molecular pathways that link inflammation in the tumor microenvironment to metastasis.


¹H, ¹⁵N and ¹³C backbone resonance assignments of the TPR1 and TPR2A domains of mouse STI1.
Hop/STI1 (Hsp-organizing protein/stress-induced-phosphoprotein 1) is a molecular co-chaperone, which coordinates Hsp70 and Hsp90 activity during client protein folding through interactions with its TPR1 and TPR2A domains. Hsp90 substrates include a diverse set of proteins, many of which have been implicated in tumorigenesis. Over-expression of Hsp90 in cancer cells stabilizes mutant oncoproteins promoting cancer cell survival. Disruption of Hsp90 and its co-chaperone machinery has become a promising strategy for the treatment of cancer. STI1 has also been described as a neurotrophic signaling molecule through its interactions with the prion protein (PrP(C)). Here, we report the (1)H, (13)C and (15)N backbone assignments of the TPR1 and TPR2A domains of mouse STI1, which interact with Hsp70 and Hsp90, respectively. (1)H-(15)N HSQC spectra of TPR2A domain in the presence of a peptide encoding the C-terminal Hsp90 binding site revealed significant chemical shift changes indicating complex formation. These results will facilitate the screening of potential molecules that inhibit STI1 complex formation with Hsp70 and/or Hsp90 for the treatment of cancer and detailed structural studies of the STI1-PrP(C) complex.


Thoracoscopic limited T-3 sympathicotomy for primary hyperhidrosis: prevention for compensatory hyperhidrosis.
Compensatory hyperhidrosis is a major and troublesome complication of thoracoscopic sympathectomy for primary hyperhidrosis. The incidence of compensatory hyperhidrosis has been reported to be as high as 50 to 97% in the patients who underwent sympathetic ganglia resection. In this study the authors evaluate the role of thoracoscopic T-3 sympathicotomy for primary hyperhidrosis and the prevention of compensatory hyperhidrosis. Thoracoscopic T-3 sympathicotomy was performed in 27 patients with either isolated palmar hyperhidrosis (24 cases) or that in combination with axillary hyperhidrosis (three cases) during a 3-year period. In the cases of combined palmar/axillary hyperhidrosis, the T-4 sympathetic ganglion also was coagulated. The mean follow-up period was 19.7 months. Surgery-related results were determined on the basis of complications, compensatory hyperhidrosis, and patient-related satisfaction. In the immediate postoperative period all 24 patients with palmar hyperhidrosis reported complete alleviation of their symptoms. One patient with palmar/axillary hyperhidrosis in whom axillary hyperhidrosis did not completely resolve underwent a repeated T-4 sympathicotomy 1 month after the initial surgery. Another patient suffered mild compensatory hyperhidrosis of the trunk 1 month postoperatively. The long-term satisfaction rate in all 27 patients was high. One patient required placement of a chest tube to treat pneumothorax. Other complications such as Homer syndrome, intercostal neuralgia, gustatory hyperhidrosis, and pulmonary edema were not observed. Thoracoscopic limited T-3 sympathicotomy is an effective method to treat primary hyperhidrosis, its rate of compensatory hyperhidrosis is low, and its rate of long-term patient satisfaction is high.


Utilization of anaerobic granular sludge for chromium (VI) removal from wastewater: optimization by response surface methodology.
In this study, anaerobic granular sludge (AGS) was used as a novel adsorbent for hexavalent chromium (Cr (VI)) removal from aqueous solutions. Factor experiments were conducted to find out the effects of different variables on the biosorption process. Among these terms, the impact of three main independent variables (contact time, initial pH and AGS dosage) on the removal efficiency of Cr (VI) was modeled using a well-fitting polynomial equation (R2 = 0.9044), by conducting 20 batch experiments designed by a central composite. The experimental isotherm data were successfully described by the Freundlich isotherm and the pseudo-second-order kinetic model was more suitable for explaining the kinetics process of adsorption. The AGS can be disposed using 0.1 M NaOH with 96.4% desorption efficiency. The results of the analyses (X-ray photoelectron spectroscopy and Fourier transformed infrared spectroscopy) suggested that Cr (VI) adsorption most likely involved electrostatic adsorption, redox reaction and complexation.


Towards a middle-range theory of mental health and well-being effects of employment transitions: Findings from a qualitative study on unemployment during the 2009-2010 economic recession.
This article builds upon previous theoretical work on job loss as a status passage to help explain how people's experiences of involuntary unemployment affected their mental well-being during the 2009-2010 economic recession. It proposes a middle-range theory that interprets employment transitions as status passages and suggests that their health and well-being effects depend on the personal and social meanings that people give to them, which are called properties of the transitions. The analyses, which used a thematic approach, are based on the findings of a qualitative study undertaken in Bradford (North England) consisting of 73 people interviewed in 16 focus groups. The study found that the participants experienced their job losses as divestment passages characterised by three main properties: experiences of reduced agency, disruption of role-based identities, for example, personal identity crises, and experiences of 'spoiled identities', for example, experiences of stigma. The proposed middle-range theory allows us to federate these findings together in a coherent framework which makes a contribution to illuminating not just the intra-personal consequences of unemployment, that is, its impact on subjective well-being and common mental health problems, but also its inter-personal consequences, that is, the hidden and often overlooked social processes that affect unemployed people's social well-being. This article discusses how the study findings and the proposed middle-range theory can help to address the theoretical weaknesses and often contradictory empirical findings from studies that use alternative frameworks, for example, deprivation models and 'incentive theory' of unemployment.


