Middle meningeal artery embolization treatment of nonacute subdural hematomas in the elderly: a multiinstitutional experience of 151 cases.
The incidence of already common chronic subdural hematomas (CSDHs) and other nonacute subdural hematomas (NASHs) in the elderly is expected to rise as the population ages over the coming decades. Surgical management is associated with recurrence and exposes elderly patients to perioperative and operative risks. Middle meningeal artery (MMA) embolization offers the potential for a minimally invasive, less morbid treatment in this age group. The clinical and radiographic outcomes after MMA embolization treatment for NASHs have not been adequately described in elderly patients. In this paper, the authors describe the clinical and radiographic outcomes after 151 cases of MMA embolization for NASHs among 121 elderly patients. In a retrospective review of a prospectively maintained database across 15 US academic centers, the authors identified patients aged ≥ 65 years who underwent MMA embolization for the treatment of NASHs between November 2017 and February 2020. Patient demographics, comorbidities, clinical and radiographic factors, treatment factors, and clinical outcomes were abstracted. Subgroup analysis was performed comparing elderly (age 65-79 years) and advanced elderly (age > 80 years) patients. MMA embolization was successfully performed in 98% of NASHs (in 148 of 151 cases) in 121 patients. Seventy elderly patients underwent 87 embolization procedures, and 51 advanced elderly patients underwent 64 embolization procedures. Elderly and advanced elderly patients had similar rates of embolization for upfront (46% vs 61%), recurrent (39% vs 33%), and prophylactic (i.e., with concomitant surgical intervention; 15% vs 6%) NASH treatment. Transfemoral access was used in most patients, and the procedure time was approximately 1 hour in both groups. Particle embolization with supplemental coils was most common, used in 51% (44/87) and 44% (28/64) of attempts for the elderly and advanced elderly groups, respectively. NASH thickness decreased significantly from initial thickness to 6 weeks, with additional decrease in thickness observed in both groups at 90 days. At longest follow-up, the treated NASHs had stabilized or improved in 91% and 98% of the elderly and advanced elderly groups, respectively, with > 50% improvement seen in > 60% of patients for each group. Surgical rescue was necessary in 4.6% and 7.8% of cases, and the overall mortality was 8.6% and 3.9% for elderly and advanced elderly patients, respectively. MMA embolization can be used safely and effectively as an alternative or adjunctive minimally invasive treatment for NASHs in elderly and advanced elderly patients.


Quantification of Relaxin-2 Connecting Peptide (Pro-RLX2) in Human Blood Samples.
The peptide hormone relaxin-2 is implicated in diverse physiological and pathophysiological processes. Several assays are available for quantification of human relaxin-2, but because stability of the mature peptide in serum is limited, measurement of the more stable connecting peptide (pro-RLX2) might be beneficial. Pro-RLX2 was measured in a sandwich immunoluminometric assay using 2 monoclonal antibodies. The concentration of pro-RLX2 was detected in healthy pregnant (n = 100) and healthy male and nonpregnant female (n = 81) subjects and compared with the concentration of mature relaxin-2 in a subset of samples. The pro-RLX2 immunoassay has an analytical and functional assay sensitivity (FAS) of 1.59 pmol/L and 1.7 pmol/L, respectively. The analyte is stable in EDTA plasma samples for 8 days at room temperature, dilutes in a linear fashion, and recovery was 103%. The assay system is not biased by common interfering substances. Measurement of 80% of plasma samples from healthy males and females is below the FAS {median 1.49 pmol/L [interquartile range (IQR) of 0.925-2.14 pmol/L]}, and no concentration difference between male and nonpregnant female plasma samples was observed. The median plasma concentration in healthy pregnant women is increased up to 562 pmol/L (IQR 341-789 pmol/L). During pregnancy, pro-RLX2 concentrations decrease with increasing gestation. The correlation coefficient with the R&D assay for mature relaxin-2 was 0.96 (P < 0.0001). Pro-RLX2 is stable in plasma of healthy individuals. Although samples of pregnant women are reliably measurable, most samples from healthy nonpregnant women and men are below the detection limit. Determination of pro-RLX2 concentrations might indicate rate of synthesis of relaxin-2 during pregnancy and therapeutic application of recombinant relaxin (Serelaxin).


Non healing leg ulcer infected with Stenotrophomonas maltophilia: first reported case from India.
Stenotrophomonas maltophilia is a recently described organism which was mainly reported either in nosocomial setup, or in immunosuppresed individuals. This was rarely reported as cutaneous pathogenic organism causing cellulitis-like lesion, paronychia, mucocutaneous ulcers and ecthyma gangrenosum in immunocompromised individuals. Here we describe a case of leg ulcer caused by S. maltophilia in an immuno-competent patient. The infection was possibly community acquired as the patient had no exposure to hospital environment. The bacillus was sensitive to cotrimoxazole and levofloxacin, and the patient was successfully treated with cotrimoxazole. Our case is unique not only because it is probably the first ever case of leg ulcer caused by S. maltophilia, but also because of its unusual occurrence in immunocompetent patient.


A chemotactic inhibitory factor in the minimal change nephrotic syndrome.
This study attempts to investigate the role of neutrophil in the increased incidence of infection in nephrotic syndrome. We investigated the function of neutrophils in the various categories of nephritis and the relationship to the response of steroid therapy in the nephrotic syndrome. We used peripheral blood for the study of chemotaxis in 62 children suffering from nephritis in the acute phase and in remission. These patients included minimal change nephrotic syndrome (9 cases), focal segmental glomerular sclerosis (3 cases), mesangial cell proliferative nephropathy (23 cases), Hepatitis B antigenemia associated membranous glomerulonephropathy (4 cases), poststreptococcal glomerulonephritis (20 cases) and chronic glomerulonephritis (3 cases). The chemotactic index was significantly increased in normal range in the remission stage. The molecular weight of the chemotactic inhibitory factor was estimated to be about 89,000 using Sephacryl S-200 column. All cases of mesangial proliferative nephropathy had nephrotic syndrome with frequent relapses or steroid resistance. These results suggest that the chemotactic index may serve as an important parameter between steroid responsive and non-responsive nephrotic syndrome.


Endothelin in renal inflammation and hypertension.
Over the years, a very large amount of evidence has accumulated indicating that endothelin (ET)-1 is an important stimulus for inflammation. This is true for a wide range of organ system diseases, including chronic kidney disease. Nonetheless, our understanding of the role and mechanisms by which ET-1 promotes the activation of both the innate and adaptive immune systems is not understood. ET-1 can directly activate neutrophils as well as endothelial cells to stimulate production of chemoattractant factors, such as monocyte chemoattractant factor-1, and increase synthesis of cell adhesion molecules, such as soluble ICAM-1. The mechanisms that trigger these events, however, are less clear. Elevated blood pressure as well as hyperglycemia could be important factors that facilitate ET-1-dependent inflammation. While renal inflammation has not been used as an endpoint for drug development, the rationale for the use of ET antagonists as anti-inflammatory agents in chronic kidney disease is quite strong, based on animal studies and at least one study in humans with nondiabetic nephritis. While the preponderance of evidence suggests that ET(A) selective antagonists are advantageous over combined ET(A/B) receptor blockers, considerably more work needs to be done in order to understand the complex role of ET in renal inflammation.


Molecular and biochemical analysis of calmodulin interactions with the calmodulin-binding domain of plant glutamate decarboxylase.
We previously provided what to our knowledge is the first evidence that plant glutamate decarboxylase (GAD) is a calmodulin (CaM)-binding protein. Here, we studied the GAD CaM-binding domain in detail. A synthetic peptide of 26 amino acids corresponding to this domain forms a stable complex with Ca2+/CaM with a 1:1 stoichiometry, and amino acid substitutions suggest that tryptophan-485 has an indispensable role in CaM binding. Chemical cross-linking revealed specific CaM/GAD interactions even in the absence of Ca2+. However, increasing KCI concentrations or deletion of two carboxy-terminal lysines abolished these interactions but had a mild effect on CaM/GAD interactions in the presence of Ca2+. We conclude that in the presence of Ca(2+)-hydrophobic interactions involving tryptophan-485 and electrostatic interactions involving the carboxy-terminal lysines mediate CaM/GAD complex formation. By contrast, in the absence of Ca2+, CaM/GAD interactions are essentially electrostatic and involve the carboxy-terminal lysines. In addition, a tryptophan residue and carboxy-terminal lysines are present in the CaM-binding domain of an Arabidopsis GAD. Finally, we demonstrate that petunia GAD activity is stimulated in vitro by Ca2+/CaM. Our study provides a molecular basis for Ca(2+)-dependent CaM/GAD interactions and suggests the possible occurrence of Ca(2+)-independent CaM/GAD interactions.


Spatial Variation of Pressure in the Lyophilization Product Chamber Part 1: Computational Modeling.
The flow physics in the product chamber of a freeze dryer involves coupled heat and mass transfer at different length and time scales. The low-pressure environment and the relatively small flow velocities make it difficult to quantify the flow structure experimentally. The current work presents the three-dimensional computational fluid dynamics (CFD) modeling for vapor flow in a laboratory scale freeze dryer validated with experimental data and theory. The model accounts for the presence of a non-condensable gas such as nitrogen or air using a continuum multi-species model. The flow structure at different sublimation rates, chamber pressures, and shelf-gaps are systematically investigated. Emphasis has been placed on accurately predicting the pressure variation across the subliming front. At a chamber set pressure of 115 mtorr and a sublimation rate of 1.3 kg/h/m2, the pressure variation reaches about 9 mtorr. The pressure variation increased linearly with sublimation rate in the range of 0.5 to 1.3 kg/h/m2. The dependence of pressure variation on the shelf-gap was also studied both computationally and experimentally. The CFD modeling results are found to agree within 10% with the experimental measurements. The computational model was also compared to analytical solution valid for small shelf-gaps. Thus, the current work presents validation study motivating broader use of CFD in optimizing freeze-drying process and equipment design.


