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Background The treatment with short-acting beta-2 agonists (SABA) alone is no longer recommended due to safety issues. Instead, the current Global Initiative for Asthma (GINA) Report recommends the use of the combination of inhaled corticosteroids (ICS) with the rapid/long-acting beta-2 agonist formoterol, although the use in steps 1 and 2 is still off-label in the EU and in many countries. It is important to understand clinicians’ knowledge and opinions on the issue with the ultimate goal to encourage the implementation of the new approach in clinical practice. Methods We performed an international survey, directed to pulmonologists interested in the management of patients with asthma. Results Most participants reported that SABA alone should not be used in GINA Step 1 asthma treatment. As-needed low-dose ICS/formoterol combination to patients in step 1, and as-needed low-dose ICS/formoterol as reliever therapy in any step were found to be of current use prescribed in their real-life settings. SABA alone was still prescribed to a proportion of patients, although the pulmonologists’ opinion was that it should no longer be used. Conclusions Most specialists are up to date and understand the relevance of the changes in GINA reports from 2019. Nevertheless, dissemination and implementation of GINA novel management strategy is still needed.

Collagen materials are widely applied in medicine due to optimal handling characteristics, biocompatibility, controlled biodegradation, the ability to form complexes with drugs and facilitate regeneration. Researchers from Sechenov University developed, studied in experiments and introduced into medicine a variety of materials based on collagen — a protein of connective tissue. At the same time, new collagen materials were launched into clinical practice abroad. In this review of Russian and world literature, we described how scientific and applied studies of collagen materials developed over time and tried to illustrate the current state and trends of collagen application for a variety of medical purposes — from hemostatic sponges to tissue-engineered constructs. The range of available collagen-based medical products and the emergence of new collagen materials indicate the keen interest in this biomaterial from the medical community and the potential of future discoveries.

IMPORTANCE: Human papillomavirus (HPV)–positive status in patients with oropharyngeal squamous cell carcinoma (OPSCC) is associated with improved survival compared with HPV-negative status. However, it remains controversial whether HPV is associated with improved survival among patients with nonoropharyngeal and cervical squamous cell tumors. OBJECTIVE: To investigate differences in the immunogenomic landscapes of HPV-associated tumors across anatomical sites (the head and neck and the cervix) and their association with survival. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used genomic and transcriptomic data from the Cancer Genome Atlas (TCGA) for 79 patients with OPSCC, 435 with nonoropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC), and 254 with cervical squamous cell carcinoma and/or endocervical adenocarcinoma (CESC) along with matched clinical data from TCGA. The data were analyzed from November 2020 to March 2021. MAIN OUTCOMES AND MEASURES: Positivity for HPV was classified by RNA-sequencing reads aligned with the HPV reference genome. Gene expression profiles, immune cell phenotypes, cytolytic activity scores, and overall survival were compared by HPV tumor status across multiple anatomical sites. RESULTS: The study comprised 768 patients, including 514 (66.9%) with HNSCC (380 male [73.9%]; mean [SD] age, 59.5 [10.8] years) and 254 (33.1%) with CESC (mean [SD] age, 48.7 [14.1] years). Human papillomavirus positivity was associated with a statistically significant improvement in overall survival for patients with OPSCC (adjusted hazard ratio [aHR], 0.06; 95% CI, 0.02-0.17; P

Given the recent successes of anti-PD-1 immunotherapy, many clinical trials have sought to assess the safety and efficacy of this treatment modality in the neoadjuvant setting. This systematic review provides a comprehensive summary of findings from neoadjuvant head and neck cancer immunotherapy clinical trials with a focus on PD-1/PD-L1 axis blockade. Pubmed, Embase, Cochrane Library, Web of Science, Google Scholar, and clinicaltrials.gov were systematically searched for all eligible neoadjuvant head and neck cancer immunotherapy clinical trials. Eight clinical trials met the inclusion criteria comprising a total of 260 patients. Study drugs included nivolumab, pembrolizumab, ipilimumab, durvalumab, and tremelimumab. The overall mean objective response rate (ORR) was 45.9 ± 5.7% with a 41.5 ± 5.6% single agent mean ORR. There were no deaths due to immune-related toxicities. Neoadjuvant immunotherapy for mucosal head and neck squamous cell cancer has demonstrated favorable response rates with no unexpected immune-related toxicities in phase I/II clinical trials.

Simple Summary Tumors of head and neck cancer are a heterogenous collection of malignancies affecting the upper aerodigestive tract, the majority of which are head and neck squamous cell carcinomas (HNSCCs). Development of immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HNSCCs, albeit only in a minority of patients. Due to the low clinical response rates for HNSCCs and the potential for immune-related adverse side effects, predictive biomarkers are necessary to characterize patients who are most likely to respond to treatment. Previous studies have indicated that patient nutritional status may impact immune response. However, the effects of pretreatment nutritional status, specifically on immunotherapy-treated HNSCC patients, remains unclear. The aim of our study is to explore the associations between baseline prognostic nutritional index and pretreatment body mass index trends on the outcomes of HNSCC patients treated with anti-PD-1 or anti-CTLA-4 immunotherapy, or both. Abstract The association between pretreatment nutritional status and immunotherapy response in patients with advanced head and neck cancer is unclear. We retrospectively analyzed a cohort of 99 patients who underwent treatment with anti-PD-1 or anti-CTLA-4 antibodies (or both) for stage IV HNSCC between 2014 and 2020 at the Johns Hopkins Hospital. Patient demographics and clinical characteristics were retrieved from electronic medical records. Baseline prognostic nutritional index (PNI) scores and pretreatment body mass index (BMI) trends were calculated. Associations between PNI and BMI were correlated with overall survival (OS), progression-free survival (PFS), and immunotherapy response. In univariate analysis, there was a significant correlation between OS and PFS with baseline PNI (OS: HR: 0.464; 95% CI: 0.265–0.814; PFS: p = 0.007 and HR: 0.525; 95% CI: 0.341–0.808; p = 0.003). Poor OS was also associated with a greater decrease in pretreatment BMI trend (HR: 0.42; 95% CI: 0.229–0.77; p = 0.005). In multivariate analysis, baseline PNI but not BMI trend was significantly associated with OS and PFS (OS: log (HR) = −0.79, CI: −1.6, −0.03, p = 0.041; PFS: log (HR) = −0.78, CI: −1.4, −0.18, p = 0.011). In conclusion, poor pretreatment nutritional status is associated with negative post-immunotherapy outcomes.