Cerebral blood flow is decoupled from blood pressure and linked to EEG bursting after resuscitation from cardiac arrest.
In the present study, we have developed a multi-modal instrument that combines laser speckle imaging, arterial blood pressure, and electroencephalography (EEG) to quantitatively assess cerebral blood flow (CBF), mean arterial pressure (MAP), and brain electrophysiology before, during, and after asphyxial cardiac arrest (CA) and resuscitation. Using the acquired data, we quantified the time and magnitude of the CBF hyperemic peak and stabilized hypoperfusion after resuscitation. Furthermore, we assessed the correlation between CBF and MAP before and after stabilized hypoperfusion. Finally, we examined when brain electrical activity resumes after resuscitation from CA with relation to CBF and MAP, and developed an empirical predictive model to predict when brain electrical activity resumes after resuscitation from CA. Our results show that: 1) more severe CA results in longer time to stabilized cerebral hypoperfusion; 2) CBF and MAP are coupled before stabilized hypoperfusion and uncoupled after stabilized hypoperfusion; 3) EEG activity (bursting) resumes after the CBF hyperemic phase and before stabilized hypoperfusion; 4) CBF predicts when EEG activity resumes for 5-min asphyxial CA, but is a poor predictor for 7-min asphyxial CA. Together, these novel findings highlight the importance of using multi-modal approaches to investigate CA recovery to better understand physiological processes and ultimately improve neurological outcome.


Animal activity around the clock with no overt circadian rhythms: patterns, mechanisms and adaptive value.
Circadian rhythms are ubiquitous in many organisms. Animals that are forced to be active around the clock typically show reduced performance, health and survival. Nevertheless, we review evidence of animals showing prolonged intervals of activity with attenuated or nil overt circadian rhythms and no apparent ill effects. We show that around-the-clock and ultradian activity patterns are more common than is generally appreciated, particularly in herbivores, in animals inhabiting polar regions and habitats with constant physical environments, in animals during specific life-history stages (such as migration or reproduction), and in highly social animals. The underlying mechanisms are diverse, but studies suggest that some circadian pacemakers continue to measure time in animals active around the clock. The prevalence of around-the-clock activity in diverse animals and habitats, and an apparent diversity of underlying mechanisms, are consistent with convergent evolution. We suggest that the basic organizational principles of the circadian system and its complexity encompass the potential for chronobiological plasticity. There may be trade-offs between benefits of persistent daily rhythms versus plasticity, which for reasons still poorly understood make overt daily arrhythmicity functionally adaptive only in selected habitats and for selected lifestyles.


Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody.
Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.


A comparative study of Barron's rubber band ligation with Kshar Sutra ligation in hemorrhoids.
Despite a long medical history of identification and treatment, hemorrhoids still pose a challenge to the medical fraternity in terms of finding satisfactory cure of the disease. In this study, Kshar Sutra Ligation (KSL), a modality of treatment described in Ayurveda, was compared with Barron's Rubber Band Ligation (RBL) for grade II and grade III hemorrhoids. This study was conducted in 20 adult patients of either sex with grade II and grade III hemorrhoids at two different hospitals. Patients were randomly allotted to two groups of 10 patients each. Group I patients underwent RBL, whereas patients of group II underwent KSL. Guggul-based Apamarga Kshar Sutra was prepared according to the principles laid down in ancient Ayurvedic texts and methodology standardized by IIIM, Jammu and CDRI, Lucknow. Comparative assessment of RBL and KSL was done according to 16 criteria. Although the two procedures were compared on 15 criteria, treatment outcome of grade II and grade III hemorrhoids was decided chiefly on the basis of patient satisfaction index (subjective criterion) and ability of each procedure to deal with prolapse of internal hemorrhoidal masses (objective criterion): Findings in each case were recorded over a follow-up of four weeks (postoperative days 1, 3, 7, 15 and 30). Statistical analysis was done using Student's t test for parametric data and Chi square test & Mann-Whitney test for non-parametric data. P < 0.05 was considered significant. RBL had the advantages of being an OPD procedure requiring no anesthesia and was attended by significantly lesser postoperative recumbency (P < 0.001 ) and significantly lesser pain (P < 0.005 on day 1) as compared to KSL. However, Group II (KSL) scored better in terms of treatment outcome. In Group II, there was significantly high (P < 0.05) patient satisfaction index as compared to Group I. Group II reported 100% 'cure' (absence of hemorrhoidal masses even on proctoscopy) of internal hemorrhoidal prolapse as against 80% in Group I (RBL); however, this difference was statistically insignificant (P > 0.05). Both the groups were comparable statistically on all other grounds. Kshar Sutra Ligation is a useful form of treatment for Grades II and III internal hemorrhoids.