Self-rated health in the last 12 years of life compared to matched surviving controls: the Health and Retirement Study.
Self-rated health (SRH) is a valid measure of health status and associated with mortality. Based on individual-level biannual repeat data on SRH we sought to characterize the natural history of poor SRH during the 12 years prior to death in men and women in different age groups. We conducted a retrospective analysis of the Health and Retirement Study participants who died between 1998 and 2010 and had at least two SRH measurements in the 12 years prior to death. We used a nested case-control design to compare SRH trajectories of deceased men and women aged 30-64, 65-79 and 80 years versus surviving participants. The cases comprised 3,350 deceased participants who were matched to surviving controls (n = 8,127). SRH was dichotomized into good vs. poor health. Men and women dying at age 65-79 and ≥ 80 years had 1.5 to 3 times higher prevalence of poor SRH already 11-12 years prior to death compared to surviving controls. The risk estimates remained statistically significant even after adjusting for life-style related risk factors and diagnosed diseases. Prevalence of poor SRH before death was lowest among those aged ≥ 80 years and highest in 30-64 year-olds. In conclusion, men and women who subsequently die perceive their health worse already 11-12 years prior to death compared to their surviving controls.


Efficacy of Oral, Topical, or Combined Oral and Topical 5-Aminosalicylates, in Ulcerative Colitis: Systematic Review and Network Meta-analysis.
5-Aminosalicylates [5-ASAs] are the mainstay of treatment for ulcerative colitis [UC]. The optimum preparation, dose, and route of administration for UC remain unclear. We conducted a network meta-analysis to examine this issue. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to December 2020. We included randomised controlled trials [RCTs] comparing oral, topical, or combined oral and topical 5-ASAs, with each other or placebo for induction of remission or prevention of relapse of UC. Results were reported as pooled relative risks [RRs] with 95% confidence intervals [CIs] to summarise effect of each comparison tested, with treatments ranked according to P-score. We identified 40 RCTs for induction of remission and 23 for prevention of relapse. Topical mesalazine [P-score 0.99], or oral and topical mesalazine combined [P-score 0.87] ranked first and second for clinical and endoscopic remission combined. Combined therapy ranked first in trials where ≥50% of patients had left-sided/extensive disease, and topical mesalazine first in trials where ≥50% of patients had proctitis/proctosigmoiditis. High-dose [≥3.3 g/day] oral mesalazine ranked third in most analyses, with the most trials and most patients. For relapse of disease activity, combined therapy and high-dose oral mesalazine ranked first and second, with topical mesalazine third. 5-ASAs were safe and well tolerated, regardless of regimen. Our results support previous evidence; however, higher doses of oral mesalazine had more evidence for induction of remission than combined therapy and were significantly more efficacious than lower doses. Future RCTs should better establish the role of combined therapy for induction of remission, as well as optimal doses of oral 5-ASAs to prevent relapse.


PD-L1 expression in nonclear-cell renal cell carcinoma.
Programmed death ligand-1 (PD-L1) expression in nonclear-cell RCC (non-ccRCC) and its association with clinical outcomes are unknown. Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 101 patients with non-ccRCC. PD-L1 expression was evaluated by immunohistochemistry in both tumor cell membrane and tumor-infiltrating mononuclear cells (TIMC). PD-L1 tumor positivity was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrate and percentage of positive cells was used. Baseline clinico-pathological characteristics and outcome data [time to recurrence (TTR) and overall survival (OS)] were correlated with PD-L1 staining. Among 101 patients, 11 (10.9%) were considered PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC, 5/50 (10%) of papillary RCC, 3/10 (30%) of Xp11.2 translocation RCC and 1/5 (20%) of collecting duct carcinoma. PD-L1 positivity (PD-L1+) in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001). On the other hand, PD-L1 positivity by TIMC was observed in 57 (56.4%) patients: 13/36 (36.1%) of chromophobe RCC, 30/50 (60%) of papillary RCC, 9/10 (90%) of Xp11.2 translocation RCC and 5/5 (100%) of collecting duct carcinoma. A trend toward shorter OS was observed in patients with PD-L1+ in TIMC (P = 0.08). PD-L1+ in both tumor cell membrane and TIMC cells were associated with shorter TTR (P = 0.02 and P = 0.03, respectively). In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade.


Seroprevalence and risk factors associated with Escherichia coli O157 in a farming population.
Evidence suggests that frequent and direct exposure to domestic animals has made farmers less susceptible to symptomatic Escherichia coli O157 infection than other members of the community. We have quantified the seroprevalence of antibodies to E. coli O157 lipopolysaccharide (LPS) from a representative cohort of farm workers in three geographically distinct regions of the United Kingdom during two sampling rounds over a 2-year period. All participants completed a questionnaire to determine the range and extent of recent animal contact alongside other potential occupational and environmental exposure routes. A total of 31/946 (3.3%) serum samples contained antibodies to E. coli O157 LPS (from both rounds combined). On the second sampling round, a significant difference in seropositivity was apparent between the three regions, with enhanced seroprevalence linked to recent contact with beef cattle, having a private water supply and contact with a child under 5 years old. Only five seropositive people reported symptoms of a gastrointestinal tract infection, although these symptoms were mild. These results further support the premise of acquired immunity to E. coli O157 associated with prolonged antigenic exposures within the farming environment.


Progress in targeting RAS with small molecule drugs.
RAS proteins have traditionally been deemed undruggable, as they do not possess an active site to which small molecules could bind but small molecules that target one form of oncogenic RAS, KRAS G12C, are already in preclinical and clinical trials, and several other compounds that bind to different RAS proteins at distinct sites are in earlier stage evaluation. KRAS is the major clinical target, as it is by far the most significant form of RAS in terms of cancer incidence. Unfortunately, KRAS exists in two isoforms, each with unique biochemical properties. This complicates efforts to target KRAS specifically. KRAS is also a member of a family of closely related proteins, which share similar effector-binding regions and G-domains, further increasing the challenge of specificity. Nevertheless, progress is being made, driven by new drug discovery technologies and creative science.


Factors associated with recurrence of catheter-related bloodstream infections in home parenteral nutrition patients.
Blood cultures from outpatients receiving home parenteral nutrition (HPN) via long-term central venous access (CVA) were retrospectively analyzed from January 2003 to May 2009. When infection of the CVA was not due to Staphylococcus aureus, Pseudomonas aeruginosa, or Candida, catheter salvage was attempted for a maximum of three consecutive infections on the same CVA. Factors influencing the time-to-next-infection were studied, whether the catheter was changed after the last infection or not. Neither the McCabe score, age, history of cancer, diabetes mellitus nor immunosuppression, curative antibiotic lock, type of bacteria, type or duration of treatment had an influence on the time-to-next-infection. The time-to-next-infection was significantly associated with the status of CVA (saved or changed) and its type (tunneled catheter with or without a cuff, or implanted port catheter).


Hormonal control of postprandial thermogenesis in dogs.
The role of catecholamines, insulin, and thyroid hormones on postprandial thermogenesis was determined in dogs. O2 consumption (VO2) and respiratory quotient (RQ) were continuously monitored 1 h before and 2 h after a 1,016-kcal meal under the three following experimental conditions corresponding to 1) normal feeding, 2) sham feeding (with food deflected into an esophageal pouch), and 3) tube feeding intragastrically. A first phase (cephalic phase), lasting at least 45 min, was observed during both normal and sham feeding, whereas a second phase (digestive phase), occurred in both normal and tube feeding. Increases of 260% for norepinephrine (NE) were found during the cephalic phase in both normal and sham feeding. Epinephrine (E) increased by 425 and 600% during this early phase in normal and sham feeding, respectively. No change in plasma catecholamines was found in the tube-feeding experiment. Large increases of 75 and 39 microU/ml of insulin occurred early after the meal in both normal and sham feeding, whereas insulin increased only after 30 min in tube feeding. Thyroxine and triiodothyronine were not changed with any feeding experiment. Insulin change was positively correlated with NE and E changes rather than with glucose change during the cephalic phase after feeding. The results suggest an important role of catecholamines in the increased postprandial thermogenesis during the cephalic phase with a possible modulating effect of insulin.


Vital signs: sodium intake among U.S. school-aged children - 2009-2010.
A national health objective is to reduce average U.S. sodium intake to 2,300 mg daily to help prevent high blood pressure, a major cause of heart disease and stroke. Identifying common contributors to sodium intake among children can help reduction efforts. Average sodium intake, sodium consumed per calorie, and proportions of sodium from food categories, place obtained, and eating occasion were estimated among 2,266 school-aged (6–18 years) participants in What We Eat in America, the dietary intake component of the National Health and Nutrition Examination Survey, 2009–2010. U.S. school-aged children consumed an estimated 3,279 mg of sodium daily with the highest total intake (3,672 mg/d) and intake per 1,000 kcal (1,681 mg) among high school–aged children. Forty-three percent of sodium came from 10 food categories: pizza, bread and rolls, cold cuts/cured meats, savory snacks, sandwiches, cheese, chicken patties/nuggets/tenders, pasta mixed dishes, Mexican mixed dishes, and soups. Sixty-five percent of sodium intake came from store foods, 13% from fast food/pizza restaurants, 5% from other restaurants, and 9% from school cafeteria foods. Among children aged 14–18 years, 16% of total sodium intake came from fast food/pizza restaurants versus 11% among those aged 6–10 years or 11–13 years (p<0.05). Among children who consumed a school meal on the day assessed, 26% of sodium intake came from school cafeteria foods. Thirty-nine percent of sodium was consumed at dinner, followed by lunch (29%), snacks (16%), and breakfast (15%). Sodium intake among school-aged children is much higher than recommended. Multiple food categories, venues, meals, and snacks contribute to sodium intake among school-aged children supporting the importance of populationwide strategies to reduce sodium intake. New national nutrition standards are projected to reduce the sodium content of school meals by approximately 25%–50% by 2022. Based on this analysis, if there is no replacement from other sources, sodium intake among U.S. school-aged children will be reduced by an average of about 75–150 mg per day and about 220–440 mg on days children consume school meals.


