Prevalence of bacterial vaginosis in postmenopausal women: a systematic review and meta-analysis.
Bacterial vaginosis (BV), the most common cause of vaginal discharge in women of reproductive age, is associated with considerable reproductive and gynaecological sequelae and increases the risk of acquiring sexually transmissible infections including HIV. Although we understand the burden of BV in women of reproductive age, much less is known about the burden of BV in postmenopausal women. We undertook this systematic review and meta-analysis to estimate the prevalence of BV in postmenopausal women. The electronic databases PubMed, EMBASE, Web of Science, and The Cochrane Library were searched for English-language papers reporting on the prevalence of BV in postmenopausal women and published up until the end of July 2020. Search terms included: (prevalence OR survey OR proportion) AND 'bacterial vaginosis'. Meta-analysis was used to calculate pooled estimates of prevalence. We identified 2461 unique references and assessed 328 full-text articles for eligibility, with 13 studies included in the meta-analysis. The prevalence of BV ranged from 2.0 to 57.1%, with a summary estimate of 16.93% (95% CI: 8.5-27.4; I 2 =97.9). There was considerable heterogeneity between studies and quality varied considerably. Further research is needed to provide a better understanding of the condition in postmenopausal women and understand its effect on their lives.


Parasites of winter flounder (Pleuronectes americanus) as an additional bioindicator of stress-related exposure to untreated pulp and paper mill effluent: a 5-year field study.
A study was conducted in a marine inlet to assess the effects of untreated discharges from a pulp and paper mill, a municipality, and industries in western Newfoundland on winter flounder (Pleuronectes americanus), a fish species shown previously to be sensitive to environmental contaminants in sediment. The fish were captured by SCUBA divers about 2 km down-current from the mill discharging effluent containing resin acids, and at three reference sites 2 to 11 km away near the opposite shore, each spring in five consecutive years and the fish were necropsied on site. A total of 360 and 339 flounder were examined near the mill and references sites, respectively. Several bioindicators were used to assess fish health including parasites. More fish exhibiting external and microscopic lesions in several tissues, lower condition factors, elevated hepatosomatic index, and delayed reproductive development were observed in samples taken near the paper mill than at the reference sites. A higher prevalence of an ectoparasite, Cryptocotyle lingua, but a significantly lower mean abundance of three metazoans infecting the digestive tract was noted in fish near the mill than in the reference samples. These results, comprising abnormal fish size distribution, low body condition factor, external and internal lesions, enlarged liver, delayed gonadal development, and changes in parasitism, were stress-related, indicative of impaired health, and associated primarily with untreated discharges from the pulp and paper mill. This integrated and multidisciplinary study also provides further evidence on the use of fish parasites as a valid and an additional bioindicator in programs monitoring environmental contaminants.


Simvastatin enhances immune responses to Aβ vaccination and attenuates vaccination-induced behavioral alterations.
Statins are widely used to lower cholesterol levels by inhibiting cholesterol biosynthesis. Some evidence has indicated that statins might have therapeutic and preventive benefits for Alzheimer's disease (AD). We and others also have shown the beneficial effect of statin treatment in reversing learning and memory deficits in animal models of AD. However, data from clinical trials are inconclusive. We previously documented that the adenovirus vector encoding 11 tandem repeats of Aβ1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A, AdPEDI-(Aβ1-6)(11), is effective in inducing an immune response against amyloid-β protein (Aβ) and reducing brain Aβ load in Alzheimer's mouse models. In the present study, we examined whether the administration of simvastatin can modulate immune and behavioral responses of C57BL/6 mice to vaccination. Simvastatin was given to the animals as a diet admixture for four weeks, followed by nasal vaccination with AdPEDI-(Aβ1-6)(11) once per week for four weeks. The cholesterol-lowering action of simvastatin was monitored by measuring the cholesterol levels in plasma. Simvastatin significantly increased the number of the mice responding to vaccination compared with the mice receiving only AdPEDI-(Aβ1-6)(11). Immunoglobulin isotyping revealed that the vaccination predominantly induced Th2 immune responses. Simvastatin treatment prevented Aβ-induced production of IFN-γ in splenocytes. The adenovirus vaccination altered mouse behavior in T- and elevated plus-maze tests and simvastatin counteracted such behavioral changes. Our results indicate that simvastatin clearly enhances the immune responses of C57BL/6 mice to the nasal vaccination with AdPEDI-(Aβ1-6)(11). Simvastatin may be effective in preventing behavioral changes associated with vaccination.


Low back pain of mechanical origin: randomised comparison of chiropractic and hospital outpatient treatment.
To compare chiropractic and hospital outpatient treatment for managing low back pain of mechanical origin. Randomised controlled trial. Allocation to chiropractic or hospital management by minimisation to establish groups for analysis of results according to initial referral clinic, length of current episode, history, and severity of back pain. Patients were followed up for up two years. Chiropractic and hospital outpatient clinics in 11 centres. 741 Patients aged 18-65 who had no contraindications to manipulation and who had not been treated within the past month. Treatment at the discretion of the chiropractors, who used chiropractic manipulation in most patients, or of the hospital staff, who most commonly used Maitland mobilisation or manipulation, or both. Changes in the score on the Oswestry pain disability questionnaire and in the results of tests of straight leg raising and lumbar flexion. Chiropractic treatment was more effective than hospital outpatient management, mainly for patients with chronic or severe back pain. A benefit of about 7% points on the Oswestry scale was seen at two years. The benefit of chiropractic treatment became more evident throughout the follow up period. Secondary outcome measures also showed that chiropractic was more beneficial. For patients with low back pain in whom manipulation is not contraindicated chiropractic almost certainly confers worthwhile, long term benefit in comparison with hospital outpatient management. The benefit is seen mainly in those with chronic or severe pain. Introducing chiropractic into NHS practice should be considered.


Variability of C-reactive protein levels among patients with stable coronary artery disease and on statin therapy.
High sensitivity C-reactive protein, a marker of inflammation, has been proposed to stratify coronary artery disease risk and is lowered by HMG-CoA reductase (statin) therapy. However, the reproducibility of persistently elevated hs-CRP levels and association with other markers of inflammation in patients with stable CAD on aggressive statin therapy is unknown. To determine the reproducibility of hs-CRP levels measured within 2 weeks in patients with documented CAD with stable symptoms and to identify associations with other markers of inflammation. Levels of hs-CRP were measured twice within 14 days (7 +/- 4) in 23 patients (22 males and 1 female, average age 66 +/- 10 years) with stable CAD and hs-CRP > or = 2.0 mg/L but < or = 10 mg/L at visit 1. All patients had received statins for cholesterol management (low density lipoprotein-cholesterol 84 +/- 25 mg/dl) with no dose change for > 3 months. None had a history or evidence of malignancy, chronic infection or inflammation, or recent trauma. There was no change in medications between visits 1 and 2, and no patient reported a change in symptoms or general health during this interval. White blood cell count and pro- and anti-inflammatory cytokines were measured at both visits. hs-CRP levels tended to be lower at visit 2 (median 2.4 mg/L, range 0.8-11 mg/L) than at visit 1 (median 3.3 mg/L, range 2.0-9.7; P = 0.1793). However, between the two visits hs-CRP levels decreased by more than 1.0 mg/L in 10 patients and increased by more than 1.0 mg/L in 4 patients. Changes in hs-CRP levels were unrelated to changes in levels of white blood cells (P = 0.4353). Of the cytokines tested, only the antiinflammatory cytokine interleukin-1 receptor antagonist and the pro-inflammatory cytokine interleukin-8 were above lower limits of detection, but there were no correlations between changes in these values and changes in hs-CRP (both P > 0.5). In stable CAD patients on aggressive statin therapy, hs-CRP levels may fluctuate over brief periods in the absence of changes in health, cardiac symptom status and medications, and without corroboration with other measures of inflammation. Accordingly, elevated hs-CRP levels should be interpreted with caution in this setting.


[Proposal of reference values of microbiological environment monitoring in foodservice establishments].
To propose a new reference of microbiological environment monitoring in foodservice establishments. The present work shows the determination and evaluation of the microbiological contamination generated in a foodservice establishment Method: It is based on surface sampling (microbial build-up) using mixed cellulose ester membrane filters and on air sampling (hourly microbial adhesion) using Petri dishes. Limits of contamination are established before and during the food elaboration, by means of the microbiological analysis of the environment, surfaces and equipment systems, until reliable limits and levels of acceptance are established of each selected point. Finally, a program of environmental microbiological monitoring was established including the evaluation of all parameters that compose and are implicit in the area, thus assuring and supporting its continuity with the documentation and registers developed for a safety area. Samples for microbiological examination were collected over a period of one moth on ten different days, at two different times. Twelve selected points having previously been identified as hazardous were monitored. Furthermore, foods though to be of high risk were periodically collected for microbiological analysis. The possibility to use of an ample range of selective media, well over the limited number used in this study, allows the analysis of many single microbial species.