Objective To identify differences in the transcriptomic profiles during placentation from pregnancies conceived spontaneously vs. those with infertility using non-in vitro fertilization (IVF) fertility treatment (NIFT) or IVF. Design Cohort study. Setting Academic medical center. Patient(s) Women undergoing chorionic villus sampling at gestational age 11–13 weeks (n = 141), with pregnancies that were conceived spontaneously (n = 74), with NIFT (n = 33), or with IVF (n = 34), resulting in the delivery of viable offspring. Intervention(s) Collection of chorionic villus samples from women who conceived spontaneously, with NIFT, or with IVF for gene expression analysis using RNA sequencing. Main Outcome Measure(s) Baseline maternal, paternal, and fetal demographics, maternal medical conditions, pregnancy complications, and outcomes. Differential gene expression of first-trimester placenta. Result(s) There were few differences in the transcriptome of first-trimester placenta from NIFT, IVF, and spontaneous pregnancies. There was one protein-coding differentially expressed gene (DEG) between the spontaneous and infertility groups, CACNA1I, one protein-coding DEG between the spontaneous and IVF groups, CACNA1I, and five protein-coding DEGs between the NIFT and IVF groups, SLC18A2, CCL21, FXYD2, PAEP, and DNER. Conclusion(s) This is the first and largest study looking at transcriptomic profiles of first-trimester placenta demonstrating similar transcriptomic profiles in pregnancies conceived using NIFT or IVF and spontaneous conceptions. Gene expression differences found to be highest in the NIFT group suggest that the underlying infertility, in addition to treatment-related factors, may contribute to the observed gene expression profiles.

Background Molecular lymph node workup with one-step nucleic acid amplification (OSNA) is a validated diagnostic adjunct in breast cancer and also appealing for colon cancer (CC) staging. This study, for the first time, evaluates the prognostic value of OSNA in CC. Patients and methods The retrospective study includes patients with stage I-III CC from three centres. Lymph nodes were investigated with haematoxylin and eosin (H&E) and with OSNA, applying a 250 copies/μL threshold of CK19 mRNA. Diagnostic value of H&E and OSNA was assessed by survival analysis, sensitivity, specificity and time-dependent receiver operating characteristic curves. Results Eighty-seven patients were included [mean follow-up 53.4 months (± 24.9)]. Disease recurrence occurred in 16.1% after 19.8 months (± 12.3). Staging with H&E independently predicted worse cancer-specific survival in multivariate analysis (HR = 10.77, 95% CI 1.07–108.7, p = 0.019) but not OSNA (HR = 3.08, 95% CI 0.26–36.07, p = 0.197). With cancer-specific death or recurrence as gold standard, H&E sensitivity was 46.7% (95% CI 21.3–73.4%) and specificity 84.7% (95% CI 74.3–92.1%). OSNA sensitivity and specificity were 60.0% (95% CI 32.3–83.7%) and 75.0% (95% CI 63.4–84.5%), respectively. Conclusions In patients with CC, OSNA does not add relevant prognostic value to conventional H&E contrasting findings in other cancers. Further studies should assess lower thresholds for OSNA (

Simple Summary Severe skin scars (i.e., hypertrophic and keloid) induce physical and emotional discomfort and functional disorders such as contractures and body part deformations. Scar’s response to treatment depends on “maturity”, which increases with time but is not merely proportional to it. When “fresh”, scars are relatively more treatable by conservative methods, while the treatment is only partially efficient. In contrast, surgery is a preferred approach for the older scars, but it is associated with a risk of the scar regrowth and worsening after excision if unrecognized immature scar tissue remains in the operated lesion. Therefore, to develop better treatment and diagnostics of scars, understanding of the scar maturation is essential. This requires biologically accurate experimental models of skin scarring. The current models only mimic the early stages of skin scar development. They are useful for testing new scar-preventing approaches while not addressing the problem of the older scars that exist for years. In our study, we demonstrate a new rabbit model of “old” scars and explore what happens to the scar tissue during maturation. We define measurable signs to delineate the scar development stages and discuss how this knowledge can improve scar diagnostics and treatment. Abstract Mature hypertrophic scars (HSs) remain a challenging clinical problem, particularly due to the absence of biologically relevant experimental models as a standard rabbit ear HS model only reflects an early stage of scarring. The current study aims to adapt this animal model for simulation of mature HS by validating the time of the scar stabilization using qualitative and quantitative criteria. The full-thickness skin and perichondrium excision wounds were created on the ventral side of the rabbit ears. The tissue samples were studied on post-operation days (PODs) 30, 60, 90 and 120. The histopathological examination and morphometry were applied in parallel with biochemical analysis of protein and glycosaminoglycans (GAGs) content and amino acid composition. The supramolecular organization of collagen was explored by differential scanning calorimetry. Four stages of the rabbit ear HS maturation were delineated and attributed with the histolomorphometrical and physicochemical parameters of the tissue. The experimental scars formed in 30 days but stabilized structurally and biochemically only on POD 90–120. This evidence-based model can be used for the studies and testing of new treatments of the mature HSs.

Introduction and Objectives Persistent airflow limitation (PAL) predicts a positive clinical response to add-on long acting muscarinic antagonist in patients with asthma taking inhaled corticosteroids and long-acting β2-receptor agonists. We conducted a post-hoc analysis of the TRIGGER study to evaluate the effect of extrafine BDP/FF/G vs BDP/FF on asthma control and the use of systemic corticosteroids for asthma exacerbations in a subset of patients with PAL. Methods TRIGGER was a phase III, randomized, parallel group trial comparing 52-week treatment with BDP/FF/G 200/6/10µg two inhalations twice daily (BID) to BDP/FF 200/6µg BID and an open-label treatment arm consisting of BDP/FF 200/6µg BID plus tiotropium (BDP/FF+Tio). PAL criteria were a post-bronchodilator FEV1≤80% of predicted normal and FEV1/FVC≤0.7; ACQ-7 response was defined as a change from baseline in ACQ-7 score ≤-0.5 unit, and asthma control days as asthma symptom-free day without using rescue medication. Results 1437 subjects were randomized and 61.2% met the PAL criteria. In this subgroup, there was a significantly higher percentage of ACQ-7 responders on BDP/FF/G compared to BDP/FF at week 26 (60.2% vs 49.4%) and week 52 (60.8% vs 51.7%). In the overall population, the difference in the percentage of ACQ-7 responders was 61.3% vs 55.9% at week 26 and 62.3% vs 58.1% at week 52, for BDP/FF/G and BDP/FF respectively. In patients with PAL, the change from baseline in the asthma control days over 52 weeks was higher in BDP/FF/G compared to BDP/FF (14.5% vs 8.8%), with a smaller difference observed in the overall population (Table 1). Patients treated with BDP/FF/G had less days of systemic corticosteroid use for asthma exacerbations compared to BDP/FF in the PAL subpopulation (34.1% reduction; RR=0.659, 95%CI (0.389–1.118) p=0.122), and in the overall population (24.4% reduction; RR=0.756, 95%CI (0.499–1.145) p=0.186), although not statistically significant. Conclusions In adult asthmatics with PAL, treatment with high ICS dose extrafine BDP/FF/G compared to BDP/FF was associated with greater odds of experiencing asthma control and a higher trend towards a decreased use of systemic corticosteroids for asthma exacerbations, compared to the overall population.