An accelerated diagnostic approach to surgical jaundice.
A clear distinction between obstructive and hepatocellular jaundice is difficult in many patients. Biochemical and clinical findings may cause confusion and result in long delays in diagnosis and treatment. Ultrasonography is a major advance in the positive identification of patients with dilated intrahepatic ducts, whether or not the gall bladder is dilated. Isotopic imaging also may be useful in identifying obstructive jaundice. If percutaneous transhepatic cholangiography (PTC) is performed soon after, the site and nature of the obstruction will become evident. Another advance is the introduction of a sheathless narrow needle for PTC. This reduces the possibility of complications and has the advantage of being able to puncture a normal, undilated biliary tree in as many as 60% of cases, ruling out an obstructive cause. The use of these newer radiological investigations will appreciably shorten the period between the onset of jaundice and the ascertainment of its cause.


Links between PPCA and subspace methods for complete Gaussian density estimation.
High-dimensional density estimation is a fundamental problem in pattern recognition and machine learning areas. In this letter, we show that, for complete high-dimensional Gaussian density estimation, two widely used methods, probabilistic principal component analysis and a typical subspace method using eigenspace decomposition, actually give the same results. Additionally, we present a unified view from the aspect of robust estimation of the covariance matrix.


Alveolar Macrophages Treated With Bacillus subtilis Spore Protect Mice Infected With Respiratory Syncytial Virus A2.
Respiratory syncytial virus (RSV) is a major pathogen that infects lower respiratory tract and causes a common respiratory disease. Despite serious pathological consequences with this virus, effective treatments for controlling RSV infection remain unsolved, along with poor innate immune responses induced at the initial stage of RSV infection. Such a poor innate defense mechanism against RSV leads us to study the role of alveolar macrophage (AM) that is one of the primary innate immune cell types in the respiratory tract and may contribute to protective responses against RSV infection. As an effective strategy for enhancing anti-viral function of AM, this study suggests the intranasal administration of Bacillus subtilis spore which induces expansion of AM in the lung with activation and enhanced production of inflammatory cytokines along with several genes associated with M1 macrophage differentiation. Such effect by spore on AM was largely dependent on TLR-MyD88 signaling and, most importantly, resulted in a profound reduction of viral titers and pathological lung injury upon RSV infection. Taken together, our results suggest a protective role of AM in RSV infection and its functional modulation by B. subtilis spore, which may be a useful and potential therapeutic approach against RSV.


Reliable polarization switching of BiFeO3.
As a room temperature multi-ferroic with coexisting anti-ferromagnetic, ferroelectric and ferroelastic orders, BiFeO(3) has been extensively studied to realize magnetoelectric devices that enable manipulation of magnetic ordering by an electric field. Moreover, BiFeO(3) is a promising candidate for ferroelectric memory devices because it has the largest remanent polarization (P(r)>100 μC cm(-2)) of all ferroelectric materials. For these applications, controlling polarization switching by an electric field plays a crucial role. However, BiFeO(3) has a complex switching behaviour owing to the rhombohedral symmetry: ferroelastic (71°, 109°) and ferroelectric (180°) switching. Furthermore, the polarization is switched through a multi-step process: 180° switching occurs through three sequential 71° switching steps. By using monodomain BiFeO(3) thin-film heterostructures, we correlated such multi-step switching to the macroscopically observed reliability issues of potential devices such as retention and fatigue. We overcame the retention problem (i.e. elastic back-switching of the 71° switched area) using monodomain BiFeO(3) islands. Furthermore, we suppressed the fatigue problem of 180° switching, i.e. loss of switchable polarization with switching cycles, using a single 71° switching path. Our results provide a framework for exploring a route to reliably control multiple-order parameters coupled to ferroelastic order in other rhombohedral and lower-symmetry materials.


Endothelial-cell-specific regulation of von Willebrand factor gene expression.
In both tissue sections and cell culture, the endothelial nature of a cell is most commonly determined by demonstration of its expression of von Willebrand factor (vWf) protein and/or mRNA. Thus, the mechanism of cell-type-specific transcriptional regulation of the vWf gene is central to studying the basis of endothelial-cell-specific gene expression. In this study, deletion analyses were carried out to identify the region of the vWf gene which regulates its endothelial-cell-specific expression. A 734-bp fragment which spans the sequence from -487 to +247 relative to the transcription start site was identified as the cell-type-specific promoter. It consists of a minimal core promoter located between -90 and +22, a strong negative regulatory element located upstream of the core promoter (ca. -500 to -300), and a positive regulatory region located downstream of the core promoter in the first exon. The activity of the core promoter is not cell type specific, and the negative regulatory region is required to inhibit its activity in all cell types. The positive regulatory region relieves this inhibition only in endothelial cells and results in endothelial-cell-specific gene expression. The positive regulatory region contains sequences predicting possible SP1, GATA, and octamer binding sites. Mutations in either the SP1 or octamer sequence have no effect on transcriptional activity, while mutation in the GATA binding element totally abolishes the promoter activity. Evidence that a GATA factor is involved in this interaction is presented. Thus, the positive regulatory region with an intact GATA binding site is required to overcome the inhibitory effect of the negative regulatory element and activate vWf gene expression in an endothelial-cell-specific manner.


S-layer protein 2 of Lactobacillus crispatus 2029, its structural and immunomodulatory characteristics and roles in protective potential of the whole bacteria against foodborne pathogens.
We have previously demonstrated that human vaginal Lactobacillus crispatus 2029 (LC2029) strain is highly adhesive to cervicovaginal epithelial cells, exhibits antagonistic activity against genitourinary pathogens and expresses surface-layer protein (Slp). The aims of the present study were elucidation of Slp structural and immunomodulatory characteristics and its roles in protective properties of the whole vaginal LC2029 bacteria against foodborne pathogens. Enteric Caco-2 and colon HT-29 cell lines were used as the in vitro models of the human intestinal epithelial layer. LC2029 strain has two homologous surface-layer (S-layer) genes, slp1 and slp2. Whilst we found no evidence for the expression of slp1 under the growth conditions used, a very high level of expression of the slp2 gene was detected. C-terminal part of the amino sequence of Slp2 protein was found to be highly similar to that of the conserved C-terminal region of SlpA protein of L. crispatus Zj001 isolated from pig intestines and CbsA protein of L. crispatus JCM5810 isolated from chicken intestines, and was substantially variable at the N-terminal and middle regions. The amino acid sequence identity between SlpA and CbsA was as high as 84%, whilst the identity levels of these sequences with that of Slp2 were only 49% and 50% (respectively). LC2029 strain was found to be both acid and bile tolerant. Survival in simulated gastric and intestinal juices of LC2029 cells unable to produce Slp2 was reduced by 2-3 logs. Vaginal L. crispatus 1385 (LC1385) strain not expressing Slp was also very sensitive to gastric and intestinal stresses. Slp2 was found to be non-covalently bound to the surface of the bacterium, acting as an adhesin and facilitating interaction of LC2029 lactobacilli with the host immature or fully differentiated Caco-2 cells, as well as HT-29 cells. No toxicity to or damage of Caco-2 or HT-29 epithelial cells were detected after 24 h of colonization by LC2029 lactobacilli. Both Slp2 protein and LC2029 cells induced NF-kB activation in Caco-2 and HT-29 cells, but did not induce expression of innate immunity mediators Il-8, Il-1β, and TNF-α. Slp2 and LC2029 inhibited Il-8 production in Caco-2 and HT-29 cells induced by MALP-2 and increased production of anti-inflammatory cytokine Il-6. Slp2 inhibited production of CXCL1 and RANTES by Caco-2 cells during differentiation and maturation process within 15 days. Culturing Caco-2 and HT-29 cells in the presence of Slp2 increased adhesion of bifidobacteria BLI-2780 to these enterocytes. Upon binding to Caco-2 and HT-29 cells, Slp2 protein and LC2029 lactobacilli were recognized by toll-like receptors (TLR) 2/6. It was shown that LC2029 strain is a strong co-aggregator of foodborne pathogens Campylobacter jejuni, Salmonella enteritidis, and Escherichia coli O157:H used in this study. The Slp2 was responsible for the ability of LC2029 to co-aggregate these enteropathogens. Slp2 and intact LC2029 lactobacilli inhibited foodborne pathogen-induced activation of caspase-9 and caspase-3 as apoptotic biomarkers in Caco-2 and HT-29 cells. In addition, Slp2 and Slp2-positive LC2029 strain reduced adhesion of tested pathogenic bacteria to Caco-2 and HT-29 cells. Slp2-positive LC2029 strain but not Slp2 alone provided bactericidal effect on foodborne pathogens. These results suggest a range of mechanisms involved in inhibition of growth, viability, and cell-adhesion properties of pathogenic Proteobacteria by the Slp2 producing LC2029, which may be useful in treatment of necrotizing enterocolitis (NEC) in newborns and foodborne infectious diseases in children and adults, increasing the colonization resistance and maintaining the intestinal homeostasis.


Medicare risk contracting: identifying factors associated with market exit.
Over the past few years, a number of HMOs have chosen to discontinue their Medicare risk contracts. Using logistic regression, this study sought to identify factors associated with Medicare risk contract market exit in 1988. Low AAPCC rates were found to systematically affect the market exit of only Medicare risk contractors that were regional components of a central HMO organization. The Medicare risk market exit of other HMOs was found to be principally related to two attributes suggestive of possible unfavorable risk selection: the dropping of a previously offered prescription drug benefit and higher proportions of categorically disabled Medicare enrollees.