Adaptive responses and disruptive effects: how major wildfire influences kinship-based social interactions in a forest marsupial.
Environmental disturbance is predicted to play a key role in the evolution of animal social behaviour. This is because disturbance affects key factors underlying social systems, such as demography, resource availability and genetic structure. However, because natural disturbances are unpredictable there is little information on their effects on social behaviour in wild populations. Here, we investigated how a major wildfire affected cooperation (sharing of hollow trees) by a hollow-dependent marsupial. We based two alternative social predictions on the impacts of fire on population density, genetic structure and resources. We predicted an adaptive social response from previous work showing that kin selection in den-sharing develops as competition for den resources increases. Thus, kin selection should occur in burnt areas because the fire caused loss of the majority of hollow-bearing trees, but no detectable mortality. Alternatively, fire may have a disruptive social effect, whereby postfire home range-shifts 'neutralize' fine-scale genetic structure, thereby removing opportunities for kin selection between neighbours. Both predictions occurred: the disruptive social effect in burnt habitat and the adaptive social response in adjacent unburnt habitat. The latter followed a massive demographic influx to unburnt 'refuge' habitat that increased competition for dens, leading to a density-related kin selection response. Our results show remarkable short-term plasticity of animal social behaviour and demonstrate how the social effects of disturbance extend into undisturbed habitat owing to landscape-scale demographic shifts. We predicted long-term changes in kinship-based cooperative behaviour resulting from the genetic and resource impacts of forecast changes to fire regimes in these forests.


p38 Mitogen-activated protein kinase/signal transducer and activator of transcription-3 pathway signaling regulates expression of inhibitory molecules in T cells activated by HIV-1-exposed dendritic cells.
Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3), T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1-primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules.


Zoonotic diseases associated with free-roaming cats.
Free-roaming cat populations have been identified as a significant public health threat and are a source for several zoonotic diseases including rabies, toxoplasmosis, cutaneous larval migrans because of various nematode parasites, plague, tularemia and murine typhus. Several of these diseases are reported to cause mortality in humans and can cause other important health issues including abortion, blindness, pruritic skin rashes and other various symptoms. A recent case of rabies in a young girl from California that likely was transmitted by a free-roaming cat underscores that free-roaming cats can be a source of zoonotic diseases. Increased attention has been placed on trap-neuter-release (TNR) programmes as a viable tool to manage cat populations. However, some studies have shown that TNR leads to increased immigration of unneutered cats into neutered populations as well as increased kitten survival in neutered groups. These compensatory mechanisms in neutered groups leading to increased kitten survival and immigration would confound rabies vaccination campaigns and produce naïve populations of cats that can serve as source of zoonotic disease agents owing to lack of immunity. This manuscript is a review of the various diseases of free-roaming cats and the public health implications associated with the cat populations.


A Bayesian Network Interpretation of the Cox's Proportional Hazard Model.
Cox's proportional hazards (CPH) model is quite likely the most popular modeling technique in survival analysis. While the CPH model is able to represent a relationship between a collection of risks and their common effect, Bayesian networks have become an attractive alternative with an increased modeling power and far broader applications. Our paper focuses on a Bayesian network interpretation of the CPH model (BN-Cox). We provide a method of encoding knowledge from existing CPH models in the process of knowledge engineering for Bayesian networks. This is important because in practice we often have CPH models available in the literature and no access to the original data from which they have been derived. We compare the accuracy of the resulting BN-Cox model to the original CPH model, Kaplan-Meier estimate, and Bayesian networks learned from data, including Naive Bayes, Tree Augmented Naive Bayes, Noisy-Max, and parameter learning by means of the EM algorithm. BN-Cox model came out as the most accurate of all BN approaches and very close to the original CPH model. We study two approaches for simplifying the BN-Cox model for the sake of representational and computational efficiency: (1) parent divorcing and (2) removing less important risk factors. We show that removing less important risk factors leads to smaller loss of accuracy.


Two-dimensional electronic excitations in self-assembled conjugated polymer nanocrystals
Several spectroscopic methods were applied to study the characteristic properties of the electronic excitations in thin films of regioregular and regiorandom polythiophene polymers. In the regioregular polymers, which form two-dimensional lamellar structures, increased interchain coupling strongly influences the traditional one-dimensional electronic properties of the polymer chains. The photogenerated charge excitations (polarons) show two-dimensional delocalization that results in a relatively small polaronic energy, multiple absorption bands in the gap where the lowest energy band becomes dominant, and associated infrared active vibrations with reverse absorption bands caused by electron-vibration interferences. The relatively weak absorption bands of the delocalized polaron in the visible and near-infrared spectral ranges may help to achieve laser action in nanocrystalline polymer devices using current injection.


[Topical Treatment of Pruritic Skin Disease and the Role of Community Pharmacists].
Itching, or pruritus, can be defined as an unpleasant sensation that evokes the desire to scratch. Pruritus is most commonly associated with a primary skin disorder such as atopic dermatitis (AD), psoriasis, etc., and can have a major impact on the quality of life of those patients. Itch-induced scratching can further damage the skin barrier, leading to a worsening of symptoms. For that reason, it is important to manage pruritus. Topical glucocorticoids are commonly the first-line therapy in the management of AD and psoriasis patients. We found that topical glucocorticoids induce pruritus in mice under certain conditions. Topical glucocorticoids may induce pruritus in a mouse model of allergic contact dermatitis via inhibition of prostaglandin (PG)D2 production in antigen-mediated activated mast cells in the skin. Additionally, topical glucocorticoids do not induce pruritus in healthy skin. These results indicate the importance of controlling skin inflammation to a healthy level by applying sufficient quantities of glucocorticoids to avoid glucocorticoid-induced pruritus. However, topical "steroid phobia" is common in Japan, and most patients apply inadequate amounts of topical glucocorticoids for this reason. This may cause glucocorticoid-induced pruritus in patients by prolonging the skin inflammation. We conducted a survey regarding community pharmacists' instructions on the application quantity of topical glucocorticoids and found that most community pharmacists have experienced inappropriate instructions concerning this point.