Intestinal vasodilation by epoxyeicosatrienoic acids: arachidonic acid metabolites produced by a cytochrome P450 monooxygenase.
Purified synthetic products from the cytochrome P450 pathway of arachidonate metabolism were applied to the intestinal serosa. Arteriolar blood flow was calculated using video microscopy. After a steady-state baseline, a bolus containing 10-60 micrograms 14,15-epoxyeicosatrienoic acid/ml (14,15-EET) had no detectable effect on blood flow. However, 25 +/- 3 micrograms 11,12-EET/ml and 36 +/- 2 micrograms 8,9-EET/ml caused increases (134 +/- 8% and 127 +/- 6%) that were similar to those elicited by 8 +/- 2 micrograms adenosine/ml (138 +/- 12%). Furthermore, the increases (275 +/- 38%) produced by 32 +/- 6 micrograms 5,6-EET/ml exceeded those elicited (160 +/- 10%) by a similar concentration (27 +/- 3 micrograms/ml) of adenosine. Thus, a structure-activity relationship is suggested. Nevertheless, these values probably underestimate the potency of the EETs because the vasoactivity was reduced by contact with water. The activity of the cyclooxygenase pathway seemed to limit the formation of vasoactive quantities of EETs, or other nonprostanoids, from exogenous arachidonate in the serosa but not the mucosa. A bolus (1.3 +/- 0.2 mg/ml) or continuous application (122 +/- 45 micrograms/ml) of arachidonate caused blood flow increases (236 +/- 14% or 229 +/- 27%) that were almost eliminated (129 +/- 5% or 121 +/- 9%) by a cyclooxygenase inhibitor; the residual response was abolished by a cytochrome P450 inhibitor. However, cytochrome P450 inhibitors alone did not attenuate the arachidonate response. In contrast, a continuous application of 194 micrograms arachidonate/ml to the mucosa caused a markedly smaller blood flow increase (119 +/- 8%) and cyclooxygenase inhibitors potentiated (132 +/- 8%), rather than reduced, this response. We conclude that EETs are a labile class of vasodilators with a potency comparable to adenosine in the intestinal microcirculation. Indirect evidence suggests regional differences in the formation of vasoactive quantities of arachidonate metabolites within the intestinal wall.


Hybrid surgery: a comparison of early postoperative outcomes between anterior cervical discectomy and fusion and cervical disc arthroplasty.
Hybrid surgery (HS) is the combination of anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) at different levels in the same operation. The aim of this study was to investigate perioperative variables, 30-day postoperative outcomes, and complications of HS in comparison with those of CDA and ACDF. The authors queried the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry for patients who underwent multilevel primary HS, CDA, and ACDF for degenerative disc disease from 2015 to 2019. The authors compared these three operations in terms of 30-day postoperative outcomes, specifically readmission and reoperation rates, discharge destination, and complications. This analysis included 439 patients who underwent HS, 976 patients who underwent CDA, and 27,460 patients who underwent ACDF. Patients in the HS and CDA groups were younger, had fewer comorbidities, and myelopathy was less often the indication for surgery compared with patients who underwent ACDF. For the HS group, the unplanned readmission rate was 0.7%, index surgery-related reoperation rate was 0.3%, and nonroutine discharge rate was 2.1%. Major and minor complications were also rare, with rates of 0.2% for each. The mean length of stay in the HS group was 1.5 days. The association of HS with better outcomes in univariate analysis was not evident after adjustment for confounding factors. The authors found that HS was noninferior to ACDF and CDA in terms of early postoperative outcomes among patients treated for degenerative disc disease.


The inflammatory infiltrate in the acute stage of the dextran sulphate sodium induced colitis: B cell response differs depending on the percentage of DSS used to induce it.
BACKGROUND: Experimental colitis with features similar to inflammatory bowel disease (IBD) has initially been described. A detailed analysis of inflammatory cells has not yet been described. Therefore in this study we characterized the cells involved in the acute phase of the colitis and compared those findings to what is known about human IBD. METHODS: Colitis was induced in BALB/C and C57Bl6 mice by ingestion of 2.5% and 5% DSS in the drinking water for 8 days. Cells were labelled by immunohistochemical staining with F4/80 and ER-MP20 for macrophages, TIB 120 for MHC Class II presentation, and anti-CD4 and anti-CD8 antibodies. They were enumerated by using a novel method that employs video image analysis. Immunoglobulin-producing cells were enumerated by immunofluorescent staining for IgA, IgG and IgM and counting by using confocal microscopy. RESULTS: Inflammatory infiltrate in the acute phase of the dextran sulphate sodium (DSS) -induced colitis consists predominantly of macrophages, neutrophils and eosinophils. Neutrophils increase in numbers and crypt abscesses were also seen. Increased macrophage numbers were due to recently recruited monocytes from the peripheral circulation. It does not appear that there are any changes in T cell numbers or distribution. The inflammation induced changes in immunoglobulin-producing cells with IgA-producing cells affected the most. CONCLUSIONS: The effect on Ig-producing cells depends on the percentage of DSS used to induce colitis. In general, 2.5% DSS induces an increase and 5% DSS a depletion of these cells.


Formation principles for vanadium selenites: the role of pH on product composition.
A series of organically templated vanadium selenites has been prepared under mild hydrothermal conditions. Single crystals of [C5H14N2][(VO)3(SeO3)2(HSeO3)4], [C5H14N2][VO(SeO3)2], [(R)-C5H14N2][(VO)3(SeO3)2(HSeO3)4], and [(S)-C5H14N2][(VO)3(SeO3)2(HSeO3)4] were grown from VOSO4, SeO2, and 2-methylpiperazine. Controlling the initial pH of the reaction mixture allows for one to select between the compounds found in the VOSO4/SeO2/2-methylpiperazine system, as the solution pH directly affects the relative ratio of the HSeO3(-) and SeO3(2-) concentrations. Moreover, partial resolution of racemic 2-methylpiperazine is observed in [C5H14N2][(VO)3(SeO3)2(HSeO3)4], which is understood through the use of a one-dimensional Ising model. The use of enantiomerically pure 2-methylpiperazine results in fully ordered and fully resolved structures.


Vulvar cancer surgery.
Surgical treatment of vulvar cancer has been shifted from ultraradical procedures associated with huge morbidity to less extensive surgery with better psychosexual result and less morbidity, without compromising survival. The authors review and discuss the recent literature regarding the surgical management of vulvar squamous cell carcinoma. Surgery remains the cornerstone in the treatment of vulvar cancer. Radical vulvectomy with inguinofemoral lymphadenectomy has been replaced by radical local excision with sentinel node procedure for early disease. However, the role and distance of pathological margins are still on debate. Recent results from a large prospective trial corroborate the safety of sentinel node biopsy for early disease, even after primary tumor resection. An experienced team should perform sentinel node procedure using combined technique (blue dye and lymphoscintigraphy) and ultrastaging pathology. Moreover, midline tumors still need lymph node biopsy from both groins. Primary vulvar cancer may be safely treated with radical/wide local resection. In case of other suspicious lesion or multifocal disease, radical vulvectomy is performed. Patients with unifocal disease, tumor size less than 4 cm, and clinically negative groins are candidates to sentinel node procedure. In the case of clinically positive node or sentinel node metastasis, a systematic inguinofemoral lymphadenectomy should be performed.


Simple and Effective Administration and Visualization of Microparticles in the Circulatory System of Small Fishes Using Kidney Injection.
The systemic administration of micro-size particles into a living organism can be applied for vasculature visualization, drug and vaccine delivery, implantation of transgenic cells and tiny optical sensors. However, intravenous microinjections into small animals, which are mostly used in biological and veterinary laboratories, are very difficult and require trained personnel. Herein, we demonstrate a robust and efficient method for the introduction of microparticles into the circulatory system of adult zebrafish (Danio rerio) by injection into the fish kidney. To visualize the introduced microparticles in the vasculature, we propose a simple intravital imaging technique in fish gills. In vivo monitoring of the zebrafish blood pH was accomplished using an injected microencapsulated fluorescent probe, SNARF-1, to demonstrate one of the possible applications of the described technique. This article provides a detailed description of the encapsulation of pH-sensitive dye and demonstrates the principles of the quick injection and visualization of the obtained microcapsules for in vivo recording of the fluorescent signal. The proposed method of injection is characterized by a low mortality rate (0-20%) and high efficiency (70-90% success), and it is easy to institute using commonly available equipment. All described procedures can be performed on other small fish species, such as guppies and medaka.


Reducing Cannabis Use in Young Adults With Psychosis Using iCanChange, a Mobile Health App: Protocol for a Pilot Randomized Controlled Trial (ReCAP-iCC).
Cannabis use is the most prevalent among adolescents and young adults; frequent consumption is associated with cannabis use disorder (CUD) and psychosis, with a high prevalence (up to 50%) of CUD in individuals with first-episode psychosis (FEP). Early Intervention Services (EIS) for psychosis include face-to-face psychosocial interventions for CUD, because reducing or discontinuing cannabis use improves clinical and health care service use outcomes. However, multiple barriers (eg, staff availability and limited access to treatment) can hinder the implementation of these interventions. Mobile health (mHealth) interventions may help circumvent some of these barriers; however, to date, no study has evaluated the effects of mHealth psychological interventions for CUD in individuals with FEP. This study describes the protocol for a pilot randomized controlled trial using a novel mHealth psychological intervention (iCanChange [iCC]) to address CUD in young adults with FEP. iCC was developed based on clinical evidence showing that in individuals without psychosis, integrating the principles of cognitive behavioral therapy, motivational interviewing, and behavioral self-management approaches are effective in improving cannabis use-related outcomes. Consenting individuals (n=100) meeting the inclusion criteria (eg, aged 18-35 years with FEP and CUD) will be randomly allocated in a 1:1 ratio to the intervention (iCC+modified EIS) or control (EIS) group. The iCC is fully automatized and contains 21 modules that are completed over a 12-week period and 3 booster modules available during the 3-month follow-up period. Validated self-report measures will be taken via in-person assessments at baseline and at 6, 12 (end point), and 24 weeks (end of trial); iCC use data will be collected directly from the mobile app. Primary outcomes are intervention completion and trial retention rates, and secondary outcomes are cannabis use quantity, participant satisfaction, app use, and trial recruiting parameters. Exploratory outcomes include severity of psychotic symptoms and CUD severity. For primary outcomes, we will use the chi-square test using data collected at week 12. We will consider participation in iCC acceptable if ≥50% of the participants complete at least 11 out of 21 intervention modules and the trial feasible if attrition does not reach 50%. We will use analysis of covariance and mixed-effects models for secondary outcomes and generalized estimating equation multivariable analyses for exploratory outcomes. Recruitment began in July 2022, and data collection is anticipated to be completed in July 2024. The main results are expected to be submitted for publication in 2024. We will engage patient partners and other stakeholders in creating a multifaceted knowledge translation plan to reach a diverse audience. If feasible, this study will provide essential data for a larger-scale efficacy trial of iCC on cannabis use outcomes in individuals with FEP and CUD. ClinicalTrials.gov NCT05310981; https://www.clinicaltrials.gov/ct2/show/NCT05310981. PRR1-10.2196/40817.