Balance and injury in elite Australian footballers.
This project measured pre-season balance ability and determined its relationship to knee and ankle ligament injuries during the season for professional Australian footballers. The balance test involved the players stepping onto a foam balance mat on top of a force plate and maintaining single limb balance. Throughout the playing season, injuries were monitored. The results from two hundred and ten players participating in this project were analysed. During the 2003 season, 8 % (17 out of 210) sustained a knee ligament injury and 10 % (21 out of 210) sustained an ankle ligament injury. Multivariate analysis revealed that pre-season balance ability was a significant independent predictor of ankle ligament injury. Players with low balance ability had at least twice as many ankle ligaments injuries as those with average or good balance ability. Balance ability was not a significant predictor of knee ligament injuries. The height of the players was the only significant independent predictor of knee ligament injuries. Low pre-season balance ability was associated with an increased risk of ankle ligament injury. A modifiable injury risk factor has been identified. Research is now required to determine the optimal training regime to enhance balance ability and whether this translates to a reduction in the incidence of ankle injuries.


Serum antibodies against the flavoprotein subunit of succinate dehydrogenase are sensitive markers of eye muscle autoimmunity in patients with Graves' hyperthyroidism.
Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.


Research trends in wireless visual sensor networks when exploiting prioritization.
The development of wireless sensor networks for control and monitoring functions has created a vibrant investigation scenario, where many critical topics, such as communication efficiency and energy consumption, have been investigated in the past few years. However, when sensors are endowed with low-power cameras for visual monitoring, a new scope of challenges is raised, demanding new research efforts. In this context, the resource-constrained nature of sensor nodes has demanded the use of prioritization approaches as a practical mechanism to lower the transmission burden of visual data over wireless sensor networks. Many works in recent years have considered local-level prioritization parameters to enhance the overall performance of those networks, but global-level policies can potentially achieve better results in terms of visual monitoring efficiency. In this paper, we make a broad review of some recent works on priority-based optimizations in wireless visual sensor networks. Moreover, we envisage some research trends when exploiting prioritization, potentially fostering the development of promising optimizations for wireless sensor networks composed of visual sensors.


Methyl carbamate. Species-dependent variations in metabolism and clearance in rats and mice.
Studies of the chronic toxicity and carcinogenicity of methyl carbamate (MC) in F344 rats and B6C3F1 mice indicate that this compound is more toxic to rats than mice. MC was also a carcinogen for rats but not a carcinogen for mice even when administered at a higher dose. The present study of the comparative metabolism and disposition of MC in these two species was conducted to determine possible sources of these varying responses. Results of this study indicate that, although the initial distribution of MC in the two species is similar, the mouse metabolizes and clears MC much more rapidly than does the rat. In the mouse, clearance was primarily by metabolism to CO2 and elimination in exhaled air, which accounted for approximately 70% of the dose in 48 hr. On the other hand, the rat eliminated approximately 18% of the dose as CO2 in 48 hr and a similar amount in urine. The parent compound accounted for approximately 90% of the material excreted in urine of both rats and mice. Only the parent compound was detected in tissues of either species. Less than 4% of the dose was excreted in feces of either species. The lesser ability of the rat to metabolize and eliminate MC as CO2 results in bioaccumulation of this compound on repeat exposure. Therefore, bioaccumulation of MC by the rat on chronic exposure probably results in both greater total exposure and higher peak exposure of most rat tissues vs. those of mice and may thus account for the greater toxicity and possibly carcinogenicity of MC to rats.


sAβPPα Improves Hippocampal NMDA-Dependent Functional Alterations Linked to Healthy Aging.
This study shows a decrease in soluble amyloid-β protein precursor-α (sAβPPα) levels, but no change in sAβPPβ, in the rat hippocampus during healthy aging, associated with the weaker expression of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in the CA1 area of hippocampal slices. Exogenous application of recombinant sAβPPα increases NMDAR activation in aged animals and could rescue the age-related LTP deficits described. In contrast, it does not affect basal synaptic transmission or glutamate release. These results indicate that improving synaptic sAβPPα availability at synapses helps in reducing the functional NMDAR-related deregulation of hippocampal networks linked to aging.


The role of family history in risk of childhood brain tumors.
Although brain tumors are the second most frequent malignancy in children, relatively little is known about the role of family history in risk of these tumors. Children under the age of 18 years (n = 361) in whom primary brain tumors were diagnosed were identified from eight United States population-based Surveillance, Epidemiology, and End Results registries and compared to matched controls (n = 1083) identified by random-digit dialing. Information regarding family history of birth defects or tumors was obtained, along with data on other potential risk factors, from interviews with the mothers and fathers of the index children. No significant differences were found in family history of epilepsy. However, moderate elevations in risk were observed for a history of birth defects in maternal relatives, particularly for female propositi. Significantly more mothers (odds ratio [OR] = 1.63, 95% confidence limits [CL] = 1.03, 2.57) and maternal female relatives (OR = 2.15, 95% CL = 1.14, 4.06) of cases than of controls were reported to have had birth defects. History of birth defects in maternal relatives was particularly associated with childhood brain tumors of "other" (not astrocytoma or medulloblastoma) histologic type (OR = 2.37, 95% CL = 1.25, 4.53) and infratentorial tumors (OR = 1.76, 95% CL = 1.06, 2.93). Slight excesses of tumors were observed in paternal relatives of children with astrocytomas (OR = 1.43, 95% CL 0.93, 2.20) or with infratentorial tumors (OR = 1.46, 95% CL 0.97, 2.20). Risk of childhood brain tumors did not increase with the number of relatives affected with brain tumors, breast cancer, leukemia or lymphoma, soft tissue sarcomas, or all of these tumor types combined (the Li-Fraumeni syndrome). These findings suggest a modest increase in risk of childhood brain tumors associated with maternal family history of birth defects. Family history of tumors does not appear to contribute appreciably to an increased risk of brain tumors in children.


LGBT testimony and the limits of trust.
In, 'Forever young: the ethics of ongoing puberty suppression (OPS) for non-binary adults,' Notini et al discuss the risks, harms and benefits of treating non-binary patients via identity-affirming OPS. Notini et al's article makes a strong case for OPS's permissibility, and their conclusion will not be disputed here. Instead, I directly focus on issues that their article addressed only indirectly. This article will use a hypothetical case study to show that while Notini et al's ethical conclusion might be spot on, that perhaps the method they took to get there was superfluous. If the medical community is to take LGBT testimony seriously (as they should) then it is no longer the job of physicians to do their own weighing of the costs and benefits of transition-related care. Assuming the patient is informed and competent, then only the patient can make this assessment, because only the patient has access to the true weight of transition-related benefits. Moreover, taking LGBT patient testimony seriously also means that parents should lose veto power over most transition-related paediatric care.


Pulse generation without gain-bandwidth limitation in a laser with self-similar evolution.
With existing techniques for mode-locking, the bandwidth of ultrashort pulses from a laser is determined primarily by the spectrum of the gain medium. Lasers with self-similar evolution of the pulse in the gain medium can tolerate strong spectral breathing, which is stabilized by nonlinear attraction to the parabolic self-similar pulse. Here we show that this property can be exploited in a fiber laser to eliminate the gain-bandwidth limitation to the pulse duration. Broad (∼200 nm) spectra are generated through passive nonlinear propagation in a normal-dispersion laser, and these can be dechirped to ∼20-fs duration.


Surviving childhood cancer: the impact on life.
With modern therapies, most children diagnosed with cancer are expected to reach adulthood. Therefore, there are large and ever-increasing numbers of children and young adults in our population who are survivors of childhood cancer. Many of the therapies responsible for improved cancer survival rates can also damage normal cells and tissues. As more children survive cancer, the physical and emotional costs of enduring cancer therapy become increasingly important. Although most childhood cancer survivors are now expected to survive, they remain at risk for relapse, second malignant neoplasms, organ dysfunction, and a negative psychologic impact. Individual risk is quite variable and is dependent on multiple factors including the type and site of cancer, the therapy utilized, and the individual's constitution. The risks are likely to change as we learn more about the specific long-term effects of cancer therapy, develop more refined and targeted therapies, and develop and apply more effective preventative strategies or therapeutic interventions. Guidelines for long-term follow-up have been established and are available to help facilitate appropriate monitoring of and care for potential late effects.


Demonstration of Eimeria tenella in bursa of Fabricius of chickens.
Coccidial life-cytle stages were detected in the bursa of Fabricius of broiler chickens inoculated with Eimeria tenella, whether or not the chickens had previously been infected with infectious bursal disease virus (IBDV). Chickens infected only with E. tenella had developing parasites in the lining epithelium, whereas chickens with both infections had gametocytes also in the epithelial cells surrounding numerous degenerating bursal cysts.


Association of Prescription With Body Composition and Patient Outcomes in Incident Peritoneal Dialysis Patients.
Objective: The nutritional status of patients on peritoneal dialysis (PD) is influenced by patient- and disease-related factors and lifestyle. This analysis evaluated the association of PD prescription with body composition and patient outcomes in the prospective incident Initiative for Patient Outcomes in Dialysis-Peritoneal Dialysis (IPOD-PD) patient cohort. Design and Methods: In this observational, international cohort study with longitudinal follow-up of 1,054 incident PD patients, the association of PD prescription with body composition was analyzed by using the linear mixed models, and the association of body composition with death and change to hemodialysis (HD) by means of a competing risk analysis combined with a spline analysis. Body composition was regularly assessed with the body composition monitor, a device applying bioimpedance spectroscopy. Results: Age, time on PD, and the use of hypertonic and polyglucose solutions were significantly associated with a decrease in lean tissue index (LTI) and an increase in fat tissue index (FTI) over time. Competing risk analysis revealed a U-shaped association of body mass index (BMI) with the subdistributional hazard ratio (HR) for risk of death. High LTI was associated with a lower subdistributional HR, whereas low LTI was associated with an increased subdistributional HR when compared with the median LTI as a reference. High FTI was associated with a higher subdistributional HR when compared with the median as a reference. Subdistributional HR for risk of change to HD was not associated with any of the body composition parameters. The use of polyglucose or hypertonic PD solutions was predictive of an increased probability of change to HD, and the use of biocompatible solutions was predictive of a decreased probability of change to HD. Conclusion: Body composition is associated with non-modifiable patient-specific and modifiable treatment-related factors. The association between lean tissue and fat tissue mass and death and change to HD in patients on PD suggests developing interventions and patient counseling to improve nutritional markers and, ultimately, patient outcomes. Study Registration: The study has been registered at Clinicaltrials.gov (NCT01285726).