Background and Aims Allograft rejection following BK virus nephropathy (BKVN) is an important cause of allograft loss in kidney transplant recipients. However, the effect of rejection type on allograft survival in patients with BKVN has not been described previously. This study aimed to investigate the relationship between allograft rejection type and graft survival in patients with BKVN. Method We retrospectively analyzed the data of 159 kidney transplant recipients diagnosed BKVN and followed-up in our center between January 2009 and December 2019. BKVN was diagnosed by persistent viremia of more than 10000 copies/mL for four weeks or allograft biopsy. Vascular, obstructive or other non-parenchymal etiologies for allograft dysfunction were excluded. All patients were investigated for the presence of anti-HLA antibody at 6 and 12 months after BKVN diagnosis. Luminex solid-phase assay was used to investigate Class I and Class II PRA and MFI values greater than 1000 were accepted as positive. Allograft biopsy was performed in patients with progressive graft dysfunction or the presence of donor-specific antibodies (DSA) and analyzed according to the Banff Classification. The primary outcomes were defined as allograft loss or the allograft dysfunction which defined as was doubling serum creatinine levels. Results Patients were followed-up median 70 (IQR 13-198) months after kidney transplantation. Demographic data and clinical characteristics are provided in the table. 28 kidney transplant recipients suffered from allograft rejection after BKVN. Median rejection time to rejection after BKVN was 9 (IQR 5-164) months. 3 patients (18,8%) in the AMR group and 1 patient (8,3%) in the TCMR group experienced graft loss during follow-up. The mean serum creatinine levels at the last clinical visit were significantly higher in the AMR group compared to the TCMR group (1,9±0,8 vs 1,3±1,2 mg/dl; p=0,002). In multivariate analysis, AMR was an independent risk factor for allograft dysfunction (HR, 1,735; 95% CI 1,060 to 2,839; p=0,028). Conclusion The occurrence of AMR after BKVN is an important indicator of allograft dysfunction compared to TCMR. DSA screening should be routinely used in this group for early diagnosis and treatment of AMR.

The model established at Orillia Soldiers Memorial Hospital involves family physicians as the most responsible physician. They act as “admission gatekeeper” for all unattached patients who are admitted to the psychiatry in-patient unit. A PubMed, EBSCO, OVID Medline, Embase, CINAHL, and Web of Science database review of the last 10 years (2006-2016) was undertaken. A satisfaction survey was undertaken. An intensive literature review found this model to be unique. The model has proved to be extremely efficient and cost-effective.

PROBLEM: Embryo implantation and placentation require a careful immunological balance. Cytokines such as IL-10 and TNFα have been implicated as markers of dysregulation, but have only been studied at a single time point or after a pregnancy loss. Our objective was to determine normative patterns of serum levels of IL-10 and TNFα and their ratio throughout the first trimester in healthy pregnancies and to determine if this pattern differs from pregnancy loss.METHOD OF STUDY: Two prospective longitudinal cohorts of gravidae including in vitro fertilization (IVF) and naturally conceived pregnancies with serial blood draws. Cytokines were assayed using Simple Plex. In the IVF cohort, we monitored from the implantation day up to 6 weeks of gestation; whereas in the naturally conceived cohort, sample collection began at 4 weeks and throughout the whole first trimester.RESULTS: IL-10 concentrations in normal pregnancies were significantly higher than in pregnancies ending in a loss starting at 6-8 weeks of gestation, while TNFα concentrations were significantly lower in normal than in pregnancies ending in a loss starting at 3-5 of gestation weeks. The IL-10 to TNFα ratio in normal pregnancies was significantly higher from 4 to 9 weeks compared to pregnancies that were lost (t test, P < .05). Changes were observed before any symptoms of miscarriage were present.CONCLUSION: We provide evidences of differences in early immunomodulation in healthy pregnancies vs those destined to end in first-trimester loss. The ratio of IL-10 to TNFα rises significantly higher in viable pregnancies as early as 4.5 weeks compared to pregnancies loss.

In this work, we brought together two existing clinical techniques used in cancer treatment—X-ray radiation and photodynamic therapy (PDT), whose combination termed X-PDT uniquely allows PDT to be therapeutically effective in deep tissue. To this end, we developed mitochondrially targeted biodegradable polymer poly(lactic-co-glycolic acid) nanocarriers incorporating a photosensitizer verteporfin, ultrasmall (2–5 nm) gold nanoparticles as radiation enhancers, and triphenylphosphonium acting as the mitochondrial targeting moiety. The average size of the nanocarriers was about 160 nm. Upon X-ray radiation our nanocarriers generated cytotoxic amounts of singlet oxygen within the mitochondria, triggering the loss of membrane potential and mitochondria-related apoptosis of cancer cells. Our X-PDT strategy effectively controlled tumor growth with only a fraction of radiotherapy dose (4 Gy) and improved the survival rate of a mouse model bearing colorectal cancer cells. In vivo data indicate that our X-PDT treatment is cytoreductive, antiproliferative, and profibrotic. The nanocarriers induce radiosensitization effectively, which makes it possible to amplify the effects of radiation. A radiation dose of 4 Gy combined with our nanocarriers allows equivalent control of tumor growth as 12 Gy of radiation, but with greatly reduced radiation side effects (significant weight loss and resultant death)., We developed a novel strategy named X-ray-induced photodynamic therapy (X-PDT) which enables chemotherapy-free treatment of deep cancer with a low dose of X-ray radiation.

Ninety years old male was admitted to hospital due to breathlessness. The prominent findings were extensive blue-grey skin pigmentation and large left chylothorax. Drug induced lupus was diagnosed due to either minocycline chronic treatment or no alternative illness to explain his sub-acute disease. Minocycline therapy was stopped with gradual improvement of pleural effusion and skin discoloration. This case is the first presentation of minocycline induced lupus with chylothorax.

Aims To examine the potential risk factors for in-hospital and 1-year mortality in elderly patients with hip fracture. Methods Included were elderly patients aged 65 years and older admitted to the orthopedic department with hip fractures. Clinical and laboratory data were obtained from electronic medical records. Results Among the significant risk factors for in-hospital and or 1-year mortality were male gender, age, higher Charlson comorbidity index (CCI), chronic renal failure (CRF) and cholesterol lower level. In a number of risk factors, there were gender differences, e.g., the survival of females and not of men treated with statins was significantly higher than for those not treated with the drug. Conclusion It is important to make efforts to identify risk factors for mortality after hip fracture to be able to devise course of action to reduce mortality rate after hip fracture.

Sclerosing mesenteritis is a rare pathology with only a few described cases in the literature. The etiology is unclear; however, several potential triggers, including abdominal surgery and abdominal trauma, have been discussed. The pathology includes a benign acute or chronic inflammatory process affecting the adipose tissue of the mesenterium. Despite it being a rare disease, sclerosing mesenteritis is an important differential diagnosis in patients after abdominal surgery or patients presenting spontaneously with signs of acute inflammation and abdominal pain. We present here three cases with sclerosing mesenteritis. In two cases, sclerosing mesenteritis occurred postoperatively after abdominal surgery. One patient was treated because of abdominal pain and specific radiological signs revealing spontaneous manifestation of sclerosing mesenteritis. So far there are no distinct treatment algorithms, so the patients were treated differently, including steroids, antibiotics and watchful waiting. In addition, we reviewed the current literature on treatment options for this rare disease.