A novel setup for 3D chasing behavior analysis in free flying flies.
Insects catching prey or mates on the wing perform one of the fastest behaviours observed in nature. Some dipteran flies are aerial acrobats specialized to detect, chase and capture their targets within the blink of an eye. Studies of aerial pursuits and its underlying sensorimotor control have been a long-standing subject of interest in neuroethology research. We designed an actuated dummy target to trigger chasing flights in male blowflies. Our setup generates arbitrary 2D target trajectories in the horizontal plane combining translation up to 1 m/s and angular rotation up to 720°/s. Using stereovision methods we reconstructed target and pursuer positions every 5 ms with a maximum 3D error of 5 mm. The pursuer's body pitch and yaw angles were resolved within an error range of 6deg. An embedded observation point provides a close-up view of the pursuer's final approach and enables us to measure its body roll angle. We observed banked turns and sideslip which have not been reported for chasing blowflies in the past. Previous studies focused on pursuit along circular paths or interception of translating targets while our method allows us to generate more complex target trajectories. Measurements of body orientation in earlier accounts were limited to the heading direction while we extended the analysis to include the full body orientation during pursuit. Our setup offers an opportunity to investigate kinematics and governing visual parameters of chasing behaviour in species up to the size of blowflies under a large variety of experimental conditions.


Using e-learning for maintenance of ALS competence.
A well-suited e-learning program might be a feasible strategy to maintain competence following a resuscitation course. This study had 2 aims: (1) to examine the effect of an e-learning program as a booster of competence acquired from an Advanced Life Support (ALS) course. (2) To identify factors related to the use of the e-learning program. The study contained two parts pertaining to the two aims. The first part was a prospective single blinded randomised controlled study on junior doctors. The intervention was the monthly use of an e-learning program during one year and effect was measured as ALS-competence, a composite of a knowledge and skills test. The second part was a telephone interview of the intervention group. An interview guide was constructed based on existing knowledge of e-learning. In order to identify factors explaining the use of e-learning a univariate correlation was used to select significant variables to be included in a multiple regression analysis. Of the 134 invited to participate, 103 accepted the invitation. There were 79/103 (77%) participants, 40/51 in the intervention group and 39/52 in the control group. There was no difference between the groups with regards to ALS competence. Only 'social interaction' was an individually significant factor influencing the use of the e-learning program. This study did not demonstrate an effect of an e-learning program as a booster of competence acquired from an ALS course. The primary factor influencing the use of e-learning was the lack of social interaction.


Global human footprint on the linkage between biodiversity and ecosystem functioning in reef fishes.
Difficulties in scaling up theoretical and experimental results have raised controversy over the consequences of biodiversity loss for the functioning of natural ecosystems. Using a global survey of reef fish assemblages, we show that in contrast to previous theoretical and experimental studies, ecosystem functioning (as measured by standing biomass) scales in a non-saturating manner with biodiversity (as measured by species and functional richness) in this ecosystem. Our field study also shows a significant and negative interaction between human population density and biodiversity on ecosystem functioning (i.e., for the same human density there were larger reductions in standing biomass at more diverse reefs). Human effects were found to be related to fishing, coastal development, and land use stressors, and currently affect over 75% of the world's coral reefs. Our results indicate that the consequences of biodiversity loss in coral reefs have been considerably underestimated based on existing knowledge and that reef fish assemblages, particularly the most diverse, are greatly vulnerable to the expansion and intensity of anthropogenic stressors in coastal areas.


Non-contact small animal fluorescence imaging system for simultaneous multi-directional angular-dependent data acquisition.
We present a novel non-contact small animal fluorescent molecular tomography (FMT) imaging system. At the heart of the system is a new mirror-based imaging head that was designed to provide 360-degree measurement data from an entire animal surface in one step. This imaging head consists of two conical mirrors, which considerably reduce multiple back reflections between the animal and mirror surfaces. These back reflections are common in existing mirror-based imaging heads and tend to degrade the quality of raw measurement data. In addition, the introduction of a novel ray-transfer operator allows for the inclusion of the angular dependent data in the image reconstruction process, which results in higher image resolution. We describe in detail the system design and implementation of the hardware components as well as the transport-theory-based image reconstruction algorithm. Using numerical simulations, measurements on a well-defined phantom and a live animal, we evaluate the system performance and show the advantages of our approach.


Overexpression of MPS antigens by squamous cell carcinomas of the head and neck: immunohistochemical and serological correlation with FDG positron emission tomography.
Survival from advanced primary or recurrent Squamous Cell Carcinoma (SCC) of the head and neck (H&N) is poor. More accurate detection of primary tumors and recurrence may provide ways to improve survival. No standard serum tumor marker is routinely used for surveillance of SCC-H&N. In this paper, we evaluated the performance characteristics of the MPS-H tumor marker test for the quantitative measurement of "MPS-H" heat-generated immunoreactive proteins and assessed the clinical utility of this marker in the detection and monitoring of SCC-H&N. In approximately 92% of the subjects having no evidence of SCC-H&N, the MPS-H levels were lower than 15 ng/mL. In 76% of patients having SCC-H&N at various stages (T1-T4), the MPS-H level was > 15 ng/mL (range: 20-200 ng/mL). In addition, we found a statistically significant correlation between PET positive cases and high MPS-H serum levels in SCC-H&N patients with recurrent disease. These results suggest that MPS-H may provide an initial screening test that would allow for selective PET imaging in these patients. Furthermore, we found that there was greater expression of MPS-1 in tumors of higher histological grades. Thus, in tumors with more histological aggressiveness there is more MPS-1, indicating the potential usefulness of this marker in prognosis for SSC-H&N. Considering the immunohistochemical, serological, and FDG-PET data presented here, and the compelling need to expedite the early diagnosis of primary and recurrent epithelial malignancies of the head and neck, we are further evaluating the system of MPS antigens in a large patient population as a tool for the early serologic and histologic diagnosis of SCC-H&N.


General physical health advice for people with serious mental illness.
There is currently much focus on provision of general physical health advice to people with serious mental illness and there has been increasing pressure for services to take responsibility for providing this. To review the effects of general physical healthcare advice for people with serious mental illness. We searched the Cochrane Schizophrenia Group's Trials Register (last update search October 2012) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and registries of Clinical Trials. There is no language, date, document type, or publication status limitations for inclusion of records in the register. All randomised clinical trials focusing on general physical health advice for people with serious mental illness.. We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. Seven studies are now included in this review. For the comparison of physical healthcare advice versus standard care we identified six studies (total n = 964) of limited quality. For measures of quality of life one trial found no difference (n = 54, 1 RCT, MD Lehman scale 0.20, CI -0.47 to 0.87, very low quality of evidence) but another two did for the Quality of Life Medical Outcomes Scale - mental component (n = 487, 2 RCTs, MD 3.70, CI 1.76 to 5.64). There was no difference between groups for the outcome of death (n = 487, 2 RCTs, RR 0.98, CI 0.27 to 3.56, low quality of evidence). For service use two studies presented favourable results for health advice, uptake of ill-health prevention services was significantly greater in the advice group (n = 363, 1 RCT, MD 36.90, CI 33.07 to 40.73) and service use: one or more primary care visit was significantly higher in the advice group (n = 80, 1 RCT, RR 1.77, CI 1.09 to 2.85). Economic data were equivocal. Attrition was large (> 30%) but similar for both groups (n = 964, 6 RCTs, RR 1.11, CI 0.92 to 1.35). Comparisons of one type of physical healthcare advice with another were grossly underpowered and equivocal. General physical health could lead to people with serious mental illness accessing more health services which, in turn, could mean they see longer-term benefits such as reduced mortality or morbidity. On the other hand, it is possible clinicians are expending much effort, time and financial resources on giving ineffective advice. The main results in this review are based on low or very low quality data. There is some limited and poor quality evidence that the provision of general physical healthcare advice can improve health-related quality of life in the mental component but not the physical component, but this evidence is based on data from one study only. This is an important area for good research reporting outcome of interest to carers and people with serious illnesses as well as researchers and fundholders.


Platelet transfusion prophylaxis for patients with haematological malignancies: where to now?
National guidelines for platelet transfusion in many countries recommend that the general platelet transfusion trigger for prophylaxis is 10x10(9)/l. This annotation reviews the evidence for this threshold level and discusses other current unresolved issues relevant to platelet transfusion practice such as the optimal dose and the clinical benefit of a strategy for the prophylactic use of platelet transfusions when the platelet count falls below a given threshold.