The Double Burden of Malnutrition in Countries Passing through the Economic Transition.
Undernutrition in both its acute and chronic forms (wasting and stunting) is strongly inversely correlated with the wealth of nations. Consequently, as many low- and middle-income countries (LMICs) achieve economic advancement and pass through the so-called "nutrition transition," their rates of undernutrition decline. Many countries successfully achieved the Millennium Development Goal of halving undernutrition and whole continents have been transformed in recent decades. The exception is Africa where the slower rates of decline in the prevalence of undernutrition has been overtaken by population growth so that the absolute number of stunted children is rising. In many regions, economic transition is causing a rapid increase in the number of overweight and obese people. The rapidity of this rise is such that many nations bear the simultaneous burdens of under- and overnutrition; termed the "double burden" of malnutrition. This double burden, accompanied as it is by the unfinished agenda of high levels of infectious diseases, is crippling the health systems of many LMICs and thus requires urgent attention. Although the prognosis looks threatening for many poor countries, they have the advantage of being able to learn from the mistakes made by other nations that have passed through the transition before them. Concerted action across many arms of government would achieve huge future dividends in health and wealth for any nations that can grasp the challenge.


Preservation of reasoning in primary progressive aphasia: further differentiation from Alzheimer's disease and the behavioral presentation of frontotemporal dementia.
Primary Progressive Aphasia (PPA) is a clinical dementia syndrome characterized by the gradual dissolution of language without impairment of other cognitive domains for at least the first 2 years of illness (M.-M. Mesulam, 1982, 2001). It is difficult to demonstrate the integrity of nonlanguage domains in PPA because most neuropsychological tests of memory, reasoning, and attention require language competence for their performance. In the present study, reasoning and cognitive flexibility were tested nonverbally in patients with PPA using a modified ten-item version of the Visual Verbal Test (Feldman & Drasgow, 1959). This test measures the ability to detect similarities among objects and to sort a single set of objects according to two different principles. The performance of PPA patients (n = 20) was compared with that of patients with dementia of the Alzheimer type (AD) (n = 20), patients with the comportmental/executive dysfunction variant of frontotemporal dementia (FTD) (n = 16), and cognitively intact controls (n = 20). Patients with PPA and controls performed similarly, detecting commonalities among objects and shifting from one sorting principle to another. In contrast, both AD and FTD subjects were significantly impaired on both measures. These results provide evidence of preserved reasoning in PPA, further differentiating this syndrome from other behaviorally focal dementia syndromes.


Current and promising therapy for primary biliary cholangitis.
Primary biliary cholangitis is a chronic, cholestatic liver disease that may progress to cirrhosis with complications of end-stage liver disease. Approved treatment options include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) but novel therapies are being investigated. In this review, the authors describe the current pharmacotherapy for the treatment of primary biliary cholangitis (PBC) and for management of side effects such as pruritus and fatigue based on the currently available literature. Patients diagnosed with PBC should be offered treatment with UDCA at 13-15 mg/kg per day if liver enzymes are elevated. If they do not meet the defined criteria of response, adjunctive therapy should be considered. This may include OCA at 5 mg per day for patients without cirrhosis or investigational therapy. Management of the most common side effects, pruritus, and fatigue, is nuanced and includes lifestyle modifications as well as pharmacological approaches. Several tools such as the Mayo Risk Score and GLOBE are available for prognostic modeling. Ultimately, patients with PBC may end up requiring liver transplantation and referral to a transplant center may also be needed.


[The strategy for vaccinal prophylaxis and the elimination of measles in the developed countries].
The data on the instability of the epidemiological situation in measles in many European countries are presented, the causes of this instability and the development of major outbreaks of measles in some countries are explained. The data on the high epidemiological effectiveness of mass revaccination of high school and college students are given: this revaccination has made it possible to reduce the number of susceptible persons, formerly vaccinated with a single injection, 8-10 times. The author believes that the mass revaccination of high school and college students may be most effective if made not later than 15-20 years after vaccination with a single injection. The main principles of the strategy of vaccination and revaccination are formulated. The analysis of the strategy of vaccinal prophylaxis and the dynamics of morbidity shows the impossibility of decreasing the morbidity rate in most European countries below 1 per 100,000, as determined by the WHO Regional Committee. The simultaneous mass revaccination of high school and college students, formerly vaccinated with a single injection, may be the most effective measure for achieving this aim.


Tc2 response at the onset of COPD exacerbations.
T lymphocytes and especially the subpopulations of CD8+ cells are believed to have a key role in COPD pathophysiology, but there are only few data regarding the role of these cells in COPD exacerbation. We aimed to study prospectively changes of CD8+ T-lymphocyte subpopulations in the sputum of COPD patients at the onset of mild exacerbations and at a stable condition in order to provide further insight in the pathophysiology of the disease. Induced-sputum samples were collected from 24 COPD patients with median age of 52 years (interquartile range [IQR], 44 to 58 years) and FEV(1) percentage of predicted of 78.05% (IQR, 75.8 to 80.1%) at the onset of mild exacerbations not requiring hospitalization and when stable. Inflammatory cells and T-lymphocyte subpopulations (CD4+, CD8+, and cells producing interferon [IFN]-gamma or interleukin [IL]-4) were measured using flow cytometry and immunocytochemical methods. A significant increase in sputum CD8+ T lymphocytes (p < 0.0001) and significant decreases in CD4+ T lymphocytes as well as in CD4+/CD8+ (p = 0.0001) and CD8+IFN-gamma+/CD8+IL-4+ (p = 0.001), CD4+IFN-gamma+/CD4+IL-4+ (p = 0.0003) sputum cells ratios were found decreased at the onset of exacerbations compared to stable condition. The changes in T-lymphocyte subpopulations were not associated with smoking history, demographic characteristics, or disease severity. The findings of the present study suggest that CD8+ lymphocytes are increased and potentially polarized toward a Tc2 profile in the airways of COPD patients at the onset of COPD exacerbations with respect to stable condition. The clinical impact of the observed phenomenon requires further investigation.


Helping Families Cope with the Severe Stress of Dravet Syndrome.
A child with Dravet syndrome shakes family life to the core. Dravet syndrome usually has three phases: (1) up to 1-1½ years: with episodes of febrile status epilepticus but normal development; (2) age 1½ to ~6-10 years: with frequent seizures of varying types, developmental stagnation, behavioural and sleep problems; (3) after ~10 years: improvement in seizures, deteriorating gait, intellectual disability but some developmental gains. Complete seizure control is rare-simply prescribing medication is inadequate to help families. Based on structured interviews with 24 families and confirmed by more informal discussions with other families, we suggest strategies for coping with this catastrophe. A child with Dravet syndrome usually means that one parent cannot work-financial pressures should be anticipated. In Stage 1, the approach to status should include a written protocol. An indwelling catheter for rapid venous access may be helpful. In Stage 2, assistance finding qualified babysitters is required, and the extended family needs encouragement to help. Appropriate equipment, rescue medication and protocols should travel with the child. Siblings may benefit from a system of one parent "on call." An internet support group provides an invaluable lifeline. In Stage 3, family isolation may be extreme-respite care and personal time for parents are important. Death from status, accidents and SUDEP (sudden unexplained death in epilepsy) occurs in 15%. Fear of SUDEP needs to be addressed. Moving from paediatric to adult care is frightening; an epilepsy transition clinic is useful. Attention to these realities may improve the quality of life for both child and family.


Thioredoxin and its role in toxicology.
Thioredoxins (Trx) are members of an evolutionarily conserved family of redox-active proteins containing a conserved active site dithiol motif. Trx supports diverse reduction reactions, including several of direct toxicologic interest, but relatively little information is available concerning the roles of Trx under specific toxicologic conditions. Accumulating evidence suggests that Trx serves a partially overlapping and highly complementary role to the glutathione (GSH) system in protecting against toxicity. GSH and Trx both function in the reduction of peroxides through the action of multiple GSH peroxidases and Trx peroxidases (peroxiredoxins), respectively. However, GSH is a small molecule that is present at millimolar concentrations, thereby providing a potential mechanism for elimination of alkylating electrophiles. In contrast, even though Trx is only present at micromolar or submicromolar concentrations, its dithiol motif makes it suited to reverse oxidative changes to proteins, including reduction of protein disulfides, methioninyl sulfoxides, and cysteinyl sulfenic acids. Moreover, Trx functions in redox-sensitive signal transduction, transcriptional activation of stress response genes, ribonucleotide reduction in synthesis of deoxyribonucleotides for DNA repair, and post-injury cell proliferation. Molecular studies show that the predominant cytoplasmic/nuclear form, Trx-1, and the mitochondrial form, Trx-2, both protect against oxidative stress, that both are essential for embryonic development, and that Trx-1 is inducible in response to oxidative stress. Because of the differences between GSH and Trx in distribution, catalytic activities and reactivities with electrophiles, particularly with the important role to be played by glutathione S-transferases, considerable research is needed to clarify their respective roles in protection against specific toxicologic conditions.