BACKGROUND There is ongoing debate about nonpalliative primary tumor surgery in metastatic breast cancer patients. This issue has become even more relevant with the introduction of increasingly sensitive imaging modalities. METHODS Metastatic breast cancer patients were identified in the SEER registry between 1998 and 2009. The effect of primary tumor surgery on overall and cancer-specific mortality using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching was assessed. RESULTS Overall, 16,247 women with metastatic breast cancer were included. Of those 7600 women underwent primary tumor surgery although 8647 did not have any surgery at all. Primary tumor surgery decreased from 62.0% in 1998 to 39.1% in 2009 (P < 0.001). Primary tumor surgery was associated with decreased overall mortality (hazard ratio (HR) = 0.53, 95% CI 0.50-0.55, P < 0.001) and cancer-specific mortality (HR = 0.51, 95% CI 0.48-0.54, P < 0.001) in the propensity score-matched model. The benefit of primary tumor surgery increased from 1998 to 2009 for overall mortality (1998: HR = 0.72, 95% CI 0.59-0.89, 2009: HR = 0.42, 95% CI 0.35-0.50) and cancer-specific mortality (1998: HR = 0.72, 95% CI 0.58-0.89, 2009: HR = 0.40, 95% CI 0.33-0.48). CONCLUSIONS The present study-the first population-based analysis using propensity score methods-provides evidence of a favorable impact of primary tumor surgery on mortality in metastatic breast cancer patients. Most importantly, the benefit of primary tumor surgery increased over time from 1998 to 2009. Although the final results of ongoing randomized studies are awaited, currently available evidence should be discussed with metastatic breast cancer patients.

// Lisa Zuckerwise 1, * , Jing Li 1, 2, * , Lingeng Lu 3 , Yi Men 1, 4 , Tingting Geng 1, 5 , Catalin S. Buhimschi 6 , Irina A. Buhimschi 6, 7, 8 , Radek Bukowski 1 , Seth Guller 1 , Michael Paidas 1, 9 , Yingqun Huang 1 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA 2 Deparment of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China 3 Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, CT, USA 4 Department of Head and Neck Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China 5 Department of Endocrinology, School of Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China 6 Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA 7 Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA 8 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA 9 Yale Women and Children's Center for Blood Disorders and Preeclampsia Advancement, Yale School of Medicine, New Haven, CT, USA * These authors contributed equally to this work Correspondence to: Yingqun Huang, email: yingqun.huang@yale.edu Keywords: fetal growth restriction, H19 long noncoding RNA, TβR3, trophoblast Received: February 15, 2016 Accepted: May 08, 2016 Published: May 21, 2016 ABSTRACT Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro . This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-β receptor (TβR3) following H19 knockdown. Decreased TβR3 expression is also seen in FGR placentae. TβR3 repression decreases EVT cell migration and invasion, owing to impaired TGF-β signaling through a non-canonical TGF-β signaling pathway. Further, we identify TβR3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/TβR3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR.

Problem Hyperglycemia increases the risk of preeclampsia. Hyperglycemia induces a placental trophoblast inflammatory (IL-1β, IL-6, IL-8), antiangiogenic (sFlt-1, sEndoglin), and anti-migratory profile. The IL-1β response is mediated via inflammasome activation by the damage-associated molecular pattern (DAMP), uric acid. The objective of this study was to determine the role of high-mobility group box-1 (HMGB1), a DAMP that activates Toll-like receptor 4 (TLR4), in human first trimester trophoblast responses to hyperglycemia. The trophoblast response to excess glucose under different oxygen tensions was also investigated. Method of study The human first trimester trophoblast cell line (Sw.71) was exposed to glucose mimicking normoglycemia (5 mmol/L) and hyperglycemia (10 mmol/L), either alone or with the TLR4 antagonist, LPS-RS; or the HMGB1 inhibitor, glycyrrhizin. Cells were also treated with glucose under hyperoxic (21% O2 ), normoxic (8% O2 ), and hypoxic (2% O2 ) conditions. Cell-free supernatants were assayed by ELISA and bioassays for inflammatory: IL-1β, IL-6, and IL-8; inflammasome-associated: uric acid and caspase-1; angiogenic: sEndoglin, sFlt-1, and PlGF; and the DAMP, HMGB1. Cell migration was measured using a two-chamber colormetric assay. Results Excess glucose triggered a trophoblast sterile inflammatory IL-8 and antimigratory response through HMGB1 activation of TLR4. The IL-1β and sFlt-1/PlGF response was TLR4-mediated, but HMGB1-independent, suggesting another DAMP may be involved. Hyperoxia rather than normoxia or hypoxia was a major driver of trophoblast dysfunction in response to excess glucose. Conclusion The findings from this study indicate a novel mechanism by which hyperglycemia may impact trophoblast function, early placentation, and ultimately, pregnancy outcome.

The increasing range of surgery in elderly patients reflects the changing demography where in the next 10 years one quarter of the population will be 65 years of age or older. There is presently no consensus concerning the optimal predictive markers for postoperative morbidity and mortality after surgery in older patients with an appreciation that physical frailty is more important than chronological age. In this retrospective analysis, we have compared the impact of age and the calculated preoperative Charlson Comorbidity Index (CCI) on early (30-day) and late (one-year) mortality in a group of patients >75 years of age dividing them into an “older old” cohort (75–84 years of age, Group A) and an “oldest old” group (≥85 years of age, Group B). Increased age was associated with a higher death rate after emergency surgery, with late deaths after elective surgery exceeding those after emergency operations. A higher mean CCI was noted in both age groups in early nonsurvivors after both elective and emergency surgery with a more significant effect of the preoperative CCI than chronological age for the prediction of late postoperative death for both groups after elective and emergency operations. Although the CCI was not designed to predict perioperative mortality in surgical cohorts, it correlates with a greater risk than age for perioperative death in the elderly.

Use of antioxidants to mitigate oxidative stress during ocular inflammatory diseases has shown therapeutic potential. This work examines a nanoscale therapeutic modality for the eye on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), termed “nanozyme.” The nanozyme is produced by electrostatic coupling of the SOD1 with a cationic block copolymer, poly(L-lysine)-poly(ethyleneglycol), followed by covalent cross-linking of the complexes with 3,3′-dithiobis(sulfosuccinimidylpropionate) sodium salt. The ability of SOD1 nanozyme as well as the native SOD1 to reduce inflammatory processes in the eye was examinedin vivoin rabbits with immunogenic uveitis. Results suggested that topical instillations of both enzyme forms demonstrated anti-inflammatory activity; however, the nanozyme was much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as the intensities of corneal and iris edema, hyperemia of conjunctiva, lens opacity, fibrin clots, and the protein content in aqueous humor. Clinical findings were confirmed by histological data. Thus, SOD1-containing nanozyme is potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.

Composites of a collagen matrix and dinitrosyl iron complexes with glutathione (DNIC-GS) (in a dose of 4.0 μmoles per item) in the form of spongy sheets (DNIC-Col) were prepared and then topically applied in rat excisional full-thickness skin wound model. The effects of DNIC-Col were studied in comparison with spontaneously healing wounds (SpWH) and wounds treated with collagen sponges (Col) without DNIC-GS. The composites induced statistically and clinically significant acceleration of complete wound closure (21±1 day versus 23±1 day and 26±1 day for DNIC-Col, Col and SpWH, respectively). Histological examination of wound tissues on days 4, 14, 18 and 21 after surgery demonstrated that this improvement was supported by enhanced growth, maturation and fibrous transformation of granulation tissue and earlier epithelization of the injured area in rats treated with DNIC-Col composites benchmarked against Col and SpWH. It is suggested that the positive effect of the new pharmaceutical material on wound healing is based on the release of NO from decomposing DNIC. This effect is believed to be potentiated by the synergy of DNIC and collagen.