Patterns in coverage of maternal, newborn, and child health interventions: projections of neonatal and under-5 mortality to 2035.
Urgent calls have been made for improved understanding of changes in coverage of maternal, newborn, and child health interventions, and their country-level determinants. We examined historical trends in coverage of interventions with proven effectiveness, and used them to project rates of child and neonatal mortality in 2035 in 74 Countdown to 2015 priority countries. We investigated coverage of all interventions for which evidence was available to suggest effective reductions in maternal and child mortality, for which indicators have been defined, and data have been obtained through household surveys. We reanalysed coverage data from 312 nationally-representative household surveys done between 1990 and 2011 in 69 countries, including 58 Countdown countries. We developed logistic Loess regression models for patterns of coverage change for each intervention, and used k-means cluster analysis to divide interventions into three groups with different historical patterns of coverage change. Within each intervention group, we examined performance of each country in achieving coverage gains. We constructed models that included baseline coverage, region, gross domestic product, conflict, and governance to examine country-specific annual percentage coverage change for each group of indicators. We used the Lives Saved Tool (LiST) to predict mortality rates of children younger than 5 years (henceforth, under 5) and in the neonatal period in 2035 for Countdown countries if trends in coverage continue unchanged (historical trends scenario) and if each country accelerates intervention coverage to the highest level achieved by a Countdown country with similar baseline coverage level (best performer scenario). Odds of coverage of three interventions (antimalarial treatment, skilled attendant at birth, and use of improved sanitation facilities) have decreased since 1990, with a mean annual decrease of 5·5% (SD 2·7%). Odds of coverage of four interventions--all related to the prevention of malaria--have increased rapidly, with a mean annual increase of 27·9% (7·3%). Odds of coverage of other interventions have slowly increased, with a mean annual increase of 5·3% (3·5%). Rates of coverage change varied widely across countries; we could not explain the differences by measures of gross domestic product, conflict, or governance. On the basis of LiST projections, we predicted that the number of Countdown countries with an under-5 mortality rate of fewer than 20 deaths per 1000 livebirths per year would increase from four (5%) of the 74 in 2010, to nine (12%) by 2035 under the historical trends scenario, and to 15 (20%) under the best performer scenario. The number of countries with neonatal mortality rates of fewer than 11 per 1000 livebirths per year would increase from three (4%) in 2010, to ten (14%) by 2035 under the historical trends scenario, and 67 (91%) under the best performer scenario. The number of under-5 deaths per year would decrease from an estimated 7·6 million in 2010, to 5·4 million (28% decrease) if historical trends continue, and to 2·3 million (71% decrease) under the best performer scenario. Substantial reductions in child deaths are possible, but only if intensified efforts to achieve intervention coverage are implemented successfully within each of the Countdown countries. The Bill & Melinda Gates Foundation.


The perceptions of informal carers of older people with dementia about the role of their pharmacists.
As medication experts, pharmacists can play a significant role in helping people living with dementia and their informal carers make the best use of medications. However, little is known about this population's needs and expectations of their pharmacists. The objective of this study was to report informal carers' perceptions about the role of their pharmacists. In a previous study, informal carers were interviewed to explore factors influencing medication adherence in older people living with dementia. The interview transcripts from the previous study were analysed thematically using an inductive approach to explore carers' perceptions about the role of community pharmacists in helping carers and people living with dementia use medications as prescribed. The interviews of 20 informal carers were analysed. Carers were primarily females (85%), married (60%), completed university (60%) and unemployed (70%). The majority of care recipients had comorbidities (75%), and the number of medications ranged from 1 to 20. Three significant roles emerged: (1) provision of medication information, (2) advising on medication organisation and (3) conducting medication reviews. Informal carers face several challenges in administering the medications to older people living with dementia. Pharmacists are expected to play a more active role in helping people living with dementia, and their carers make safe and effective use of medications.


Chronic stress induces a hyporeactivity of the autonomic nervous system in response to acute mental stressor and impairs cognitive performance in business executives.
The present study examined the incidence of chronic stress in business executives (109 subjects: 75 male and 34 female) and its relationship with cortisol levels, cognitive performance, and autonomic nervous system (ANS) reactivity after an acute mental stressor. Blood samples were collected from the subjects to measure cortisol concentration. After the sample collection, the subjects completed the Lipp Inventory of Stress Symptoms for Adults and the Stroop Color-Word Test to evaluate stress and cognitive performance levels, respectively. Saliva samples were collected prior to, immediately after, and five minutes after the test. The results revealed that 90.1% of the stressed subjects experienced stress phases that are considered chronic stress. At rest, the subjects with chronic stress showed higher cortisol levels, and no gender differences were observed. No differences were found between the stressed and non-stressed subjects regarding salivary amylase activity prior to test. Chronic stress also impaired performance on the Stroop test, which revealed higher rates of error and longer reaction times in the incongruent stimulus task independently of gender. For the congruent stimulus task of the Stroop test, the stressed males presented a higher rate of errors than the non-stressed males and a longer reaction time than the stressed females. After the acute mental stressor, the non-stressed male group showed an increase in salivary alpha-amylase activity, which returned to the initial values five minutes after the test; this ANS reactivity was not observed in the chronically stressed male subjects. The ANS responses of the non-stressed vs stressed female groups were not different prior to or after the Stroop test. This study is the first to demonstrate a blunted reactivity of the ANS when male subjects with chronic psychological stress were subjected to an acute mental stressor, and this change could contribute to impairments in cognitive performance.


Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function.
Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a nonadipogenic PPARγ agonist and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of lung squamous cell carcinoma (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU), which is applied topically, reliably triggering the development of SCC within 24 to 26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol-treated group (P = 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol-treated group. P = 0.004). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1-S cell-cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol changed redox status in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent.


A seasonal model to assess intervention strategies for preventing periodic recurrence of Lassa fever.
Lassa haemorrhagic fever is listed in WHO's Blueprint priority list of diseases and pathogens prioritized for research and development, affecting several hundreds of thousands of people each year. Lassa fever is spread via infected Natal multimammate mice and also through human-to-human contacts and it is a particular threat to pregnant women. Despite its importance, relatively few mathematical models have been established for modelling Lassa fever transmission up to now. We establish and study a new compartmental model for Lassa fever transmission including asymptomatic carriers, quarantine and periodic coefficients to model annual weather changes. We determine parameter values providing the best fit to data from Nigerian states Edo and Ondo from 2018-20. We perform uncertainty analysis and PRCC analysis to assess the importance of different parameters and numerical simulations to estimate the possible effects of control measures in eradicating the disease. The results suggest that the most important parameter which might be subject of control measures is death rate of mice, while mouse-to-human and human-to-human transmission rates also significantly influence the number of infected. However, decreasing the latter two parameters seems insufficient to eradicate the disease, while a parallel application of decreasing transmission rates and increasing mouse death rate might be able to stop the epidemic.


"He's the Number One Thing in My World": Application of the PRECEDE-PROCEED Model to Explore Child Car Seat Use in a Regional Community in New South Wales.
We explored the factors influencing the use of age-appropriate car seats in a community with a high proportion of Aboriginal families in regional New South Wales. We conducted a survey and three focus groups with parents of children aged 3-5 years enrolled at three early learning centres on the Australian south-east coast. Survey data were triangulated with qualitative data from focus groups and analysed using the PRECEDE-PROCEED conceptual framework. Of the 133 eligible families, 97 (73%) parents completed the survey including 31% of parents who reported their children were Aboriginal. Use of age-appropriate car seats was reported by 80 (83%) of the participants, and awareness of the child car seat legislation was high (91/97, 94%). Children aged 2-3 years were less likely reported to be restrained in an age-appropriate car seat than were older children aged 4-5 years (60% versus 95%: χ² = 19.14, p < 0.001). Focus group participants highlighted how important their child's safety was to them, spoke of the influence grandparents had on their use of child car seats and voiced mixed views on the value of authorised child car seat fitters. Future programs should include access to affordable car seats and target community members as well as parents with clear, consistent messages highlighting the safety benefits of using age-appropriate car seats.


Household catastrophic healthcare expenditure and impoverishment due to rotavirus gastroenteritis requiring hospitalization in Malaysia.
While healthcare costs for rotavirus gastroenteritis requiring hospitalization may be burdensome on households in Malaysia, exploration on the distribution and catastrophic impact of these expenses on households are lacking. We assessed the economic burden, levels and distribution of catastrophic healthcare expenditure, the poverty impact on households and inequities related to healthcare payments for acute gastroenteritis requiring hospitalization in Malaysia. A two-year prospective, hospital-based study was conducted from 2008 to 2010 in an urban (Kuala Lumpur) and rural (Kuala Terengganu) setting in Malaysia. All children under the age of 5 years admitted for acute gastroenteritis were included. Patients were screened for rotavirus and information on healthcare expenditure was obtained. Of the 658 stool samples collected at both centers, 248 (38%) were positive for rotavirus. Direct and indirect costs incurred were significantly higher in Kuala Lumpur compared with Kuala Terengganu (US$222 Vs. US$45; p<0.001). The mean direct and indirect costs for rotavirus gastroenteritis consisted 20% of monthly household income in Kuala Lumpur, as compared with only 5% in Kuala Terengganu. Direct medical costs paid out-of-pocket caused 141 (33%) households in Kuala Lumpur to experience catastrophic expenditure and 11 (3%) households to incur poverty. However in Kuala Terengganu, only one household (0.5%) experienced catastrophic healthcare expenditure and none were impoverished. The lowest income quintile in Kuala Lumpur was more likely to experience catastrophic payments compared to the highest quintile (87% vs 8%). The concentration index for out-of-pocket healthcare payments was closer to zero at Kuala Lumpur (0.03) than at Kuala Terengganu (0.24). While urban households were wealthier, healthcare expenditure due to gastroenteritis had more catastrophic and poverty impact on the urban poor. Universal rotavirus vaccination would reduce both disease burden and health inequities in Malaysia.


Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair.
Whereas cardiac-derived c-kit(+) stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p < .05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p < .05). Whereas 1 × 10(6) MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit(+)CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair.


Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons.
Recent evidence indicating formation of functional homomeric/heterotypic gap junction channels by connexin40 (Cx40) and connexin43 (Cx43) raises the question of whether data previously interpreted as support for heteromeric channel formation by these connexins might not instead reflect the activity of homomeric/heterotypic channels. To address this question and to further characterize the behavior of these channels, we used dual whole cell voltage-clamp techniques to examine the junctions formed between cells that express only Cx40 (Rin40) or Cx43 (Rin43) and compared the results with those obtained when either of these cell types was paired with cells that naturally express both connexins (A7r5 cells). Rin40/Rin43 cell pairs formed functional gap junctions that displayed a strongly asymmetric voltage-dependent gating response. Single-channel event amplitudes ranged between 34 and 150 pS, with 90- to 130-pS events predominating. A7r5/Rin43 and A7r5/Rin40 cell pairs had voltage-dependent gating responses that varied greatly, with most pairs demonstrating strong asymmetry. These cell pairs exhibited a variety of single-channel events that were not consistent with homomeric/homotypic Cx40 or Cx43 channels or homomeric/heterotypic Cx40/Cx43 channels. These data indicate that Cx40 and Cx43 form homomeric/heterotypic as well as heteromeric/heterotypic channels that display unique gating and conductance properties.