Visual impairment and age-related eye diseases in Florida: Findings from 2006 Behavioral Risk Factors Surveillance System (BRFSS) in Nine states.
To compare the prevalence of age-related eye disease, visual impairment, and eye care service utilization among adults aged 65 and older in Florida with eight other states. In 2006, nine states conducted the visual impairment and access to eye care module using the Behavioral Risk Factors Surveillance System (BRFSS) survey (N = 62,750). Visual impairment was based on self-reported ability to see distant and near objects. Age-related eye diseases including cataract, glaucoma, macular degeneration, and diabetic retinopathy were self-reported with diagnosis confirmed by a health care professional. Eye care visit or examination was assessed by whether a respondent reported an eye visit or dilated eye examination within the past year. THE ESTIMATED PREVALENCE OF DISTANT AND NEAR VISUAL IMPAIRMENT WAS LOWER IN FLORIDA THAN IN THE EIGHT OTHER STATES (DISTANT: 11.5% vs 15.2%, P < 0.001; near: 22.3% vs 28.7%, P < 0.001). There was no significant difference with the prevalence of age-related macular degeneration and diabetic retinopathy between these two groups. The prevalence of glaucoma and cataract was higher in Florida. The rates of eye care visits (80.5% vs 74.8%, P < 0.01) and dilated eye examinations (74.7% vs 64.0%, P < 0.01) were higher in Florida. After controlling for demographic variables, chronic conditions, insurance, and eye examination, results for elderly in Florida continued to demonstrate less visually impaired. Fewer elderly in Florida reported visual impairment in spite of comparable or higher prevalence of age-related eye diseases with other states. Health care utilization and health insurance for eye care coverage were also higher in Florida, which may account for the phenomena. More research is needed to investigate the association.


Decrease of beta-receptors after the antigen-specific bronchial provocation test in bronchial asthma.
Airway hyperreactivity to different stimuli is a characteristic feature of bronchial asthma. The beta-adrenergic theory, as proposed by Szentivanyi in 1968, tried to explain with beta-adrenergic dysfunction, the cause not only of bronchial hyperreactivity but of all atopic diseases. In a previous work, we found that asymptomatic asthmatic patients presented a number of beta-receptors similar to that of a normal control group, while symptomatic asthmatic patients presented a significantly decreased number when compared to both groups (40% decrease). In view of these results, we proposed to study the possible changes in the number of beta-receptors in asymptomatic asthmatic patients after a bronchial provocation test. Fifteen patients, diagnosed of bronchial asthma and sensitive to the house dust mite, D. pteronyssinus, were studied. All were free of medication and asymptomatic at least 90 days before the study. A test of specific bronchial provocation was performed on 10 patients, determining the number of beta-receptors in basal conditions, after 30 minutes and 24 hours. The other five patients underwent an unspecific provocation test with methacholine, with determination of the beta-receptor number at basal conditions, and 24 hours later. Only a significant decrease (30.4%) was found in the beta-receptor numbers, 24 hours after specific bronchial provocation with p less than 0.025 with the Student test for paired data. With regards the beta-adrenergic theory of atopy, in our opinion our results show that the detected decrease of beta-receptors would be the consequence and not the cause of atopic diseases.


Neural probes with multi-drug delivery capability.
Multi-functional neural probes are promising platforms to conduct efficient and effective in-depth studies of brain by recording neural signals as well as modulating the signals with various stimuli. Here we present a neural probe with an embedded microfluidic channel (chemtrode) with multi-drug delivery capability suitable for small animal experiments. We integrated a staggered herringbone mixer (SHM) in a 3-inlet microfluidic chip directly into our chemtrode. This chip, which also serves as a compact interface for the chemtrode, allows for efficient delivery of small volumes of multiple or concentration-modulated drugs via chaotic mixing. We demonstrated the successful infusion of combinatorial inputs of three chemicals with a low flow rate (170 nl min(-1)). By sequentially delivering red, green, and blue inks from each inlet and conducting visual inspections at the tip of the chemtrode, we measured a short residence time of 14 s which corresponds to a small swept volume of 66 nl. Finally, we demonstrated the potential of our proposed chemtrode as an enabling tool through extensive in vivo mice experiments. Through simultaneous infusions of a chemical (pilocarpine or tetrodotoxin (TTX) at inlet 1), a buffer solution (saline at inlet 2), and 4',6-diamidino-2-phenylindole (DAPI at inlet 3) locally into a mouse brain, we not only modulated the neural activities by varying the concentration of the chemical but also locally stained the cells at our target region (CA1 in hippocampus). More specifically, infusion of pilocarpine with a higher concentration resulted in an increase in neural activities while infusion of TTX with a higher concentration resulted in a distinctive reduction. For each chemical, we acquired multiple sets of data using only one mouse through a single implantation of the chemtrode. Our proposed chemtrode offers 1) multiplexed delivery of three drugs through a compact packaging with a small swept volume and 2) simultaneous recording to monitor near real-time effects on neural signals, which allows for more versatile in vivo experiments with a minimum number of animals to be sacrificed.