Body mass index, exercise, and other lifestyle factors in relation to age at natural menopause: analyses from the breakthrough generations study.
The authors examined the effect of women's lifestyles on the timing of natural menopause using data from a cross-sectional questionnaire used in the United Kingdom-based Breakthrough Generations Study in 2003-2011. The analyses included 50,678 women (21,511 who had experienced a natural menopause) who were 40-98 years of age at study entry and did not have a history of breast cancer. Cox competing risks proportional hazards models were fitted to examine the relation of age at natural menopause to lifestyle and anthropometric factors. Results were adjusted for age at reporting, smoking status at menopause, parity, and body mass index at age 40 years, as appropriate. All P values were 2-sided. High adult weight (P(trend) < 0.001), high body mass index (P(trend) < 0.001), weight gain between the ages of 20 and 40 years (P(trend) = 0.01), not smoking (P < 0.001), increased alcohol consumption (P(trend) < 0.001), regular strenuous exercise (P < 0.01), and not being a vegetarian (P < 0.001) were associated with older age at menopause. Neither height nor history of an eating disorder was associated with menopausal age. These findings show the importance of lifestyle factors in determining menopausal age.


[The effect of cardiovascular rehabilitation on the variability of the RR cycle after a first uncomplicated acute myocardial infarct].
The aim of this study was to verify the changes in the autonomic balance by means of heart rate variability assessment in patients with myocardial infarction referred for cardiac rehabilitation. We studied 122 patients (79 males, 43 females, mean age 56 +/- 5 years), with a first uncomplicated myocardial infarction (anterior 48, thrombolysis 72), Killip class 1, preserved left ventricular function (ejection fraction 49 +/- 6%). All patients were free of inducible residual ischemia. Four weeks after myocardial infarction, patients were randomized into two groups; Group 1 (n = 58) referred for an 8 week cardiac rehabilitation program (scheduled: 24 sessions); Group 2 (n = 64): normal daily physical activity. During a 24-hour Holter ECG monitoring the following parameters were calculated in pharmacological wash-out at randomization (T0) and at the end of cardiac rehabilitation/control period (T1): mean value of RR intervals (RR), its standard deviation (SDNN), pNN50, rMSSD in the time domain; low frequency (LF) and high frequency (HF) value and the LF/HF ratio in the frequency domain. T1-T0 changes in percent values (delta %) were considered and compared between the two groups. Thirty-one patients were excluded from the study either for insufficient adhesion to the cardiac rehabilitation program (< 13 sessions, 22 patients) or recurrent ischemia (3 Group 1 patients and 3 Group 2 patients) and non-assessable 24-hour Holter ECG monitoring (3 patients). Thirty-one Group 1 patients and 60 Group 2 patients completed the study with a first and a second 24-hour Holter ECG monitoring performed at 30 +/- 3 days and 60 +/- 4 days respectively. At the same time an ergospirometric test was performed to evaluate cardiopulmonary function by means of exercise time, maximum oxygen consumption, anaerobic threshold, exercise time at the anaerobic threshold, and maximum oxygen consumption at the anaerobic threshold. Twenty-eight Group 1 patients and 44 Group 2 patients completed the study with a first and a second ergospirometric test. Baseline heart rate variability parameters were comparable in the two groups. During the observation period only in Group 1 patients heart rate variability parameters changed significantly: RR (Group 1 = +18.3 +/- 21.3; Group 2 = +4.2 +/- 5.2, p = 0.000), pNN50 (Group 1 = 45.0 +/- 38.9; Group 2 = +24.2 +/- 34.7, p = 0.011), HF (Group 1 = +81.6 +/- 124; Group 2 = -28.7 +/- 75.4, p = 0.014) and LF/HF ratio (Group 1 = -26.0 +/- 16.1; Group 2 = -4.9 +/- 6.1, p = 0.062). There were no significant differences in SDNN, rMSSD and LF. A linear correlation between delta LF/HF ratio and baseline LF/HF ratio values was found in Group 1 (r = 0.489, p = 0.006), whereas no correlation was found between this parameter and age, ejection fraction, creatine phosphokinase, and infarct localization. Group 1 patients had a significant improvement in exercise tolerance compared to Group 2 patients. A cardiac rehabilitation program positively modifies the sympatho-vagal balance in patients with uncomplicated myocardial infarction, increasing the parasympathetic tone and exercise tolerance.


Recognition and management of autonomic dysreflexia in pediatric spinal cord injury.
Autonomic dysreflexia (AD) is a well-documented complication of spinal cord injury (SCI) at or above the T6 level. However, research into AD has focused primarily on the adult. Because research that involves children with SCI is scarce, current guidelines may not be appropriate for children. Therefore, many episodes of AD may be unrecognized or inappropriately treated. To address this issue, Shriners Hospitals for Children undertook the development of a protocol specific to children and adolescents. A task force was developed to look at current literature on AD and blood pressure in children. Utilizing this literature and consensus among the task force members, the tools necessary to treat children with SCI at risk for AD were developed. The task force developed several products intended to assist in the recognition and management of AD. These include an event flow sheet for recording incidents of AD, a letter for the child's school or primary care physician that provides a brief summary of AD and the child's baseline blood pressure, and a policy/protocol with 2 age-specific algorithms to standardize interventions across the 3 Shriners Hospitals in the United States with SCI programs (California, Illinois, and Pennsylvania). The Shriners Hospitals for Children Task Force on Autonomic Dysreflexia in Children with Spinal Cord Injury has developed several tools specific to children. However, many questions remain to be answered concerning blood pressure norms and the clinical presentation of AD in children.


Consequences of restenosis after coronary angioplasty.
The consequences of restenosis after angioplasty were evaluated in 466 patients who had coronary angiography 3 to 12 months after successful coronary angioplasty and were followed long term. The 236 subjects with restenosis resembled the 230 without restenosis with respect to age, sex, presence of multivessel disease, mean ejection fraction, prior myocardial infarction, prior coronary artery bypass grafting, and completeness of revascularization. The 5-year relative risk of revascularization for patients with restenosis markedly exceeded that for patients without restenosis. The relative risk of repeat angioplasty in the former group was 4.26 times that in the latter group (95% confidence interval, 2.80 to 6.51), and the risk of coronary artery bypass grafting in patients with restenosis was 3.68 (95% confidence interval, 2.16 to 6.28). There was no difference between the 2 groups in the relative risk of myocardial infarction or death. When the completeness of revascularization was considered, patients with incomplete revascularization and restenosis had the worst outcomes, with 50% needing coronary artery bypass grafting within 5 years. Early restenosis markedly increases the probability of revascularization, but it has little effect on infarction or mortality. Even when early restenosis is absent, further revascularization procedures are still frequent. A solution to the problem of restenosis might reduce by half the need for revascularization during the subsequent 5 years.


Fermion-parity anomaly of the critical supercurrent in the quantum spin-Hall effect.
The helical edge state of a quantum spin-Hall insulator can carry a supercurrent in equilibrium between two superconducting electrodes (separation L, coherence length ξ). We calculate the maximum (critical) current I(c) that can flow without dissipation along a single edge, going beyond the short-junction restriction L << ξ of earlier work, and find a dependence on the fermion parity of the ground state when L becomes larger than ξ. Fermion-parity conservation doubles the critical current in the low-temperature, long-junction limit, while for a short junction I(c) is the same with or without parity constraints. This provides a phase-insensitive, dc signature of the 4 π-periodic Josephson effect.


OATP1B3 Expression in Hepatocellular Carcinoma Correlates with Intralesional Gd-EOB-DTPA Uptake and Signal Intensity on Gd-EOB-DTPA-Enhanced MRI.
To evaluate the predictive value of the OATP1B3 expression in hepatocellular carcinoma (HCC) for the gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) uptake and the signal intensity (SI) in the hepatobiliary (HB) phase. In this retrospective study, we analyzed 69 liver nodules of 64 patients who underwent Gd-EOB-DTPA enhancement magnetic resonance imaging (MRI) before operation. Based on the SI in the HB phase, the patients were categorized into the hypointense HCC and iso- or hyperintense HCC groups. The OATP1B3 expression was detected by polymerase chain reaction (PCR) and immunohistochemistry. The differences between the expression of OATP1B3 and Gd-EOB-DTPA enhanced magnetic resonance imaging between the two groups of hepatocellular carcinoma were compared. The relationship between the OATP1B3 expression and the SI and relative enhancement (RE) was analyzed. The examined HCC nodules were 59 hypointense HCC and 10 iso- or hyperintense. The relative expressions of OATP1B3, HB-phase signal, and the RE of the HB phase in iso- or hyperintense were significantly higher than those of the hypointense HCC, while the RE of the HB phase increased with an increase in the OATP1B3 expression (P < 0.05). The OATP1B3 expression in HCC can predict the uptake of Gd-EOB-DTPA and the SI of the HB phase. We believe that the evaluation of OATP1B3 expression will facilitate the comprehension of imaging performance of HCC in Gd-EOB-DTPA-enhanced MRI.


Stepped care for depression and anxiety: from primary care to specialized mental health care: a randomised controlled trial testing the effectiveness of a stepped care program among primary care patients with mood or anxiety disorders.
Mood and anxiety disorders are highly prevalent and have a large impact on the lives of the affected individuals. Therefore, optimal treatment of these disorders is highly important. In this study we will examine the effectiveness of a stepped care program for primary care patients with mood and anxiety disorders. A stepped care program is characterized by different treatment steps that are arranged in order of increasing intensity. This study is a randomised controlled trial with two conditions: stepped care and care as usual, whereby the latter forms the control group. The stepped care program consists of four evidence based interventions: (1) Watchful waiting, (2) Guided self-help, (3) Problem Solving Treatment and (4) Medication and/or specialized mental health care. The study population consists of primary care attendees aged 18-65 years. Screeners are sent to all patients of the participating general practitioners. Individuals with a Diagnostic and Statistical Manual of mental disorders (DSM) diagnosis of major depression, dysthymia, panic disorder (with or without agoraphobia), generalized anxiety disorder, or social phobia are included as well as individuals with minor depression and anxiety disorders. Primary focus is the reduction of depressive and anxiety symptoms. Both conditions are monitored at 8, 16 and 24 weeks. This study evaluates the effectiveness of a stepped care program for patients with depressive and anxiety disorder. If effective, a stepped care program can form a worthwhile alternative for care as usual. Strengths and limitations of this study are discussed. Current Controlled Trails: ISRCTN17831610.