Evaluation of hemostasis in patients with end-stage renal disease.
An increased bleeding risk is reported for patients with end-stage renal disease. This study aims to analyze, whether bleeding risk can be assessed by global tests of hemostasis. Standard laboratory tests and an extended evaluation of hemostasis by rotational thromboelastometry, platelet function analyzer (PFA) and multiple electrode aggregometry as well as thrombin generation assays and measurement of fibrinolytic potential were performed in 20 patients on hemodialysis, 10 patients on peritoneal dialysis, 10 patients with chronic kidney disease stage G5 (CKD5) and in 10 healthy controls (HC). Hemoglobin was significantly lower in patients with end-stage renal disease versus HC (each p<0.01). Patients on peritoneal dialysis showed increased fibrinogen levels compared to HC (p<0.01), which were also reflected by FIBTEM results (each p<0.05). 41% of hemodialysis patients and 44% of CKD5 patients presented with prolonged PFA-ADP-test (p<0.05), while no patient on peritoneal dialysis and no HC offered this modification. Thrombin generating potential was significantly lower in patients on hemodialysis, while clot lysis time revealed a hypofibrinolytic state in patients on hemo- and peritoneal dialysis compared to HC (p<0.001). In conclusion, patients with end-stage renal disease have complex hemostatic changes with both hyper- and hypocoagulable features, which are dependent on use and type of dialysis. Hypercoagulable features include elevated fibrinogen levels and a hypofibrinolytic state, whereas hypocoagulable features include decreased thrombin generating capacity and platelet dysfunction. Our results may contribute to a more rational approach to hemostatic management in these patients.


Characterization of extracellular polymeric substances from acidophilic microbial biofilms.
We examined the chemical composition of extracellular polymeric substances (EPS) extracted from two natural microbial pellicle biofilms growing on acid mine drainage (AMD) solutions. The EPS obtained from a mid-developmental-stage biofilm (DS1) and a mature biofilm (DS2) were qualitatively and quantitatively compared. More than twice as much EPS was derived from DS2 as from DS1 (approximately 340 and 150 mg of EPS per g [dry weight] for DS2 and DS1, respectively). Composition analyses indicated the presence of carbohydrates, metals, proteins, and minor quantities of DNA and lipids, although the relative concentrations of these components were different for the two EPS samples. EPS from DS2 contained higher concentrations of metals and carbohydrates than EPS from DS1. Fe was the most abundant metal in both samples, accounting for about 73% of the total metal content, followed by Al, Mg, and Zn. The relative concentration profile for these metals resembled that for the AMD solution in which the biofilms grew, except for Si, Mn, and Co. Glycosyl composition analysis indicated that both EPS samples were composed primarily of galactose, glucose, heptose, rhamnose, and mannose, while the relative amounts of individual sugars were substantially different in DS1 and DS2. Additionally, carbohydrate linkage analysis revealed multiply linked heptose, galactose, glucose, mannose, and rhamnose, with some of the glucose in a 4-linked form. These results indicate that the biochemical composition of the EPS from these acidic biofilms is dependent on maturity and is controlled by the microbial communities, as well as the local geochemical environment.


Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance.
Despite clinical potential and recent advances, durable immunotherapeutic ablation of solid tumors is not routinely achieved. IL15 expands natural killer cell (NK), natural killer T cell (NKT) and CD8(+) T-cell numbers and engages the cytotoxic program, and thus is under evaluation for potentiation of cancer immunotherapy. We found that short-term therapy with IL15 bound to soluble IL15 receptor α-Fc (IL15cx; a form of IL15 with increased half-life and activity) was ineffective in the treatment of autochthonous PyMT murine mammary tumors, despite abundant CD8(+) T-cell infiltration. Probing of this poor responsiveness revealed that IL15cx only weakly activated intratumoral CD8(+) T cells, even though cells in the lung and spleen were activated and dramatically expanded. Tumor-infiltrating CD8(+) T cells exhibited cell-extrinsic and cell-intrinsic resistance to IL15. Our data showed that in the case of persistent viral or tumor antigen, single-agent systemic IL15cx treatment primarily expanded antigen-irrelevant or extratumoral CD8(+) T cells. We identified exhaustion, tissue-resident memory, and tumor-specific molecules expressed in tumor-infiltrating CD8(+) T cells, which may allow therapeutic targeting or programming of specific subsets to evade loss of function and cytokine resistance, and, in turn, increase the efficacy of IL2/15 adjuvant cytokine therapy. Cancer Immunol Res; 4(9); 799-811. ©2016 AACR.


Co-evolutionary dynamics between a defensive microbe and a pathogen driven by fluctuating selection.
Microbes that protect their hosts from pathogenic infection are widespread components of the microbiota of both plants and animals. It has been found that interactions between 'defensive' microbes and pathogens can be genotype-specific and even underlie the variation in host resistance to pathogenic infection. These observations suggest a dynamic co-evolutionary association between pathogens and defensive microbes, but direct evidence of co-evolution is lacking. We tested the hypothesis that defensive microbes and pathogens could co-evolve within host populations by co-passaging a microbe with host-defensive properties (Enterococcus faecalis) and a pathogen (Staphylococcus aureus) within Caenorhabditis elegans nematodes. Using both phenotypic and genomic analyses across evolutionary time, we found patterns of pathogen local adaptation and defensive microbe-pathogen co-evolution via fluctuating selection dynamics. Moreover, co-evolution with defensive microbes resulted in more rapid and divergent pathogen evolution compared to pathogens evolved independently in host populations. Taken together, our results indicate the potential for defensive microbes and pathogens to co-evolve, driving interaction specificity and pathogen evolutionary divergence in the absence of host evolution.


Endothelial function and arterial stiffness in minimally symptomatic obstructive sleep apnea.
Moderate-severe obstructive sleep apnea (OSA) is associated with endothelial dysfunction, increased arterial stiffness, and hypertension. It is not known whether minimally symptomatic OSA is also associated with impaired vascular function. To determine whether minimally symptomatic OSA is associated with impaired vascular function. In 64 patients (7 females) with minimally symptomatic OSA (oxygen desaturation index, 23.1 [SD, 15.6]; Epworth Sleepiness Scale score, 8 [SD, 3.8]), and 15 matched control subjects without OSA, endothelial function was assessed by ultrasonographic measurement of flow-mediated dilatation, and by applanation tonometry-derived pulse wave analysis (forearm ischemia and salbutamol-induced changes in augmentation index, AI(x)). Arterial stiffness was assessed by AI(x) and ambulatory blood pressure (ABP) was measured over 1 week. In patients with OSA, flow-mediated dilatation was significantly lower than in control subjects (5.0% [SD, 2.7%] and 7.5% [SD, 3.3%], respectively; P = 0.003). AI(x) was significantly higher in the OSA group compared with the control group (26.0% [interquartile range (IQR), 19.0-29.5%] and 21.0% [IQR, 8.0-27.0%], respectively; P = 0.04). Change in AI(x) after both forearm ischemia and salbutamol was significantly smaller in patients with OSA (-2.0% [IQR, -5.0 to +4.0%] and -3.0% [IQR, -7.0 to 0.0%], respectively), than in control subjects (-6.0% [IQR, -8.0 to -5.0%] and -7.0% [IQR, -10.0 to -3.0%]; P = 0.005 and P = 0.04, respectively). ABP was similar (97.6 mm Hg [SD, 7.9 mm Hg] and 94.8 mm Hg [SD, 7.4 mm Hg], OSA and control groups, respectively; P = 0.21). In patients with minimally symptomatic OSA, diverse properties of endothelial function are impaired and arterial stiffness is increased. Although this was not associated with a significantly increased ABP, the findings suggest that patients with minimally symptomatic OSA are at increased cardiovascular risk.


Comprehensive measurement of stroke gait characteristics with a single accelerometer in the laboratory and community: a feasibility, validity and reliability study.
Application of objective measurement of stroke gait with accelerometer-based wearable technology and associated algorithms is increasing, despite reports questioning the accuracy of this technique in quantifying specific stroke-related gait impairments. The aim of this study is to determine the feasibility, validity and reliability of a low-cost open-source system incorporating algorithms and a single tri-axial accelerometer-based wearable to quantify gait characteristics in the laboratory and community post-stroke. Twenty-five participants with stroke wore the wearable (AX3, Axivity) on the lower back during a laboratory 2 minute continuous walk (preferred pace) on two occasions a week apart and continuously in the community for two consecutive 7 day periods. Video, instrumented walkway (GaitRite) and an OPAL accelerometer-based wearable were used as laboratory references. Feasibility of the proposed system was good. The system was valid for measuring step count (ICC 0.899). Inherent differences in gait quantification between algorithm and GaitRite resulted in difficulties comparing agreement between the different systems. Agreement was moderate-excellent (ICC 0.503-0.936) for mean and variability gait characteristics vs. OPAL. Agreement was moderate-poor between the system and OPAL for asymmetry characteristics. Moderate-excellent reliability (ICC 0.534-0.857) was demonstrated for 11/14 laboratory measured gait characteristics. Community test-retest reliability was good-excellent (ICC 0.867-0.983) for all except one (ICC 0.699) of the 19 gait characteristics. The proposed system is a low-cost, reliable tool for quantifying gait post-stroke with multiple potential applications. Further refinement to optimise gait quantification algorithms for certain gait characteristics including gait asymmetry is required.