Differential responses to virus challenge of laboratory and wild accessions of australian species of nicotiana, and comparative analysis of RDR1 gene sequences.
Nicotiana benthamiana is a model plant utilised internationally in plant virology because of its apparent hyper-susceptibility to virus infection. Previously, others showed that all laboratory accessions of N. benthamiana have a very narrow genetic basis, probably originating from a single source. It is unknown if responses to virus infection exhibited by the laboratory accession are typical of the species as a whole. To test this, 23 accessions of N. benthamiana were collected from wild populations and challenged with one to four viruses. Additionally, accessions of 21 other Nicotiana species and subspecies from Australia, one from Peru and one from Namibia were tested for susceptibility to the viruses, and for the presence of a mutated RNA-dependent RNA polymerase I allele (Nb-RDR1m) described previously from a laboratory accession of N. benthamiana. All Australian Nicotiana accessions tested were susceptible to virus infections, although there was symptom variability within and between species. The most striking difference was that plants of a laboratory accession of N. benthamiana (RA-4) exhibited hypersensitivity to Yellow tailflower mild mottle tobamovirus infection and died, whereas plants of wild N. benthamiana accessions responded with non-necrotic symptoms. Plants of certain N. occidentalis accessions also exhibited initial hypersensitivity to Yellow tailflower mild mottle virus resembling that of N. benthamiana RA-4 plants, but later recovered. The mutant Nb-RDR1m allele was identified from N. benthamiana RA-4 but not from any of 51 other Nicotiana accessions, including wild accessions of N. benthamiana, demonstrating that the accession of N. benthamiana used widely in laboratories is unusual.


Estimating sludge loadings to land based on trace metal sorption in soil: effect of dissolved organo-metallic complexes.
This paper describes the results of research examining the effect of dissolved organo-metallic complexes of copper (Cu) and zinc (Zn) from sewage sludge leachate on sorption by a humic-gley soil A-horizon, and the influence of such complexes on resultant sludge loading estimates. Sorption was described with Linear, Freundlich or Langmuir equations, and compared between a sample of sludge leachate (containing 97.4% of Cu and 63.2% of Zn as dissolved organo-metallic complexes) and a reference solution (which mimicked the leachate, except for a lack of dissolved organic material). This comparison revealed that dissolved organo-metallic complexes significantly depressed Cu and Zn sorption in the study soil. The isotherm equations were then used to estimate sludge-derived Cu and Zn loadings to soil in order to result in an "allowable" output concentration from the soil solution to the surrounding environment. These loadings, together with soil bulk density and "availability" of sludge Cu and Zn, were incorporated in a preliminary model to estimate sludge application rates which are acceptable in terms of off-site movement of these metals through leaching losses. In the absence of dissolved organo-metallic complexes (sorption from the reference solution), levels of Cu and Zn sorption in the study soil indicated a sludge application rate of approximately 3500 kg/ha. However, when Cu and Zn sorption from the sludge leachate with dissolved organo-metallic complexes was considered, calculated loading rates were reduced to approximately 690 kg-sludge/ha. This suggests that for sludge loading estimates based on soil sorption characteristics to be relevant to environmental protection, the sorption depressing effect of dissolved organo-metallic complexes should be quantitatively considered.


Gadolinium-enhanced imaging of liver tumors and manifestations of hepatitis: pharmacodynamic and technical considerations.
The ability for contrast-enhanced magnetic resonance imaging to provide significant diagnostic impact to focal and diffuse liver diseases requires knowledge, analysis, and technical optimization of the imaging techniques. Our review outlines the technical requirements needed to perform reproducible contrast-enhanced liver imaging and describes the important imaging features for assessing liver disease with conventional and alternate gadolinium-based contrast media. We present an experimental review of timing and quantification methods in dynamic contrast-enhanced liver imaging, with results of analysis showing perfusion and uptake curves in a series of patients and healthy subjects. An evidence-based methodology for reproducible arterial-phase imaging is detailed for performing a real-time bolus-tracking method. Additional diagnostic imaging features manifest at later imaging phases, in which the kinetic behavior of the contrast media serves to further specify focal lesions, while revealing detailed information of diffuse liver disease, particularly hepatic fibrosis. We review the utility of alternate gadolinium-based contrast media that undergo hepatocyte uptake, for applications related to liver tumor imaging. We also introduce results showing the potential for using alternate hepatocyte uptake agents to detect and quantify liver changes related to acute and chronic hepatitides.