Vitrectomy for epiretinal membranes: visual outcome and prognostic criteria.
The treatment of choice for epiretinal membranes (ERM) causing marked retinal distortion and substantial visual impairment remains vitreoretinal surgery. The purpose of this study was to evaluate the results of surgery performed in our department and to investigate the prognostic value of different factors such as preoperative best-corrected visual acuity (BCVA), pre-existing cystoid macular edema (CME), intra-operative peeling of the internal limiting membrane (ILM), age and duration of symptoms. Eighty-eight consecutive eyes of 88 patients were operated on for ERM from July 1998 to June 2000. Both idiopathic and secondary cases were included. In all cases the ERM was successfully removed from the fovea. Mean BCVA after surgery increased from Snellen 0.2 (hand motion (HM) - 0.6) to Snellen 0.5 (HM - 1.0) (p<0.0001). Our results confirm the efficacy of surgical removal of the ERM in improving the visual acuity. Although not statistically significant, mean postoperative BCVA was slightly better in the group without pre-existing CME (p>0.05) and in the group where peeling of the ILM was performed (p>0.05). The data suggest that early surgery is likely to decrease the risk of developing irreversible macular damage (p<0.05). Because accelerated nuclear sclerosis with visual impairment is a common phenomenon after vitrectomy, one might consider performing a phaco-emulsification at the same time, especially in the elderly.


Level of involvement of clinical nurses in the evaluation of competence of nursing students.
To determine the level of involvement of clinical nurses accredited by the Universitat Jaume I (Spain) as mentors of practice (Reference Nurses) in the evaluation of competence of nursing students. METHODOLGY: Cross-sectional study, in which the "Clinical Practice Assessment Manual'' (CPAM) reported by reference 41 nurses (n=55) were analyzed. Four quality criteria for completion were established: with information at least 80% of the required data, the presence of the signature and final grade in the right place. Verification of learning activities was also conducted. Data collection was performed concurrently reference for nurses and teachers of the subjects in the formative evaluations of clinical clerkship period in the matter "Nursing Care in Healthcare Processes ", from March to June 2013. 63% of CPAM were completed correctly, without reaching the quality threshold established (80%). The absence of the signature is the main criteria of incorrect completion (21%). Nine learning activities do not meet the quality threshold set (80%) (p < 0.05). There are significant differences according to clinical units p < 0.05. From the 30 learning activities evaluated in the CPAM, it can be stated that nine of them do not reach the verification threshold established (80%), therefore it cannot be assumed that these activities had been completed by students and evaluated by the RefN throughout the clinical clerkship period. The level of involvement of Reference Nurse cannot be considered adequate, although strategies to encourage involvement through collaboration and training must be developed.


Phenolic-containing organic extracts of mulberry (Morus alba L.) leaves inhibit HepG2 hepatoma cells through G2/M phase arrest, induction of apoptosis, and inhibition of topoisomerase IIα activity.
The entire plant of Morus alba L. (Family Moraceae), or mulberry, possesses medical benefits, including anticancer properties. In this study, we investigated the effect of mulberry leaf extracts on the human hepatoma HepG2 cell line, which is related to hepatocellular carcinoma. Mulberry leaf extracts were prepared using four solvents, each with different polarities: 100% methanol (MeOH), 50% aqueous MeOH, 1-butanol (BuOH), and hot water (W). The phenolic profile, total polyphenol content, antioxidant capacity, and effect on human hepatoma HepG2 cells of the leaf extracts were analyzed by examining cytotoxicity, cell cycle progression, apoptosis, expression of topoisomerase IIα, and proteins involved in cell cycle progression. High-performance liquid chromatography-mass spectrometry analysis revealed that 100% MeOH, 50% MeOH, and BuOH extracts contained rutin, isoquercetin, and various derivatives of kaempferol and quercetin glycosides as their major constituents; the W extract contained primarily chlorogenic acid and caffeoylquinic acid derivatives. Total phenolic content based on rutin equivalents was 17.1%, 9.6%, 8.3%, and 6.5% of dry 100% MeOH, 50% MeOH, BuOH, and W extracts, respectively. 2,2-Diphenyl-1-picrylhydrazyl radical scavenging activities were 70.0%, 45.8%, 41.0%, and 33.6%, and 50% inhibitory concentration values were 33.1, 79.4, 35.6, and 204.2 μg/mL for HepG2 cell proliferation inhibition for 100% MeOH, 50% MeOH, BuOH, and W extracts, respectively. MeOH extracts caused cell cycle G2/M arrest and induced the caspase cascade and apoptosis, but the W extract had very little effect on cell cycle progression. MeOH extracts reduced the level of topoisomerase IIα but increased the level of p27(Kip1), with no significant effect on p21(Cip1/waf1). Therefore, we concluded that phenolic-containing organic extracts of mulberry leaves inhibit the growth of HepG2 hepatoma cells through coordinated actions of inducing cell cycle arrest in the G2/M phase (with p27(Kip1) protein expression), inhibiting topoisomerase IIα activity, and inducing cell apoptosis by activation of caspases.


Unconscious physiological response of healthy volunteers to dynamic respiration-synchronized couch motion.
Intrafractional motion can be a substantial uncertainty in precision radiotherapy. Conventionally, the target volume is expanded to account for the motion. Couch-tracking is an alternative, where the patient is moved to compensate for the tumor motion. However, the couch motion may influence the patient's stress and respiration behavior decreasing the couch-tracking effectiveness. In total, 100 volunteers were positioned supine on a robotic couch, which moved dynamically and respiration synchronized. During the measurement, the skin conductivity, the heartrate, and the gaze location were measured indicating the volunteer's stress. Volunteers rated the subjective motion sickness using a questionnaire. The measurement alternated between static and tracking segments (three cycles), each 1 min long. The respiration amplitude showed no significant difference between tracking and static segments, but decreased significantly from the first to the last tracking segment (p < 0.0001). The respiration frequency differed significantly between tracking and static segments (p < 0.0001), but not between the first and the last tracking segment. The physiological parameters and the questionnaire showed mild signals of stress and motion sickness. Generally, people tolerated the couch motions. The interaction between couch motion and the patient's breathing pattern should be considered for a clinical implementation. The study was registered at ClinicalTrials.gov (NCT02820532) and the Swiss national clinical trials portal ( SNCTP000001878 ) on June 20, 2016.


Pathway Diversity in the Self-Assembly of DNA-Derived Bioconjugates.
The pathway diversity of the self-assembly of amphiphilic DNA-pyrene conjugates is described. The hydrophobic pyrene units drive the self-assembly of the anionic oligomers in an aqueous environment into ribbon-shaped, DNA-grafted supramolecular polymers. Isothermal mixing of two types of sorted ribbons, each of which contains only one of two kinds of complementary oligonucleotides, results in the formation of tight networks. Thermal disassembly of these kinetically trapped networks and subsequent reassembly of the liberated components leads to mixed supramolecular polymers, which now contain both types of oligonucleotides. The scrambling of the oligonucleotides prevents the interaction between ribbons and, thus, network formation. The results show that a high local density of DNA strands in linear arrays favors hybridization among sorted polymers, whereas hybridization among mixed arrays is prevented. The lack of DNA hybridization among mixed ribbons is ascribed to the electrostatic repulsion between identical, hence noncomplementary, oligonucleotides. The findings highlight the importance of kinetically trapped states on the structural and functional properties of supramolecular polymers containing orthogonal self-assembly motifs.


Stress, anxiety, and depression in hospital consultants, general practitioners, and senior health service managers.
To study stress, anxiety, and depression in a group of senior health service staff. Postal survey. 81 hospital consultants, 322 general practitioners, and 121 senior hospital managers (total 524). Scores on the general health questionnaire and the hospital anxiety and depression scale. Sixty five (80%) consultants, 257 (80%) general practitioners, and 67 (56%) managers replied. Of all 389 subjects, 183 (47%) scored positively on the general health questionnaire, indicating high levels of stress. From scores on the hospital anxiety and depression scale only 178 (46%) would be regarded as free from anxiety, with 100 (25%) scoring as borderline cases and 111 (29%) likely to be experiencing clinically measurable symptoms. The findings for depression were also of some concern, especially for general practitioners, with 69 (27%) scoring as borderline or likely to be depressed. General practitioners were more likely to be depressed than managers (69 (27%) v 4 (6%) scored > or = 8 on hospital anxiety and depression scale-D; P = 0.004) with no significant difference between general practitioners and consultants. General practitioners were significantly more likely to show suicidal thinking than were consultants (36 (14%) v 3 (5%); P = 0.04) but not managers (9 (13%)). No significant difference could be found between the three groups on any other measure. The levels of stress, anxiety, and depression in senior doctors and managers in the NHS seem to be high and perhaps higher than expected.


Implications for Geophysics of the Precise Measurement of the Earth's Rotation.
A radio interferometer could yield an error on the order of 10(-9) second at the semidiurnal frequency. With errors of this magnitude, yearly changes in the rate at which the earth's rotation is slowing down could be determined. The proposed interferometer could also yield significant improvements in the determination of the Love number k and its variation with frequency, and in the changes in angular momentum of the atmosphere for periods greater than 1 week.