Sustained plasma progesterone (P4) levels suggest initiation of human term labor by functional P4 withdrawal, reflecting reduced progesterone receptor (PR) and/or glucocorticoid receptor (GR) expression or activity. The steroid-induced immunophilin cochaperone FKBP51 inhibits PR- and GR-mediated transcription, suggesting a labor-initiating role. Gestational age-matched decidual sections were immunostained for FKBP51 and decidual cell (DC) and interstitial trophoblast (IT) markers, vimentin and cytokeratin, respectively. Term DC cultures were incubated with vehicle (control), estradiol (E2) with or without medroxyprogesterone acetate, dexamethasone (Dex), or Organon 2058. FKBP51 histologic scoring was significantly higher in DC nuclei during labor versus prelabor decidua, whereas FKBP51 immunostaining was undetected in interstitial trophoblasts (P0.05). In term DC cultures, E2 + medroxyprogesterone acetate or E2 + Dex enhanced FKBP51 expression (P0.01), whereas E2 + Organon 2058 inhibited PR expression (P0.05), and E2 + Dex inhibited GR expression (P0.05). Unlike term DCs, FKBP51 was undetected in control or Dex-treated cultured third-trimester trophoblasts. Electrophoretic mobility shift assays revealed that FKPB51 overexpression or silencing in cultured DCs altered PR-DNA binding. Increased FKBP51 levels in term DCs during labor complement our prior in situ observations of significantly lower PR in labor versus prelabor DCs. In a milieu of sustained plasma P4 levels, these reciprocal changes will amplify functional P4 withdrawal in DCs via FKBP51-mediated PR resistance coupled with declining PR levels, whereas the lack of FKBP51 expression in interstitial trophoblasts suggests unopposed constitutive GR action.

The generation of gaseous mixtures containing nitric oxide (gNO) from different plasma sources has been widely used for various clinical applications. Concentrations of biologically active species generated in those discharges in addition to gNO were calculated for different gas temperatures. Synergistic actions of gNO with other plasma species are discussed. New therapeutic effects of gNO-containing plasmas achieved for the treatment of skin scars, rheumatoid arthritis, osteoarthritis and sport injuries are reported.

We used atomic force microscopy (AFM) to diagnose pathological changes in the extracellular matrix (ECM) of skin connective tissue in patients with pelvic organ prolapse (POP). POP is a common condition affecting women that considerably decreases the patients’ quality of life. Deviations from normal morphology of the skin ECM from patients with POP occur including packing and arrangement of individual collagen fibers and arrangement of collagen fibrils. The nanoindentation study revealed significant deterioration of the mechanical properties of collagen fibril bundles in the skin of POP patients as compared with the skin of healthy subjects. Changes in the skin ECM appeared to correlate well with changes in the ECM of the pelvic ligament tissue associated with POP. AFM data on the ECM structure of normal and pathologically altered connective tissue were in agreement with results of the standard histological study on the same clinical specimens. Thus, AFM and related techniques may serve as independent or complementary diagnostic tools for tracking POP-related pathological changes of connective tissue.

AIM: To investigate the potential distinct risk factors associated with trochanteric and cervical hip fractures. METHODS: Elderly patients aged 65 years and older (n = 1161) were admitted to the orthopedic department with hip fractures during the years 2006-2011. Demographic and clinical data, as well as routine blood tests, were retrieved from the patient electronic medical records. RESULTS: Approximately 58% of patients had trochanteric fractures and 42% had cervical fractures. Women were more likely to have trochanteric fractures than men (P = 0.002). Female sex, frailty, falls, diabetes and subnormal calcium, as well as subnormal hemoglobin levels, were significant risk factors for trochanteric fractures (OR 1.39, P = 0.0202, OR 1.36, P = 0.0166, OR 1.49, P = 0.0015, OR 1.33, P = 0.0343, OR 0.68, P = 0.0054, OR 0.70, P = 0.0036, respectively). Patients with Parkinson's disease were at a lower risk for trochanteric fractures (OR 0.6, P = 0.007). CONCLUSION: As there are some differences between risk factors for trochanteric and cervical hip fractures, there is a need for further studies in order to understand the etiology of fractures and to be able to carry out effective preventive efforts. Geriatr Gerontol Int 2014; ●●: ●●-●●. Language: en

The method of atomic force microscopy (AFM) is used for the first time for morphological investigation of pathological changes in the extracellular matrix of skin connective tissue upon the prolapse of pelvic organs (common disorder among women). Skin samples of patients with clinically proven pelvic-organ prolapse and of patients that do not have any connective tissue related disease (control group) are investigated via AFM. The AFM study reveals that the extracellular matrix of the skin connective tissues from patients with pelvic-organ prolapse diverges from the normal in various organization levels including both micro- and nanotexture (packing of collagen fibers and fibrils, respectively). The results of AFM study of the normal and pathologically changed skin connective tissues are in good agreement with the data of clinical morphological analysis, which indicates the potential of AFM as an independent diagnostic tool.

OBJECTIVES: Patients with pancreatic adenocarcinoma often present with distant metastatic disease. We aimed to assess whether improvements in survival of clinical trials translated to a population-based level. METHODS: The US Surveillance, Epidemiology, and End Results registry was queried. Adult patients with distant metastatic adenocarcinoma of the pancreas were included from 1988 to 2008. Overall survival was analyzed using Kaplan-Meier curves as well as multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 32,452 patients were included. Mean age was 67.6 (SD: 11.7) years, and 15,341 (47.3%) were female. Median overall survival was 3 months (95% confidence interval [CI], 3-3 months), which increased from 2 (CI, 2-2) months in 1988 to 3 (CI, 3-4) months in 2008. After adjustment for multiple covariates, the hazard ratio (HR) decreased by 0.977 per year (CI, 0.975-0.980). In multivariable-adjusted survival analyses, tumor location in the pancreatic body/tail (HR, 1.10), male sex (HR, 1.09), increasing age (HR, 1.016), African American ethnicity (HR, 1.16), nonmarried civil status (HR, 1.18), and absence of radiotherapy (HR, 1.41) were associated with worse survival (P < 0.001 for all predictors). CONCLUSIONS: The improvement in overall survival over the past 2 decades among patients with metastatic pancreatic adenocarcinoma is modest and disappointing. More effective therapeutic strategies for advanced disease are desperately needed.

This study tested a brief eating disorder risk measure, originally developed for use with college students, in young adolescents. The measure is called the COEDS (College Eating Disorders Screen) and is constructed of items written in everyday language used by youth to discuss weight issues, rather than in the language of symptom assessment. A sample of 246 early adolescents (mean age, 13) completed questionnaire measures of puberty, eating disorder behavior, and eating disorder risk two times in a 12-month span. We found that: (a) the COEDS was internally consistent; (b) COEDS scores were stable across one year; and (c) COEDS scores predicted restricting and compensatory behavior one year later, above and beyond prediction from sex, race, prior restricting and compensatory behavior, and prior BMI. The COEDS appears to be a reliable and valid measure for risk assessment in youth; it may prove useful for researchers and clinicians interested in screening for risk and as a means to test whether prevention efforts have reduced risk.