Clinical risk indices, prediction of osteoporosis, and prevention of fractures: diagnostic consequences and costs.
The primary aim of this study was to validate the Osteoporosis Self-Assessment Tools for Asians (OSTA) instrument in Thai women, and to evaluate its utility in terms of economic costs and fracture prediction. Femoral neck and lumbar spine BMD was measured by dual energy X-ray absorptiometry in 322 Thai women, aged 60+/-10 years (mean+/-SD; range: 45-84 years). The women were classified as having osteoporosis if their BMD T-scores were < or =-2.5. The OSTA score was calculated for each woman using her age and weight according to the formula: 0.2(weight-age). Women with OSTA scores < or =-1 and >-1 were classified as "high risk" and "low risk," respectively. The prevalence of osteoporosis was 33% by femoral neck or lumbar spine BMD. Using the OSTA score, 165 (51.2%) women were classified as high risk. The sensitivity, specificity and positive predictive value of OSTA was 82% 64% and 53%, respectively. If the OSTA score is used to identify women with high risk of fracture, and assuming that the incidence of fracture among osteoporotic and non-osteoporotic women are 2% and 1% per year, respectively, the OSTA score can identify 59% of fracture cases correctly, and 41% are expected to be missed. Furthermore, if the high-risk subjects identified by OSTA are to be treated, and if the treatment reduces fracture incidence by 50%, and assuming that the treatment cost is $1 per day, then the cost to prevent one fracture is estimated to be $48,530. Results of this study suggest that, in the Thai population, the OSTA score had high sensitivity but low specificity and low positive predictive value in the identification of osteoporotic women. Its use in the general population can result in a high false-positive rate and incur significant cost to the community.


Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia.
Acute mixed myeloid-lymphoid leukemia is uncommon. We report four cases in which myeloid and lymphoid cell markers were observed simultaneously or sequentially when 94 patients with acute leukemia were phenotyped according to the French-American-British (FAB) classification system, with cytochemical stains, and with immunologically defined differentiation markers (identified by monoclonal antibodies and antiterminal deoxynucleotidyl transferase [TdT]). In one case, conversion from acute lymphoblastic leukemia to acute myeloid leukemia was noted (FAB L1, TdT+ to FAB M4, Auer rods, TdT-). In another patient, two distinct populations of myeloid and lymphoid blast cells were observed simultaneously (TdT-, LeuM1+/TdT+, LeuM1-). In two additional patients, acute leukemia was characterized by the expression of both lymphoid and myeloid markers on the same cell (TdT+/Leu M1+, B4+/Leu M1+ and greater than or equal to 70% TdT+, T11+, My9+). The Philadelphia (Ph1) chromosome was negative in all cases, though other chromosomal abnormalities were noted in three out of four cases. Malignant transformation of a pluripotential stem cell for both lymphoid and myeloid lineages, with or without the Ph1 chromosome marker, could explain the coexistence of distinct populations of lymphoblasts and myeloblasts in acute leukemia. Acute leukemia with a biphenotypic profile may reflect genome depression accompanying neoplasia.


Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms.
The present study aimed to investigate the molecular mechanisms underlying the anticancer properties of ginger extract (GE) in mice bearing solid Ehrlich carcinoma (SEC) and to evaluate the use of GE in combination with doxorubicin (DOX) as a complementary therapy against SEC. SEC was induced in 60 female mice. Mice were divided into four equal groups: SEC, GE, DOX and GE + DOX. GE (100 mg/kg orally day after day) and DOX (4 mg/kg i.p. for 4 cycles every 5 days) were given to mice starting on day 12 of inoculation. On the 28th day, blood samples were collected, mice were scarified, tumor volume was measured, and tumor tissues were excised. The anti-cancer effect of GE was mediated by activation of adenosine monophosphate protein kinase (AMPK) and down-regulation of cyclin D1 gene expression. GE also showed pro-apoptotic properties as evidenced by elevation of the P53 and suppression of nuclear factor-kappa B (NF-κB) content in tumor tissue. Co-administration of GE alongside DOX markedly increased survival rate, decreased tumor volume, and increased the level of phosphorylated AMPK (PAMPK) and improved related pathways compared to DOX group. In addition, the histopathological results demonstrated enhanced apoptosis and absence of multinucleated cells in tumor tissue of GE + DOX group. AMPK pathway and cyclin D1 gene expression could be a molecular therapeutic target for the anticancer effect of GE in mice bearing SEC. Combining GE and DOX revealed a greater efficacy as anticancer therapeutic regimen.


Quorum sensing regulates type III secretion in Vibrio harveyi and Vibrio parahaemolyticus.
In a process known as quorum sensing, bacteria communicate with one another by producing, releasing, detecting, and responding to signal molecules called autoinducers. Vibrio harveyi, a marine pathogen, uses two parallel quorum-sensing circuits, each consisting of an autoinducer-sensor pair, to control the expression of genes required for bioluminescence and a number of other target genes. Genetic screens designed to discover autoinducer-regulated targets in V. harveyi have revealed genes encoding components of a putative type III secretion (TTS) system. Using transcriptional reporter fusions and TTS protein localization studies, we show that the TTS system is indeed functional in V. harveyi and that expression of the genes encoding the secretion machinery requires an intact quorum-sensing signal transduction cascade. The newly completed genome of the closely related marine bacterium Vibrio parahaemolyticus, which is a human pathogen, shows that it possesses the genes encoding both of the V. harveyi-like quorum-sensing signaling circuits and that it also has a TTS system similar to that of V. harveyi. We show that quorum sensing regulates TTS in V. parahaemolyticus. Previous reports connecting quorum sensing to TTS in enterohemorrhagic and enteropathogenic Escherichia coli show that quorum sensing activates TTS at high cell density. Surprisingly, we find that at high cell density (in the presence of autoinducers), quorum sensing represses TTS in V. harveyi and V. parahaemolyticus.