An integrative genomics approach to the reconstruction of gene networks in segregating populations.
The reconstruction of genetic networks in mammalian systems is one of the primary goals in biological research, especially as such reconstructions relate to elucidating not only common, polygenic human diseases, but living systems more generally. Here we propose a novel gene network reconstruction algorithm, derived from classic Bayesian network methods, that utilizes naturally occurring genetic variations as a source of perturbations to elucidate the network. This algorithm incorporates relative transcript abundance and genotypic data from segregating populations by employing a generalized scoring function of maximum likelihood commonly used in Bayesian network reconstruction problems. The utility of this novel algorithm is demonstrated via application to liver gene expression data from a segregating mouse population. We demonstrate that the network derived from these data using our novel network reconstruction algorithm is able to capture causal associations between genes that result in increased predictive power, compared to more classically reconstructed networks derived from the same data.


The effect of selective drainage positions on oxygen saturation in obese patients after upper abdominal surgery.
The obese patients undergoing upper abdominal surgery are at particularly high risk to develop postoperative pulmonary complications, and hypoxemia is one of the most common ones reported. During the initial postoperative period, they are often advised to maintain a semi-sitting position to optimize oxygenation. Although chest physical therapy usually avoids a Trendelenburg position, no published data indicate this position as being able to induce desaturation in obese patients following upper abdominal surgery. We studied fifteen adult obese patients without cardiopulmonary disease undergoing upper abdominal surgery. All patients were tested for 5 minutes during the first 3 postoperative days in each of 3 positions: semi-sitting, bed-flat lateral decubitus, and 15 degrees of Trendelenburg lateral decubitus positions. A statistically significant difference in oxygen saturation related to position was found only on the first postoperative day between semi-sitting and bed-flat lateral decubitus positions. The difference in mean SaO2 value between these 2 positions, however, was only 0.88%; and no significant correlation between the magnitude of obesity and the mean SaO2 difference was found. Although arterial oxygen saturation demonstrated statistically significant daily improvement during the first 3 postoperative days, the mean SaO2 values for any 2 consecutive days differed by less than 0.78%. Thus, in obese patients following upper abdominal surgery, 15 degrees of Trendelenburg lateral decubitus and bed-flat lateral decubitus positions do not induce clinically significant desaturation and can be used if necessary and appropriate. In obese patients with borderline oxygenation, supplemental oxygen used postoperatively can maintain adequate oxygenation and allow aggressive positioning.


Conditions with high intracellular glucose inhibit sensing through glucose sensor Snf3 in Saccharomyces cerevisiae.
Gene expression in micro-organisms is regulated according to extracellular conditions and nutrient concentrations. In Saccharomyces cerevisiae, non-transporting sensors with high sequence similarity to transporters, that is, transporter-like sensors, have been identified for sugars as well as for amino acids. An alternating-access model of the function of transporter-like sensors has been previously suggested based on amino acid sensing, where intracellular ligand inhibits binding of extracellular ligand. Here we studied the effect of intracellular glucose on sensing of extracellular glucose through the transporter-like sensor Snf3 in yeast. Sensing through Snf3 was determined by measuring degradation of Mth1 protein. High intracellular glucose concentrations were achieved by using yeast strains lacking monohexose transporters which were grown on maltose. The apparent affinity of extracellular glucose to Snf3 was measured for cells grown in non-fermentative medium or on maltose. The apparent affinity for glucose was lowest when the intracellular glucose concentration was high. The results conform to an alternating-access model for transporter-like sensors.


Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules.
We performed yeast two-hybrid screening of a human kidney cell cDNA library to study the biological role of the hantavirus nucleocapsid protein (NP). We found that Seoul virus (SEOV) and Hantaan virus (HTNV) NPs were associated with small ubiquitin-like modifier (SUMO)-1-interacting proteins PIAS1, PIASxbeta, HIPK2, CHD3, and TTRAP, which interacted with the SUMO-1 conjugating enzyme (Ubc-9) and SUMO-1 in the yeast two-hybrid assay. Interactions between the HIPK2, CHD3, and TTRAP proteins and SEOV NP were also shown in a mammalian two-hybrid assay. However, there was no interaction between PIAS proteins and NP, which was probably due to the inhibitory effect of PIAS on transcription in the mammalian two-hybrid assay. Nevertheless, a co-expression experiment suggested the existence of a PIAS-NP interaction in the cytoplasm. The region spanning amino acids 100-125 of SEOV NP, which represents a critical region for NP-NP polymerization, was found to be responsible for the interaction with SUMO-1-related molecules in both the yeast and mammalian two-hybrid assays. These results add to the information on interactions of hantavirus NP and host cellular proteins.


Effective UO22+ removal from aqueous solutions using lichen biomass as a natural and low-cost biosorbent.
The UO22+ biosorption properties of a lichen, Evernia prunastri, from aqueous solutions were investigated. The widely occurring lichen samples were collected from the forest in Bilecik-Turkey. The UO22+ biosorption onto lichen was characterized by FT-IR and SEM-EDX analysis techniques before and after biosorption. The effects of the solution pH, biosorbent dosage, UO22+ concentration, contact time, and temperature on UO22+ biosorption on lichen sample were studied by using the batch method. The isotherm experimental data were described using isotherm models of Langmuir, Freundlich and Dubinin Radushkevich. The maximum UO22+ biosorption capacity of the lichen sample was estimated by the Langmuir equation to be 0.270 mol kg-1. The adsorption energy from the Dubin Radushkevich model was found to be 8.24 kJ mol-1. Kinetic data determined that the biosorption was best described by the pseudo-second-order kinetic model. Thermodynamic findings showed that the biosorption process was endothermic, entropy increased and spontaneous. In conclusion, the lichen appears to be a promising biosorbent for the removal of UO22+ ions from aqueous solutions because of high biosorption capacity, easy usability, low cost, and high reusability performance.


Enrichments of post-translational modifications in proteomic studies.
More than 300 different protein post-translational modifications are currently known, but only a few have been extensively investigated because modified proteoforms are commonly present in sub-stoichiometry amount. For this reason, improvement of specific enrichment techniques is particularly useful for the proteomic characterization of post-translationally modified proteins. Enrichment proteomic strategies could help the researcher in the challenging issue to decipher the complex molecular cross-talk existing between the different factors influencing the cellular pathways. In this review the state of art of the platforms applied for the enrichment of specific and most common post-translational modifications, such as glycosylation and glycation, phosphorylation, sulfation, redox modifications (i.e. sulfydration and nitrosylation), methylation, acetylation, and ubiquitinylation, are described. Enrichments strategies applied to characterize less studied post-translational modifications are also briefly discussed.


Robust and accurate quantification of biomarkers of immune cells in lung cancer micro-environment using deep convolutional neural networks.
Recent years have seen a growing awareness of the role the immune system plays in successful cancer treatment, especially in novel therapies like immunotherapy. The characterization of the immunological composition of tumors and their micro-environment is thus becoming a necessity. In this paper we introduce a deep learning-based immune cell detection and quantification method, which is based on supervised learning, i.e., the input data for training comprises labeled images. Our approach objectively deals with staining variation and staining artifacts in immunohistochemically stained lung cancer tissue and is as precise as humans. This is evidenced by the low cell count difference to humans of 0.033 cells on average. This method, which is based on convolutional neural networks, has the potential to provide a new quantitative basis for research on immunotherapy.


Genome wide expression profiling identifies genes associated with colorectal liver metastasis.
Tumour cells have to undergo gene expression changes in order to metastasise and adapt to a new site. We investigated these changes in liver metastases of colorectal cancer by using genome-wide microarray analysis to profile the expression of 48 primary tumours and 28 liver metastases. Statistical analysis of these expression profiles using the significance analysis of microarrays (SAM) method identified 778 genes differentially expressed between primary tumours and metastases. Gene ontology analysis revealed that genes associated with tissue remodelling and immune response were upregulated in metastases relative to primary tumours, whereas genes associated with proliferation and oxidative phosphorylation were downregulated. Quantitative real-time PCR confirmed the differential expression of selected genes, osteopontin, versican, ADAM17, CKS2, PRDX1, CXCR4, CXCL12, and LCN2. The upregulation of genes associated with tissue remodelling and immune response are likely to be involved in metastatic invasion and colonisation of the new site because these genes can promote tumour progression. However, downregulation of genes associated with proliferation suggests that proliferation in metastases was reduced relative to primary tumours.


Late onset group B streptococcal disease manifests as submandibular cellulitis.
A 3033g male infant was born to a healthy mother at 39 weeks gestation by normal vaginal delivery with Grade 1 meconium stained liquor. There was no prolonged rupture of membranes or any antenatal risk factors for sepsis. The immediate neonatal period was uneventful and the baby was discharged after two days. At 6 weeks of age the baby was admitted with an 8-hour history of inconsolable crying. He was pyrexial. Initially the possibility of intussuception was considered, however, the submandibular swelling became more obvious and tender. His airway was clear. Chest x-ray and abdominal x-ray were normal. Ultrasound of the submandibular region showed soft tissue swelling with no fluid collection. CRP was initially 0.7 but increased to 87 the next day. Blood cultures grew group B streptococcus. (GBS) He was treated for five days with appropriate intravenous antibiotics. He was discharged home and recovered fully.


Characterization and regulation of the major histocompatibility complex-encoded proteins Hsp70-Hom and Hsp70-1/2.
Vertebrate cells contain at least 12 different genes for Hsp70 proteins, 3 of which are encoded in the major histocompatibility complex (MHC) class III region. In the human MHC, these are named Hsp70-1, -2, and -Hom. To characterize these proteins, we have determined their substrate binding specificity, their cellular and tissue distribution, and the regulation of their expression. We show for the first time (1) peptide binding specificity of Hsp70-Hom; (2) endogenous expression of Hsp70-Hom in human cell lines; (3) cytoplasmic location of Hsp70-Hom protein under basal conditions and concentration in the nucleus after heat shock; (4) unique RNA expression profiles in human tissues for each of the MHC-encoded Hsp70s, significantly different from that for the constitutive Hsc70; (5) a relative increase in levels of Hsp70-Hom protein, compared with other Hsp70s, in response to interferon gamma; and (6) a specific increase on lipopolysaccharide (LPS) treatment of in vivo messenger RNA levels for the MHC-encoded Hsp70s and the DnaJ homologue, hdj2, relative to other chaperones. The unique tissue distributions and specific up-regulation by LPS of the MHC-encoded Hsp70s suggest some specialization of functions for these members of the Hsp70 family, possibly in the inflammatory response.