Problem Pre-eclampsia (PE), a pregnancy complication of unknown etiology, is a major cause of maternal and fetal mortality and morbidity. Previous studies have described placental genes that are up-regulated in expression in PE, but few studies have addressed placental gene suppression in this syndrome. Method of study Gene profiling and quantitative reverse transcription PCR (qRTPCR) analyses were used to identify genes down-regulated in placentas from women with severe preterm PE compared with gestational age-matched normotensive controls with spontaneous preterm birth (sPTB). Western blotting and immunohistochemistry were used to evaluate levels and patterns of cell type–specific protein expression in PE and sPTB group placentas. Results Levels of macrophage marker [folate receptor (FR)-β, CD163, and CD68] mRNA and FR-β protein were significantly down-regulated in PE group placentas compared with the sPTB group. Numbers of Hofbauer cells (HBCs, fetal macrophages) and FR-β protein in these cells were reduced in PE group placentas. Conclusion Severe PE is associated with decreased placental expression of FR-β and a reduction in the number of HBCs. Reduced placental macrophage function is likely to play a key role in the pathophysiology of PE.

Amianthoid transformation (AT) is the accumulations of abnormal collagen structures (amianthoid fibers) in the hyaline cartilages, tumors, and tendons. Neither functional value of costal cartilage matrix AT, nor its role in the pathogenesis of congenital chest deformities is known now.to examine the morphological features of AT in the costal cartilage of children with the normal and keeled chest.Costal cartilages were studied in 6 children with the normal chest (autopsy material) and in 5 ones with keeled chest (surgical material). Tissue fragments were fixed in 10% neutral formalin and embedded in compacted paraffin. The sections were stained with hematoxylin and eosin, picrofuchsin by van Gieson, with picrosirius, toluidine blue and by the Malaurie method modified by Gallego. The specimens were examined by light, phase-contrast, dark-field, fluorescence, and polarization microscopy. The frequency of AT sites and their area were morphometrically studied and the findings were then statistically processed.Various types of AT in the costal cartilages were described as both the normal and keeled chest. According to their morphological features, classic, fine-fiber, twisted, and intralacunar types were identified. There were statistically significant increases in the incidence of all types (except the intralacunar one) and in the area of the fine-fiber AT type in keeled chest deformity as compared to health. There were positive correlations between the area of classic, intralacunar, and twisted types in both groups and between the area of a classic type and age in the controls.A classification of AT areas varying in structures in health and disease has been given for the first time; their relation to each other and to the presence of keeled deformity shown, which, in our opinion, suggests that AT is implicated in the pathogenesis of the disease.Амиантоидная трансформация (АТ) - это образование скоплений аномальных коллагеновых структур (амиантоидных волокон) в гиалиновых хрящах, опухолях, сухожилиях. В настоящее время ни функциональное значение АТ матрикса реберных хрящей, ни ее роль в патогенезе врожденных деформаций грудной клетки неизвестны. Цель исследования - изучение морфологических особенностей АТ реберных хрящей у детей с нормальной и килевидной грудной клеткой. Материал и методы. Изучены реберные хрящи у 6 детей с нормальной (аутопсийный материал) и у 5 детей с килевидной грудной клеткой (операционный материал). Фрагменты ткани фиксировали в 10% нейтральном формалине и заливали в уплотненный парафин. Срезы окрашивали гематоксилином и эозином, пикрофуксином по Ван Гизону, пикросириусом, толуидиновым синим и методом Маллори в модификации Gallego. Препараты изучали с помощью световой, фазово-контрастной, темнопольной, флюоресцентной и поляризационной микроскопии. Проведено морфометрическое исследование частоты встречаемости и площади участков АТ с последующей статистической обработкой полученных данных. Результаты. Описаны различные типы АТ в реберных хрящах как нормальной, так и килевидной грудной клетки. В соответствии с их морфологическими особенностями выделены 'классический', тонковолокнистый, переплетенный и внутрилакунарный типы. Показано статистически значимое увеличение частоты встречаемости всех типов (кроме внутрилакунарного), а также площади тонковолокнистого типа АТ при килевидной деформации грудной клетки по сравнению с нормой. Выявлены положительные корреляционные связи между площадью 'классического', внутрилакунарного и переплетенного типов в обеих группах и между площадью 'классического' типа и возрастом в контроле. Заключение. Впервые дана классификация участков АТ разной структуры в норме и при патологии, показана их взаимосвязь друг с другом и с наличием килевидной деформации, что, по нашему мнению, свидетельствует о роли АТ в патогенезе заболевания.Амиантоидная трансформация (АТ) — это образование скоплений аномальных коллагеновых структур (амиантоидных волокон) в гиалиновых хрящах, опухолях, сухожилиях. В настоящее время ни функциональное значение АТ матрикса реберных хрящей, ни ее роль в патогенезе врожденных деформаций грудной клетки неизвестны. Цель исследования — изучение морфологических особенностей АТ реберных хрящей у детей с нормальной и килевидной грудной клеткой. Материал и методы. Изучены реберные хрящи у 6 детей с нормальной (аутопсийный материал) и у 5 детей с килевидной грудной клеткой (операционный материал). Фрагменты ткани фиксировали в 10% нейтральном формалине и заливали в уплотненный парафин. Срезы окрашивали гематоксилином и эозином, пикрофуксином по Ван Гизону, пикросириусом, толуидиновым синим и методом Маллори в модификации Gallego. Препараты изучали с помощью световой, фазово-контрастной, темнопольной, флюоресцентной и поляризационной микроскопии. Проведено морфометрическое исследование частоты встречаемости и площади участков АТ с последующей статистической обработкой полученных данных. Результаты. Описаны различные типы АТ в реберных хрящах как нормальной, так и килевидной грудной клетки. В соответствии с их морфологическими особенностями выделены «классический», тонковолокнистый, переплетенный и внутрилакунарный типы. Показано статистически значимое увеличение частоты встречаемости всех типов (кроме внутрилакунарного), а также площади тонковолокнистого типа АТ при килевидной деформации грудной клетки по сравнению с нормой. Выявлены положительные корреляционные связи между площадью «классического», внутрилакунарного и переплетенного типов в обеих группах и между площадью «классического» типа и возрастом в контроле. Заключение. Впервые дана классификация участков АТ разной структуры в норме и при патологии, показана их взаимосвязь друг с другом и с наличием килевидной деформации, что, по нашему мнению, свидетельствует о роли АТ в патогенезе заболевания.

OBJECTIVES The objectives of this investigation were to (1) compare short-term outcomes for patients undergoing primary gastric bypass surgery with those who had gastric bypass procedures performed as a rescue procedure after failed gastric banding and (2) study trends in the frequency of reoperations between 2005 and 2008 for patients who had prior gastric banding. BACKGROUND The use of gastric banding to treat obesity has increased drastically in the United States. However, the frequency of reoperations related to gastric banding and associated short-term outcomes are unknown. METHODS The Nationwide Inpatient Sample from 2005 to 2008 was used for this population-based study. Descriptive statistics as well as unadjusted and risk-adjusted generalized linear models were performed to assess adverse short-term outcomes. RESULTS A total of 66,303 patients were included in the analysis, 63,171 (95.3%) underwent a primary gastric bypass procedure and 3132 patients (4.7%) underwent a gastric band-related reoperation. Patients undergoing a gastric bypass procedure concomitant with a band-related reoperation had more intraoperative complications [risk-adjusted odds ratio (OR): 2.3, P = 0.002] and postoperative complications (risk-adjusted OR: 8.0, P < 0.001), were at higher risk of reoperations/reinterventions (risk-adjusted OR: 6.0, P < 0.001), increased length of hospital stay (adjusted mean difference: 0.89 days, P < 0.001), and higher hospital charges (adjusted mean difference: $13,257, P < 0.001). The number of gastric band-related reoperations increased from 579 in 2005 to 1132 in 2008 (196%). CONCLUSIONS The number of reoperations after gastric banding is rapidly increasing in the United States. To our knowledge, this is the first population-based study providing strong evidence that patients undergoing gastric bypass procedure after failed gastric banding have more adverse outcomes than those undergoing gastric bypass alone. The broad indication for gastric banding should be reaffirmed for the US population.