BRAF(V600E) Mutation, RET/PTC1 and PAX8-PPAR Gamma Rearrangements in Follicular Epithelium Derived Thyroid Lesions - Institutional Experience and Literature Review.
Thyroid cancers are the most frequently occurring endocrine malignancy worldwide. In Turkey, thyroid cancers are ranked 2(nd) on the incidence list in women, with a rate of 16.2%, but they are not included among the top 10 cancer types in men. To identify the contribution of the BRAF(V600E) mutation, and the RET/PTC1 and PAX8-PPARγ rearrangements in the diagnosis and differential diagnosis of follicular epithelial-derived thyroid lesions. Retrospective clinical and molecular genetic study. A total of 86 thyroid cases diagnosed between 2001 and 2012 at the Department of Pathology were included in the retrospective study group. Samples best representing the lesion and comprising capsules were chosen in the selection of paraffin blocks pertaining to the cases. The BRAF(V600E) mutation, and the RET/PTC1 and PAX8-PPARγ rearrangements were investigated in all cases. The BRAF(V600E) mutation was observed in 12 out of 37 papillary carcinoma cases (32.4%), in 1 out of 15 follicular carcinoma cases (6.6%), and in 1 out of 7 undifferentiated carcinoma cases (14.3%). No mutation was detected in benign lesions. The RET/PTC1 rearrangement was detected in 2 out of 7 undifferentiated carcinoma cases (28.6%), and in 1 out of 15 follicular carcinoma cases (6.6%). No gene rearrangement was detected in benign lesions. The PAX8-PPARγ rearrangement was detected in 5 out of 15 follicular thyroid carcinoma cases (33.3%) and in 1 out of 15 follicular adenoma cases (6.6%). The BRAF(V600E) mutation and RET/PTC1 rearrangement were effective in distinguishing the follicular epithelium-derived benign and malignant lesions of the thyroid in the resection materials. The BRAF(V600E) mutation was rather specific to papillary carcinoma in the thyroid, and in cases where the BRAF(V600E) mutation was detected, multi-centricity, lymph node metastasis and capsular invasion findings were observed more frequently compared to cases in which no mutation was observed. The PAX8-PPARγ rearrangement was observed to be more effective in the differentiation of adenomas and carcinomas in follicular neoplasms of the thyroid, whereas the RET/PTC1 analysis contributed to the differential diagnosis of papillary carcinoma histogenesis at a frequency of 29% in undifferentiated thyroid carcinomas.


Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB.
Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaalpha)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kappaB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kappaB, were both inhibited by RES. The patterns for NF-kappaB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kappaB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kappaB and calpain protease activity. Therefore, Bcl-2 and NF-kappaB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells.


Case report: Acute Intermittent Porphyria in a 21 year-old active duty male.
Acute Intermittent Porphyria (AIP) is one of a group of rare metabolic disorders arising from reduced activity of any of the enzymes in the heme biosynthetic pathway. The porphyrias can be very difficult for the practitioner to understand. There are several types of porphyrias, which have been known by various different names and are classified from different perspectives1 based on where the defective synthesis site is, or what the clinical manifestations are. Since practitioners rarely encounter this disease process, it is commonly not considered in the differential diagnoses. AIP can be confused with other causes of acute abdominal disorders such as appendicitis with peritonitis or nephrolithiasis. Patients with AIP typically give a history of constipation, fatigue, irritability, and insomnia that precede their acute attack. Symptoms occur intermittently in some patients with acute attacks lasting for several days or longer and were usually followed by complete recovery. This case report deals with an initial presentation of AIP in an otherwise healthy 21-year-old active duty male Soldier. Clinical presentation, diagnosis and treatment are discussed as is a brief historical anecdote.


Population dynamic models of the spread of Wolbachia.
Wolbachia are endosymbionts that are found in many insect species and can spread rapidly when introduced into a naive host population. Most Wolbachia spread when their infection frequency exceeds a threshold normally calculated using purely population genetic models. However, spread may also depend on the population dynamics of the insect host. We develop models to explore interactions between host population dynamics and Wolbachia infection frequency for an age-structured insect population regulated by larval density dependence. We first derive a new expression for the threshold frequency that extends existing theory to incorporate important details of the insect's life history. In the presence of immigration and emigration, the threshold also depends on the form of density-dependent regulation. We show how the type of immigration (constant or pulsed) and the temporal dynamics of the host population can strongly affect the spread of Wolbachia. The results help understand the natural dynamics of Wolbachia infections and aid the design of programs to introduce Wolbachia to control insects that are disease vectors or pests.