Imprinted silicon-based nanophotonics.
We demonstrate and optically characterize silicon-on-insulator based nanophotonic devices fabricated by nanoimprint lithography. In our demonstration, we have realized ordinary and topology-optimized photonic crystal waveguide structures. The topology-optimized structures require lateral pattern definition on a sub 30-nm scale in combination with a deep vertical silicon etch of the order of ~300 nm. The nanoimprint method offers a cost-efficient parallel fabrication process with state-of-the-art replication fidelity, comparable to direct electron beam writing.


Establishment and characterization of a differentiated epithelial cell culture model derived from the porcine cervix uteri.
Cervical uterine epithelial cells maintain a physiological and pathogen-free milieu in the female mammalian reproductive tract and are involved in sperm-epithelium interaction. Easily accessible, differentiated model systems of the cervical epithelium are not yet available to elucidate the underlying molecular mechanisms within these highly specialized cells. Therefore, the aim of the study was to establish a cell culture of the porcine cervical epithelium representing in vivo-like properties of the tissue. We tested different isolation methods and culture conditions and validated purity of the cultured cells by immunohistochemistry against keratins. We could reproducibly culture pure epithelial cells from cervical tissue explants. Based on a morphology score and the WST-1 Proliferation Assay, we optimized the growth medium composition. Primary porcine cervical cells performed best in conditioned Ham's F-12, containing 10% FCS, EGF and insulin. After cultivation in an air-liquid interface for three weeks, the cells showed a discontinuously multilayered phenotype. Finally, differentiation was validated via immunohistochemistry against beta catenin. Mucopolysaccharide production could be shown via alcian blue staining. We provide the first suitable protocol to establish a differentiated porcine epithelial model of the cervix uteri, based on easily accessible cells using slaughterhouse material.


The effect of structured exercise classes and a lifestyle intervention on cardiovascular risk factors in primary schoolchildren: an exploratory trial (The A-CLASS Project).
This exploratory trial evaluates the effect of a structured exercise (STEX) or lifestyle intervention (PASS) program upon cardiovascular (CV) disease risk factors in children. Sixty-one schoolchildren were randomly assigned by school to an intervention or control (CON) condition. The effect of the STEX (compared with CON) was a mean benefit of -0.018 mm for average maximum carotid intimamedia thickness. The PASS intervention did not result in clinically important effects, and no other substantial changes were observed. Relatively high probability of clinically beneficial effects of the STEX intervention suggests that a larger, definitive randomized trial with longer follow-up is warranted.


Magnetic resonance imaging (MRI)-based radiomics for prostate cancer radiotherapy.
In radiotherapy (RT) of prostate cancer, dose escalation has been shown to reduce biochemical failure. Dose escalation only to determinate prostate tumor habitats has the potential to improve tumor control with less toxicity than when the entire prostate is dose escalated. Other issues in the treatment of the RT patient include the choice of the RT technique (hypo- or standard fractionation) and the use and length of concurrent/adjuvant androgen deprivation therapy (ADT). Up to 50% of high-risk men demonstrate biochemical failure suggesting that additional strategies for defining and treating patients based on improved risk stratification are required. The use of multiparametric MRI (mpMRI) is rapidly gaining momentum in the management of prostate cancer because of its improved diagnostic potential and its ability to combine functional and anatomical information. Currently, the Prostate Imaging, Reporting and Diagnosis System (PIRADS) is the standard of care for region of interest (ROI) identification and risk classification. However, PIRADS was not designed for 3D tumor volume delineation; there is a large degree of subjectivity and PIRADS does not accurately and reproducibly elucidate inter- and intra-lesional spatial heterogeneity. "Radiomics", as it refers to the extraction and analysis of large number of advanced quantitative radiological features from medical images using high throughput methods, is perfectly suited as an engine to effectively sift through the multiple series of prostate mpMRI sequences and quantify regions of interest. The radiomic efforts can be summarized in two main areas: (I) detection/segmentation of the suspicious lesion; and (II) assessment of the aggressiveness of prostate cancer. As related to RT, the goal of the latter is in particular to identify patients at high risk for metastatic disease; and the aim of the former is to identify and segment cancerous lesions and thus provide targets for radiation boost. The article is structured as follows: first, we describe the radiomic approach; and second, we discuss the radiomic pipeline as tailored for RT of prostate cancer. In this process we summarize the current efforts and progress in integrating mpMRI radiomics into the radiotherapeutic management of prostate cancer with emphasis placed on its role in treatment target definition, treatment plan strategizing, and prognostic assessment. The described concepts, methods and tools are not currently applicable to the radiation oncology practice outside of the research setting. More data are required in the form of clinical trials to assess the robustness of radiomics-based predictive models, and to maximize the efficacy of these models.


Characterisation of PduS, the pdu metabolosome corrin reductase, and evidence of substructural organisation within the bacterial microcompartment.
PduS is a corrin reductase and is required for the reactivation of the cobalamin-dependent diol dehydratase. It is one component encoded within the large propanediol utilisation (pdu) operon, which is responsible for the catabolism of 1,2-propanediol within a self-assembled proteinaceous bacterial microcompartment. The enzyme is responsible for the reactivation of the cobalamin coenzyme required by the diol dehydratase. The gene for the cobalamin reductase from Citrobacter freundii (pduS) has been cloned to allow the protein to be overproduced recombinantly in E. coli with an N-terminal His-tag. Purified recombinant PduS is shown to be a flavoprotein with a non-covalently bound FMN that also contains two coupled [4Fe-4S] centres. It is an NADH-dependent flavin reductase that is able to mediate the one-electron reductions of cob(III)alamin to cob(II)alamin and cob(II)alamin to cob(I)alamin. The [4Fe-4S] centres are labile to oxygen and their presence affects the midpoint redox potential of flavin. Evidence is presented that PduS is able to bind cobalamin, which is inconsistent with the view that PduS is merely a flavin reductase. PduS is also shown to interact with one of the shell proteins of the metabolosome, PduT, which is also thought to contain an [Fe-S] cluster. PduS is shown to act as a corrin reductase and its interaction with a shell protein could allow for electron passage out of the bacterial microcompartment.


Psychological distress, killer lymphocytes and disease severity in HIV/AIDS.
Immunocellular mechanisms that account for the association between psychosocial risk factors and increased susceptibility to faster progression of HIV/AIDS are largely unknown. This study used structural equation modeling to test the hypothesis that enumerative and functional alterations in killer lymphocytes mediate the relationship between higher levels of psychological distress (defined by perceived stress, anxiety and depressive symptoms) and greater HIV disease severity (defined by HIV-1 viral load and T-helper (CD4(+)) cell count), independent of standard demographic and various HIV-related covariates. Participants were 200 HIV-1 seropositive adults on combination antiretroviral therapy (ages 20-55 years; 67% men; 62% black; 84% AIDS). The data fit a psychoimmune model in which the significant relationship between higher distress levels and greater disease severity was mediated by diminished natural killer (NK) cell count and cytotoxic function, as well as increased cytotoxic (CD8(+)) T-cell activation. Overall the findings indicated that the psychoimmune model accounted for 67% of the variation in HIV disease severity. In contrast, the data did not support a reverse directionality mediation model, where greater HIV disease severity predicted greater distress as a function of killer lymphocyte status. In sum, the psychoimmune associations of the final model are physiologically consistent and suggest that distress-related alterations in killer lymphocyte immunity may play a role in the biobehavioral mechanisms linked with HIV-1 pathogenesis.


Gap junctions in the ventral hippocampal-medial prefrontal pathway are involved in anxiety regulation.
Anxiety disorders are highly prevalent but little is known about their underlying mechanisms. Gap junctions exist in brain regions important for anxiety regulation, such as the ventral hippocampus (vHIP) and mPFC, but their functions in these areas have not been investigated. Using pharmacological blockade of neuronal gap junctions combined with electrophysiological recordings, we found that gap junctions play a role in theta rhythm in the vHIP and mPFC of adult mice. Bilateral infusion of neuronal gap junction blockers into the vHIP decreased anxiety-like behavior on the elevated plus maze and open field. Similar anxiolytic effects were observed with unilateral infusion of these drugs into the vHIP combined with contralateral infusion into the mPFC. No change in anxious behavior was observed with gap junction blockade in the unilateral vHIP alone or in the bilateral dorsal HIP. Since physical exercise is known to reduce anxiety, we examined the effects of long-term running on the expression of the neuronal gap junction protein connexin-36 among inhibitory interneurons and found a reduction in the vHIP. Despite this change, we observed no alteration in theta frequency or power in long-term runners. Collectively, these findings suggest that neuronal gap junctions in the vHIP-mPFC pathway are important for theta rhythm and anxiety regulation under sedentary conditions but that additional mechanisms are likely involved in running-induced reduction in anxiety.