Periplacental levels of glucocorticoid (GC) peak at parturition, and synthetic GC is administered to women at risk for preterm delivery. However, little is known concerning cell-type-specific effects of GC in placenta. Hofbauer cells (HBCs) are fetal macrophages that are located adjacent to fetal capillaries in placenta. The goal of the current study was to determine whether GC treatment altered HBC gene expression and function. Western blotting and flow cytometry revealed CD163 and folate receptor-β (FR-β), markers of antiinflammatory M2 macrophages, were specifically expressed by primary cultures of HBCs immunopurified from human term placentas. GC receptor mRNA and protein levels were higher in HBCs compared with placental fibroblasts. Treatment of HBCs with cortisol or dexamethasone (DEX) markedly and specifically enhanced CD163 protein and mRNA levels, whereas expression of FR-β and CD68 were largely unresponsive to GC treatment. DEX treatment also increased hemoglobin uptake by HBCs, evidence of enhanced HBC function. The level of CD163 mRNA, but not FR-β or CD68 mRNA, was stimulated in placental explant cultures by DEX treatment, and increased CD163/FR-β and CD163/CD68 mRNA ratios sensitively reflected the response to GC. Maternal GC administration was associated with increased CD163/FR-β and CD163/CD68 mRNA ratios in placentas from women with spontaneous preterm birth. In conclusion, in vitro studies indicated that GC treatment specifically up-regulated CD163 expression in HBCs and enhanced HBC function. In addition, the observed alterations in patterns of expression of macrophage marker genes associated with maternal GC administration suggest that HBCs are in vivo targets of GC action.

Problem There is a strong correlation between intrauterine bacterial infection and preterm labor. While inflammation is a common mechanism, certain pathogens may trigger placental apoptosis. TLR2 activation by gram-positive bacterial peptidoglycan (PDG) induces first-trimester trophoblast apoptosis and decreased IL-6 secretion. This is dependent upon the presence of TLR1 and the absence of TLR6 and both TLR2 coreceptors. As TLR10 is also a TLR2 coreceptor, the objective of this study was to determine its expression and function in the trophoblast. Method of study First-and third-trimester human placental tissue and isolated trophoblast were evaluated for TLR10 expression. A first-trimester human trophoblast cell line stably transfected with a TLR10 dominant negative (TLR10-DN) or vector control was treated with or without PDG and analyzed for apoptosis and IL-6. Results TLR10 was expressed by trophoblasts during the first and third trimesters of pregnancy. PDG-induced trophoblast caspase-3 activity was inhibited by the presence of the TLR10-DN. The presence of the TLR10-DN had no effect on PDG reduction in trophoblast IL-6 secretion. Conclusion This study demonstrates that trophoblast TLR10 plays a role in promoting apoptosis triggered by gram-positive bacterial components and suggests that TLR10 may regulate the balance between trophoblast survival and cell death.

To assess the predictive value of C-reactive protein (CRP) level for postoperative infectious complications after colorectal surgery.

Atypical antipsychotics seem to be preferable than conventional agents in treating psychological symptoms of dementia (BPSD), because they have substantially lower risks of extrapyramidal neurological effects with lower reported rates of parkinsonism and tardive dyskinesia. However, in the course of time, with the increase in their use, more and more side effects have been reported. The benefits and risks of antipsychotic treatment should be carefully evaluated according to the co-morbidity and the severity of the psychological and behavioral symptoms and their impact on the individual elderly patient. It is recommended to keep those medications in the lower range of therapeutic doses. Due to the complexity of the individual patient, no guidelines have been yet established. Therefore, clinical judgment should be used in applying the dose and the type of those drugs.

Objective:To compare clinical outcomes after laparoscopic cholecystectomy (LC) for acute cholecystitis performed at various time-points after hospital admission.Background:Symptomatic gallstones represent an important public health problem with LC the treatment of choice. LC is increasingly offered

Aim: To find out which of the two predictors, Charlson co-morbidity index or vitamin B12, better estimates the risk of in-hospital mortality in seriously ill patients. Method: Electronic hospital records of 1509 elderly patients aged 65 and older were retrospectively surveyed. Results: Albumin, age and elevated vitamin B12 levels were significantly associated with increased in-hospital mortality. Charlson co-morbidity index was not significantly associated with death. The highest mortality (24.3%) was found in the group of patients who were concomitantly in the lowest albumin quartile and the highest vitamin B12 levels quartile. In this group, mortality increased significantly with age. By elasticity calculation, vitamin B12 capability to predict mortality was higher by ∼3 times than that of Charlson co-morbidity index. Conclusions: In view of the fact that vitamin B12 levels have been found to predict mortality, they should be measured in geriatric practice, in addition to albumin levels, as a practical and reliable tool for identifying high risk elderly hospitalized patients. Probably, a combination of two or more available and inexpensive routinely taken tests can give a better estimation of mortality than some complicated tools, like Charlson co-morbidity index.

Laparoscopic appendectomy for acute appendicitis has become increasingly used over the past decade. The objective of this trend analysis is to assess whether clinical outcomes after laparoscopic appendectomy have improved over the past 12 years.This analysis is based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery. All patients undergoing emergency laparoscopic appendectomy for acute appendicitis from 1995 to 2006 were included. The following outcomes were assessed for each of the 12 years: conversion rates, intraoperative complications, surgical postoperative complications, general postoperative complications, rate of reoperations, and length of hospital stay. Unadjusted and risk-adjusted multivariable analyses were performed. Statistical significance was set at a level of P0.05. All statistical tests were 2-sided.Data from 7446 patients undergoing laparoscopic appendectomy for acute appendicitis were prospectively collected. Over the period of observation, the conversion rate decreased significantly from 2.2% to 1.2% (P(trend)0.001), as did intraoperative complications (from 3.1% to 0.7%; P(trend)0.001), surgical postoperative complications (from 6.1% to 1.9%; P(trend)0.001), general postoperative complications (from 4.9% to 1.5%; P(trend)0.001), and rates of reoperations (from 3.4% to 0.7%; P(trend)0.001). Average postoperative length of hospital stay also significantly decreased from 4.9 to 3.5 days (P(trend)0.001).Our investigation provides compelling evidence that intraoperative complications, surgical and general postoperative complications, conversion rates, rates of reoperations, and average length of hospital stay have significantly decreased over the past decade in patients undergoing surgery for acute appendicitis. The present trend analysis is the first one in the literature encompassing more than a decade and reporting clinical outcomes after laparoscopic appendectomy for acute appendicitis, which represents an important quality control.