Overcoming double-step CO2 adsorption and minimizing water co-adsorption in bulky diamine-appended variants of Mg2(dobpdc).
Alkyldiamine-functionalized variants of the metal-organic framework Mg2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) are promising for CO2 capture applications owing to their unique step-shaped CO2 adsorption profiles resulting from the cooperative formation of ammonium carbamate chains. Primary,secondary (1°,2°) alkylethylenediamine-appended variants are of particular interest because of their low CO2 step pressures (≤1 mbar at 40 °C), minimal adsorption/desorption hysteresis, and high thermal stability. Herein, we demonstrate that further increasing the size of the alkyl group on the secondary amine affords enhanced stability against diamine volatilization, but also leads to surprising two-step CO2 adsorption/desorption profiles. This two-step behavior likely results from steric interactions between ammonium carbamate chains induced by the asymmetrical hexagonal pores of Mg2(dobpdc) and leads to decreased CO2 working capacities and increased water co-adsorption under humid conditions. To minimize these unfavorable steric interactions, we targeted diamine-appended variants of the isoreticularly expanded framework Mg2(dotpdc) (dotpdc4- = 4,4''-dioxido-[1,1':4',1''-terphenyl]-3,3''-dicarboxylate), reported here for the first time, and the previously reported isomeric framework Mg-IRMOF-74-II or Mg2(pc-dobpdc) (pc-dobpdc4- = 3,3'-dioxidobiphenyl-4,4'-dicarboxylate, pc = para-carboxylate), which, in contrast to Mg2(dobpdc), possesses uniformally hexagonal pores. By minimizing the steric interactions between ammonium carbamate chains, these frameworks enable a single CO2 adsorption/desorption step in all cases, as well as decreased water co-adsorption and increased stability to diamine loss. Functionalization of Mg2(pc-dobpdc) with large diamines such as N-(n-heptyl)ethylenediamine results in optimal adsorption behavior, highlighting the advantage of tuning both the pore shape and the diamine size for the development of new adsorbents for carbon capture applications.


Visceral and somatic hypersensitivity in TNBS-induced colitis in rats.
Inflammation of visceral structures in rats has been shown to produce visceral/somatic hyperalgesia. Our objectives were to determine if trinitrobenzene sulfonic acid (TNBS) induced colitis in rats leads to visceral/somatic hypersensitivity. Male Sprague-Dawley rats (200-250 g) were treated with 20 mg of TNBS in 50% ethanol (n = 40) or an equivalent volume of ethanol (n = 40) or saline (n = 25) via the colon. Colonic distension, Von Frey, Hargreaves, and tail reflex tests were used to evaluate for visceral, mechanical, and thermal sensitivity. The rats demonstrated visceral hypersensitivity at 2-28 days following TNBS administration (P < 0.0001). The ethanol-treated rats also demonstrated visceral hypersensitivity that resolved after day 14. TNBS-treated rats demonstrated somatic hypersensitivity at days 14-28 (P < 0.0001) in response to somatic stimuli of the hind paw. TNBS colitis is associated with visceral and somatic hypersensitivity in areas of somatotopic overlap. This model of colitis should allow further investigation into the mechanisms of visceral and somatic hypersensitivity.


Responsibility-sharing for pets in disasters: lessons for One Health promotion arising from disaster management challenges.
During disasters, the behaviour of pet owners and of pets themselves may compromise the ability of emergency responders to perform their duties safely. Furthermore, pet loss can have deleterious effects on personal and community recovery. To explore these issues and their implications for health promotion and disaster management practice, we conducted semi-structured interviews with 27 emergency responders in Australia, where disaster policy embraces shared responsibility yet does not acknowledge pets. We found that responders commit to being responsible for protecting human lives, especially members of their teams. Frontline emergency responders did not regard pets as their responsibility, yet decisions made with tragic consequences for pets exacted an emotional toll. Emergency managers consider community education as a pivotal strategy to support building people's capacity to reduce their own risk in disasters. While important, we question whether this is sufficient given that human life is lived in more-than-human contexts. Reformulating the parameters of the Ottawa Charter for Health Promotion as 'One Health Promotion' may help to account for the intermeshed lives of people and pets, while acknowledging human priority in public policy and programming. To acknowledge the influence of people's pets in disaster responses and recovery, we recommend five overlapping spheres of action: (i) integrate pets into disaster management practice and policy; (ii) create pet-friendly environments and related policies; (iii) engage community action in disaster management planning; (iv) develop personal skills by engaging owners in capacity building and (v) reorient health and emergency services toward a more-than-human approach.


Core/shell poly(ethylene oxide)/Eudragit fibers for site-specific release.
Electrospinning was used to prepare core/shell fibers containing the active pharmaceutical ingredients indomethacin (IMC) or mebeverine hydrochloride (MB-HCl). The shell of the fibers was fabricated from the pH sensitive Eudragit S100 polymer, while the drug-loaded core was based on the mucoadhesive poly(ethylene oxide) (PEO). Three different drug loadings (from 9 to 23% (w/w) of the core mass) were prepared, and for MB-HCl two different molecular weights of PEO were explored. The resultant fibers generally comprise smooth cylinders, although in some cases defects such as surface particles or flattened or merged fibers were visible. Transmission electron microscopy showed all the systems to have clear core and shell compartments. The drugs are present in the amorphous physical form in the fibers. Dissolution tests found that the fibers can effectively prevent release in acidic conditions representative of the stomach, particularly for the acidic indomethacin. After transfer to a pH 7.4 medium, sustained release over between 6 and 22h is observed. Given the mucoadhesive nature of the PEO core, after dissolution of the shell the fibers will be able to adhere to the walls of the intestinal tract and give sustained local drug release. This renders them promising for the treatment of conditions such as irritable bowel disease and colon cancer.