Atypical marginal zone hyperplasia of mucosa-associated lymphoid tissue: a reactive condition of childhood showing immunoglobulin lambda light-chain restriction.
Mucosa-associated lymphoid tissue (MALT) lymphomas usually arise at sites of acquired MALT and are uncommon in native MALT (eg, Peyer patches and tonsil). Malignancy in these low-grade lymphomas is often inferred by immunoglobulin light-chain restriction and expression of CD43; molecular genetic evidence is sought only if these are in doubt. We report 6 cases (4 tonsils, 2 appendixes) of marginal zone (MZ) hyperplasia in children aged 3 to 11 years that, despite histologic and immunophenotypic features indicative of lymphoma, were polyclonal by molecular analysis. No lymphoma-directed therapy was given and patients remain alive and well (5 cases, median follow-up 35.3 months). The involved tonsil and appendix showed florid MZ hyperplasia with prominent intraepithelial B cells (IEBCs). The MZ B cells and IEBCs showed a high-proliferation fraction and a CD20(+), CD21(+), CD27(-), immunoglobulin (Ig) superfamily receptor translocation-associated 1-positive (IRTA-1(+)), CD43(+), multiple myeloma oncogene 1 (MUM-1), IgM(+)D(+) phenotype. Polymerase chain reaction (PCR), cloning, and sequencing of rearranged IgH and Iglambda genes (whole tissue sections [6 cases]; microdissected cells [2 cases]) showed that the MZ B cells and IEBCs were polyclonal and the IgH genes nonmutated. In contrast, MZ (intraepithelial) B cells of 6 control tonsils had a similar immunophenotype, except for expression of CD27 and polytypic light chains, whereas molecular studies showed that they were polyclonal with mutated Ig genes.


Minimally invasive versus open mitral valve surgery: a consensus statement of the international society of minimally invasive coronary surgery (ISMICS) 2010.
: The purpose of this consensus conference was to deliberate the evidence regarding whether minimally invasive mitral valve surgery via thoracotomy improves clinical and resource outcomes compared with conventional open mitral valve surgery via median sternotomy in adults who require surgical intervention for mitral valve disease. : Before the consensus conference, the consensus panel reviewed the best available evidence up to March 2010, whereby systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. The accompanying meta-analysis article in this issue of the Journal provides the systematic review of the evidence. Based on this systematic review, evidence-based statements were created for prespecified clinical questions, and consensus processes were used to derive recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. : Considering the underlying level of evidence, and notwithstanding the limitations of the evidence base (retrospective studies with important differences in baseline patient characteristics, which may produce bias in results of the evidence syntheses), the consensus panel provided the following evidence-based statements and overall recommendation:In patients with mitral valve disease, minimally invasive surgery may be an alternative to conventional mitral valve surgery (Class IIb), given that there was comparable short-term and long-term mortality (level B), comparable in-hospital morbidity (renal, pulmonary, cardiac complications, pain perception, and readmissions) (level B), reduced sternal complications, transfusions, postoperative atrial fibrillation, duration of ventilation, and intensive care unit and hospital length of stay (level B). However, this should be considered against the increased risk of stroke (2.1% vs 1.2%) (level B), aortic dissection (0.2% vs 0%) (level B), phrenic nerve palsy (3% vs 0%) (level B), groin infections/complications (2% vs 0%) (level B), and, prolonged cross-clamp time, cardiopulmonary bypass time, and procedure time (level B). The available evidence consists almost entirely of observational studies and must not be considered definitive until future adequately controlled randomized trials further address the risk of stroke, aortic complications, phrenic nerve complications, pain, long-term survival, need for reintervention, quality of life, and cost-effectiveness.


Maternal hypertension, antihypertensive medication use, and the risk of severe hypospadias.
Hypertensive disorders occur in an estimated 5-10% of pregnancies, but few studies have examined birth defects in relation to high blood pressure and antihypertensive medication use. The objective of this study was to investigate the relationship between high blood pressure, antihypertensive medication use, and severe hypospadias. We used data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects to assess risks for severe hypospadias in relation to self-reported high blood pressure and prenatal exposures to antihypertensive drugs in 758 male infants with severe hypospadias and 2,058 male controls born between 1997 and 2002. Logistic regression analyses estimated ORs and 95% CIs, adjusted for potential confounders. We observed slight to moderate elevations in the risk of severe hypospadias for maternal untreated hypertension (adjusted OR 2.1; 95% CI: 1.6-2.9) and antihypertensive medication use during 1 month preconception through pregnancy month 4 (adjusted OR 1.4; 95% CI: 0.7-2.9). The association was strongest for subjects initiating medications after the fourth month (adjusted OR 5.0; 95% CI: 1.9-12.9). We observed an association between hypertension, antihypertensive medication use, and the risk of severe hypospadias, particularly when medication use began late in pregnancy. Because hypospadias occurs in early pregnancy, the data suggest that hypertension and its morphologic/physiologic precursors play an etiologic role, perhaps via compromised uteroplacental perfusion. Birth Defects Research (Part A) 2008.


MCPIP1 suppresses hepatitis C virus replication and negatively regulates virus-induced proinflammatory cytokine responses.
Human MCP-1-induced protein 1 (MCPIP1, also known as ZC3H12A and Regnase-1) plays important roles in negatively regulating the cellular inflammatory response. Recently, we found that as an RNase, MCPIP1 has broad-spectrum antiviral effects by targeting viral RNA. In this study, we demonstrated that MCPIP1 expression was induced by hepatitis C virus (HCV) infection in Huh7.5 hepatoma cells. MCPIP1 expression was higher in liver tissue from patients with chronic HCV infection compared with those without chronic HCV infection. Knockdown of MCPIP1 increased HCV replication and HCV-mediated expression of proinflammatory cytokines, such as TNF-α, IL-6, and MCP-1. However, overexpression of MCPIP1 significantly inhibited HCV replication and HCV-mediated expression of proinflammatory cytokines. Various mutants of functional domains of MCPIP1 showed disruption of the RNA binding and oligomerization abilities, as well as RNase activity, but not deubiquitinase activity, which impaired the inhibitory activity against HCV replication. On immunocytochemistry, MCPIP1 colocalized with HCV RNA. Use of a replication-defective HCV John Cunningham 1/AAG mutant and in vitro RNA cleavage assay demonstrated that MCPIP1 could directly degrade HCV RNA. MCPIP1 may suppress HCV replication and HCV-mediated proinflammatory responses with infection, which might contribute to the regulation of host defense against the infection and virus-induced inflammation.


Th1 and Th2 cells form morphologically distinct immunological synapses.
The arrangement of molecules at the interface between T cells and APCs is known as the immunological synapse (IS). We conducted experiments with supported planar bilayers and transfected fibroblast APC to examine the IS formed by polarized Th1 and Th2 cells. Th1 cells formed typical "bull's-eye" IS with a ring of adhesion molecules surrounding MHC/TCR interactions at all Ag concentrations tested, while Th2 cells formed multifocal IS at high concentrations of Ag. At low Ag concentrations, the majority of Th2 cells formed IS with a compact, central accumulation of MHC/TCR, but ICAM-1 was not excluded from the center of the IS. Additionally, CD45 was excluded from the center of the interface between Th1 cells and APC, while CD45 was found at the center of the multifocal IS formed by Th2 cells. Finally, phosphorylated signaling molecules colocalized with MHC/TCR to a greater extent in Th2 IS. Together, our results indicate that the IS formed by Th1 and Th2 cells are distinct in structure, with Th2 cells failing to form bull's-eye IS.


Sequence-structure-function relations of the mosquito leucine-rich repeat immune proteins.
The discovery and characterisation of factors governing innate immune responses in insects has driven the elucidation of many immune system components in mammals and other organisms. Focusing on the immune system responses of the malaria mosquito, Anopheles gambiae, has uncovered an array of components and mechanisms involved in defence against pathogen infections. Two of these immune factors are LRIM1 and APL1C, which are leucine-rich repeat (LRR) containing proteins that activate complement-like defence responses against malaria parasites. In addition to their LRR domains, these leucine-rich repeat immune (LRIM) proteins share several structural features including signal peptides, patterns of cysteine residues, and coiled-coil domains. The identification and characterisation of genes related to LRIM1 and APL1C revealed putatively novel innate immune factors and furthered the understanding of their likely molecular functions. Genomic scans using the shared features of LRIM1 and APL1C identified more than 20 LRIM-like genes exhibiting all or most of their sequence features in each of three disease-vector mosquitoes with sequenced genomes: An. gambiae, Aedes aegypti, and Culex quinquefasciatus. Comparative sequence analyses revealed that this family of mosquito LRIM-like genes is characterised by a variable number of 6 to 14 LRRs of different lengths. The "Long" LRIM subfamily, with 10 or more LRRs, and the "Short" LRIMs, with 6 or 7 LRRs, also share the signal peptide, cysteine residue patterning, and coiled-coil sequence features of LRIM1 and APL1C. The "TM" LRIMs have a predicted C-terminal transmembrane region, and the "Coil-less" LRIMs exhibit the characteristic LRIM sequence signatures but lack the C-terminal coiled-coil domains. The evolutionary plasticity of the LRIM LRR domains may provide templates for diverse recognition properties, while their coiled-coil domains could be involved in the formation of LRIM protein complexes or mediate interactions with other immune proteins. The conserved LRIM cysteine residue patterns are likely to be important for structural fold stability and the formation of protein complexes. These sequence-structure-function relations of mosquito LRIMs will serve to guide the experimental elucidation of their molecular roles in mosquito immunity.


Vascular adhesion and transendothelial migration of eosinophil leukocytes.
Tissues respond to injury with inflammation in an effort to protect and repair the damaged site. During inflammation, leukocytes typically accumulate in response to certain chemicals produced within the tissue itself. The passage of leukocytes through the vascular lumen into tissues occurs in several phases, including rolling, activation, firm adhesion, transendothelial migration, and subendothelial migration. Although infiltration of eosinophil leukocytes is one of the most important aspects of allergic inflammatory reactions, eosinophils also participate in nonallergic inflammation. Eosinophil accumulation is regulated not only by endothelial adhesion molecules, but also by interactions between eosinophil adhesion molecules and extracellular matrix elements. This review summarizes the regulation of eosinophil leukocyte adhesion and migration. A better understanding of eosinophil recruitment responses may lead to the development of novel therapeutics for chronic allergic diseases.