Problem Preeclampsia is associated with hyperuricemia, which correlates with the disease severity. Levels of circulating uric acid increase before the clinical manifestations, suggesting they may be causally related. Uric acid, or monosodium urate (MSU), activates the Nod-like receptor, Nalp3, leading to inflammasome activation and IL-1β processing. Since preeclampsia is associated with placental immune/inflammatory dysregulation, we sought to determine in the trophoblast, the presence of the Nalp3 inflammasome, and the effect of MSU on its activation.

Shedding of syncytiotrophoblast microparticles (MPs) from placenta to maternal blood occurs in normal pregnancy and is enhanced during preeclampsia (PE). The syncytiotrophoblast synthesizes plasminogen activator inhibitors (PAIs) which regulate fibrinolysis, as well as soluble forms of the fms-like tyrosine kinase (sFlt-1) and endoglin, which exert anti-angiogenic actions. An increase in the ratio of PAI-1/PAI-2 and elevated levels of sFlt-1 and sEng in maternal serum are linked to placental damage and maternal endothelial cell dysfunction in PE. The goal of the current study was to determine whether MPs released to maternal perfusate during dual perfusion contain these factors associated with placental pathophysiology in PE. Initially, high levels of alkaline phosphatase activity and Annexin V binding were found in MPs isolated by sequential centrifugation of maternal perfusates at 10,000 and 150,000×g(10 K and 150 K MPs), indicating their plasma membrane origin. ELISA revealed the presence of these factors at the following relative levels: Eng>PAI-2⋙PAI-1>sFlt-1. Based on comparisons of their concentration in perfusates, MPs, and MP-free 150 K supernatants, we determined that MPs constitute a significant portion of Eng released by placenta. Flow cytometric analysis of 10 K MPs supported the levels of expression found by ELISA and indicated that Eng and PAI-2 were almost exclusively localized to the surface of MPs, a site with biological potential. These results indicate that MPs shed from the syncytial surface express factors which may alter the fibrinolytic and angiogenic balance at the maternal–fetal interface and play a role in the pathophysiology of PE.

Deuterium-depleted water (DDW) is a new promising agent in cancer therapy. The efficiency of the method is based on the discovery, that cancer cells are extremely sensitive to depletion of deuterium (D) and might cause necrosis of the tumour. The purpose of this study was to show the efficacy of D-depletion in prostate cancer (PC) patients. In the double blind, four-month-long, randomized Phase II clinical trial the daily water intake was replaced with DDW in 22 PC patients. Other 22 PC patients took normal water while both groups received the same forms of conventional treatment. In the retrospective study, 91 DDW-treated PC patients were evaluated and median survival time (MST) in the subgroups was calculated. The time course of changes in DDW dose and PSA is presented in two cases. In the prospective trial seven patients in the treated group and one patient in the placebo group achieved partial response (p = 0.046). In the treated group, the net decrease in the prostate volume was three times higher (160.3 cm3 vs. 54.0 cm3; p = 0.0019), urination complaints ceased at a higher rate (8 vs. 0 patients, p = 0.0041), and the one-year survival rate was also higher (2 vs. 9 deaths; p = 0.034). The 91 retrospectively evaluated patients achieved an MST of 11.02 years, despite the fact that 46 of them suffered from distant metastasis. In the two monitored patients, drop of PSA level correlated with the DDW intake. In summary, D-depletion prolonged MST in patients with PC. The method proved to be safe thus its integration in the PC cure as an adjuvant or complementary therapy would be considered.

Maintaining skeletal muscle function throughout the lifespan is a prerequisite for good health and independent living. For skeletal muscle to consistently function at optimal levels, the efficient activation of processes that regulate muscle development, growth, regeneration and metabolism is required. Numerous conditions including neuromuscular disorders, physical inactivity, chronic disease and ageing are associated with perturbations in skeletal muscle function. A loss or reduction in skeletal muscle function often leads to increased morbidity and mortality either directly, or indirectly, via the development of secondary diseases such as diabetes, obesity, cardiovascular and respiratory disease. Identifying mechanisms which influence the processes regulating skeletal muscle function is a key priority. The discovery of microRNAs (miRNAs) provides a new avenue that will extend our knowledge of factors controlling skeletal muscle function. miRNAs may also improve our understanding and application of current therapeutic approaches as well as enable the identification of new therapeutic strategies and targets aimed at maintaining and/or improving skeletal muscle health. This review brings together the latest developments in skeletal muscle miRNA biology and focuses on their role and regulation under physiological and patho-physiological conditions with an emphasis on: myogenesis, hypertrophy, atrophy and regeneration; exercise and nutrition; muscle disease, ageing, diabetes and obesity.

BackgroundThe use of laparoscopic sigmoid resection for diverticular disease has become increasingly popular. The objective of this trend analysis was to assess whether clinical outcomes following laparoscopic sigmoid resection for diverticular disease have improved over the past 10 years.MethodsThe analysis was based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery. Some 2813 patients undergoing elective laparoscopic sigmoid resection for diverticular disease from 1995 to 2006 were included. Unadjusted and risk-adjusted analyses were performed.ResultsOver time, there was a significant reduction in the conversion rate (from 27·3 to 8·6 per cent; Ptrend < 0·001), local postoperative complication rate (23·6 to 6·2 per cent; Ptrend = 0·004), general postoperative complication rate (14·6 to 4·9 per cent; Ptrend = 0·024) and reoperation rate (5·5 to 0·6 per cent; Ptrend = 0·015). Postoperative median length of hospital stay significantly decreased from 11 to 7 days (Ptrend < 0·001).ConclusionThis first trend analysis in the literature of clinical outcomes after laparoscopic sigmoid resection, based on almost 3000 patients, has provided compelling evidence that rates of postoperative complications, conversion and reoperation, and length of hospital stay have decreased significantly over the past 10 years.

Problem: The cytoplasmic pattern recognition receptors, Nod1 and Nod2, are thought to be important for detecting intracellular bacteria. We have previously reported that first trimester trophoblast cells express Nod1 and Nod2, and that trophoblast Nod2 activation triggers an inflammatory response. The objectives of this study were to characterize the effects of Nod1 stimulation, and to determine the regulation of Nod1 and Nod2, in the trophoblast. Method of Study: The effect of Nod1 activation on trophoblast cells was determined by analyzing the cytokine response following treatment with γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP). The regulation of Nod1 and Nod2 expression by trophoblast cells was evaluated by RT-PCR. Results: Treatment of trophoblast cells with iE-DAP significantly increased their production of cytokines and chemokines. In addition, Nod1 and Nod2 mRNA expression was upregulated following treatment of trophoblast cells with lipopolysaccharide (LPS), and this was significantly reduced by the presence of a NFκB inhibitor and a TLR4-dominant negative (DN). Conclusion: This study demonstrates that LPS, through TLR4, increases trophoblast expression of Nod1 and Nod2 via the NFκB pathway; and that Nod1 is functional in the trophoblast. These findings suggest that extracellular recognition of bacterial LPS by TLR4 may prime the trophoblast in preparation for its cytoplasmic recognition of, and response to, bacterial peptides through the Nod proteins.