Mechanism of alpha 2-adrenoceptor agonist-induced diuresis.
In vivo and in vitro studies were performed to assess the mechanism of the diuretic effect of B-HT 933, a selective alpha 2-adrenoceptor agonist. In conscious Sprague-Dawley rats whose plasma vasopressin (AVP) levels were increased by infusion of hypertonic NaCl, B-HT 933 had no effect on AVP secretion. In Brattleboro homozygous (DI) rats, the antidiuretic dose response to AVP was shifted to the right by B-HT 933. In addition, a sustained antidiuresis induced in rats by infusion of 10 pg/min AVP was attenuated by B-HT 933 in a concentration-dependent manner. Pretreatment of DI rats with pertussis toxin (2 micrograms/kg iv) 4-5 days before testing abolished the inhibitory effect of B-HT 933 on AVP-induced antidiuresis. In outer medullary collecting ducts of DI rats, norepinephrine and B-HT 933 produced significant inhibition of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. In contrast, the selective alpha 1-adrenoceptor agonist cirazoline had no effect on AVP-induced cAMP formation. The inhibitory effect of norepinephrine was antagonized by the selective alpha 2-adrenoceptor antagonist rauwolscine but not by prazosin, a selective alpha 1-antagonist. In outer medullary collecting ducts dissected from the pertussis toxin-treated DI rats used in the in vivo studies, the inhibitory effect of norepinephrine and B-HT 933 on AVP-stimulated cAMP accumulation was abolished. The results indicate that the hydrosmotic action of AVP is inhibited by alpha 2-agonists via a pertussis toxin-sensitive mechanism.


Empirical Bayes estimation of farm prevalence adjusting for multistage sampling and uncertainty in test performance: a Brucella cross-sectional serostudy in southern Kazakhstan.
Estimation of farm prevalence is common in veterinary research. Typically, not all animals within the farm are sampled, and imperfect tests are used. Often, assumptions about herd sizes and sampling proportions are made, which may be invalid in smallholder settings. We propose an alternative method for estimating farm prevalence in the context of Brucella seroprevalence estimation in an endemic region of Kazakhstan. We collected 210 milk samples from Otar district, with a population of about 1000 cattle and 16 000 small ruminants, and tested them using an indirect ELISA. Individual-level prevalence and 95% confidence intervals were estimated using Taylor series linearization. A model was developed to estimate the smallholding prevalence, taking into account variable sampling proportions and uncertainty in the test accuracy. We estimate that 73% of households that we sampled had at least one Brucella-seropositive animal (95% credible interval 68-82). We estimate that 58% (95% confidence interval 40-76) of lactating small ruminants and 14% (95% confidence interval 1-28) of lactating cows were seropositive. Our results suggest that brucellosis is highly endemic in the area and conflict with those of the official brucellosis-testing programme, which found that in 2013 0% of cows and 1·7% of small ruminants were seropositive.


Multiple relaxation modes in associative polymer networks with varying connectivity.
The dynamics and mechanics of networks depend sensitively on their spatial connectivity. To explore the effect of connectivity on local network dynamics, we prepare transient polymer networks in which we systematically cut connecting bonds. We do this by creating networks formed from hydrophobically modified difunctionalized polyethylene glycol chains. These form physical gels, consisting of flowerlike micelles that are transiently cross-linked by connecting bridges. By introducing monofunctionalized chains, we can systematically reduce the number of bonds between micelles and thus lower the network connectivity, which strongly reduces the network elasticity and relaxation time. Dynamic light scattering reveals a complex relaxation dynamics that are not apparent in bulk rheology. We observe three distinct relaxation modes. First we find a fast diffusive mode that does not depend on the number of bridges and is attributed to the diffusion of micelles within a cage formed by neighboring micelles. A second, intermediate mode depends strongly on network connectivity but surprisingly is independent of the scattering vector q. We attribute this viscoelastic mode to fluctuations in local connectivity of the network. The third, slowest mode is also diffusive and is attributed to the diffusion of micelle clusters through the viscoelastic matrix. These results shed light on the microscopic dynamics in weakly interconnected transient networks.


MRI of groove pancreatitis.
The purpose of this work is to describe the findings on MRI in patients with groove pancreatitis, a specific form of chronic pancreatitis affecting the groove between the pancreatic head, the duodenum, and the common bile duct. MR images, including MR cholangiopancreatography, of five patients with groove pancreatitis were reviewed. Three patients underwent pancreatoduodenectomy due to serve duodenal stenosis, and the MR findings were compared to the histologic findings. A sheet-like mass was demonstrated between the pancreatic head and the duodenum in all patients. The masses were hypointense relative to pancreatic parenchyma on T1-weighted images and iso- to slightly hyperintense on T2-weighted images. After administration of Gd-DTPA, the masses showed delayed enhancement. Histologically, fibrous scar tissue was detected in the groove. MR images can clearly demonstrate the fibrous tissue in the groove in groove pancreatitis, and MR cholangiopancreatography can also provide useful information.


Modular biosynthesis of plant hemicellulose and its impact on yeast cells.
The carbohydrate polymers that encapsulate plants cells have benefited humans for centuries and have valuable biotechnological uses. In the past 5 years, exciting possibilities have emerged in the engineering of polysaccharide-based biomaterials. Despite impressive advances on bacterial cellulose-based hydrogels, comparatively little is known about how plant hemicelluloses can be reconstituted and modulated in cells suitable for biotechnological purposes. Here, we assembled cellulose synthase-like A (CSLA) enzymes using an optimized Pichia pastoris platform to produce tunable heteromannan (HM) polysaccharides in yeast. By swapping the domains of plant mannan and glucomannan synthases, we engineered chimeric CSLA proteins that made β-1,4-linked mannan in quantities surpassing those of the native enzymes while minimizing the burden on yeast growth. Prolonged expression of a glucomannan synthase from Amorphophallus konjac was toxic to yeast cells: reducing biomass accumulation and ultimately leading to compromised cell viability. However, an engineered glucomannan synthase as well as CSLA pure mannan synthases and a CSLC glucan synthase did not inhibit growth. Interestingly, Pichia cell size could be increased or decreased depending on the composition of the CSLA protein sequence. HM yield and glucose incorporation could be further increased by co-expressing chimeric CSLA proteins with a MANNAN-SYNTHESIS-RELATED (MSR) co-factor from Arabidopsis thaliana. The results provide novel routes for the engineering of polysaccharide-based biomaterials that are needed for a sustainable bioeconomy. The characterization of chimeric cellulose synthase-like enzymes in yeast offers an exciting avenue to produce plant polysaccharides in a tunable manner. Furthermore, cells modified with non-toxic plant polysaccharides such as β-mannan offer a modular chassis to produce and encapsulate sensitive cargo such as therapeutic proteins.


Central and peripheral limitations to upright exercise in untrained cardiac transplant recipients.
Functional capacity and quality of life are subjectively improved after cardiac transplantation. However, the objective improvement in exercise tolerance after transplantation has been disappointing. The extent to which allograft diastolic dysfunction contributes to this exercise intolerance has not been defined. Thirty cardiac transplant recipients between 3 and 16 months after transplantation and 30 age-matched normal control subjects underwent maximal symptom-limited graded upright bicycle exercise testing with simultaneous radionuclide angiography, invasive hemodynamic monitoring, and breath-by-breath gas analysis. Mean blood pressure was higher in the transplant group at supine rest (112.1 versus 97.7 mm Hg), normalized with upright posture, and became lower than normal at peak exercise (121.1 versus 133.2 mm Hg). Systolic function as measured by ejection fraction was normal in both groups. However, the cardiac transplant recipients had significantly lower exercise tolerance, achieving a mean maximal work rate of 390 kilopond-meters per minute (kpm/min), compared with 825 kpm/min in the normal subjects. Peak oxygen consumption was 12.3 mL.min-1.kg-1 in the transplant group, 46% lower than the normal group's value of 22.9 mL.min-1.kg-1. The transplant patients had a resting tachycardia (94 beats per minute) and a 79% reduction in exercise heart rate reserve compared with normal. Despite this chronotropic incompetence, stroke index response to exercise was consistently lower after transplantation, accounting for a 41% reduction in cardiac index at maximal exercise. The lower stroke index was accompanied by a 32% lower end-diastolic volume index at rest and a 14% lower end-diastolic volume index at peak exercise. Despite the smaller ventricular volumes after transplantation, pulmonary capillary wedge pressure was 35% higher than normal at supine rest and 50% higher at maximal exercise. Right atrial and mean pulmonary arterial pressures were similarly elevated. The ratio of pulmonary capillary wedge pressure to end-diastolic volume index was significantly higher during the postural change and exercise, suggesting allograft diastolic dysfunction. Arteriovenous oxygen difference was similar between groups at rest and with submaximal exercise but was 24% lower at maximal exercise in the transplant group, suggesting an abnormality in peripheral oxygen uptake or utilization. Exercise tolerance is severely limited during the first 16 months after cardiac transplantation despite preservation of allograft left ventricular systolic function. This intolerance is due to an inadequate cardiac index response from a combination of chronotropic incompetence and diastolic dysfunction limiting the appropriate compensatory use of the Starling mechanism. In addition, there is a peripheral abnormality in oxygen transport or utilization that may partially reflect the effects of deconditioning.


Learner-Adaptive Educational Technology for Simulation in Healthcare: Foundations and Opportunities.
Despite evidence that learners vary greatly in their learning needs, practical constraints tend to favor ''one-size-fits-all'' educational approaches, in simulation-based education as elsewhere. Adaptive educational technologies - devices and/or software applications that capture and analyze relevant data about learners to select and present individually tailored learning stimuli - are a promising aid in learners' and educators' efforts to provide learning experiences that meet individual needs. In this article, we summarize and build upon the 2017 Society for Simulation in Healthcare Research Summit panel discussion on adaptive learning. First, we consider the role of adaptivity in learning broadly. We then outline the basic functions that adaptive learning technologies must implement and the unique affordances and challenges of technology-based approaches for those functions, sharing an illustrative example from healthcare simulation. Finally, we consider future directions for accelerating research, development, and deployment of effective adaptive educational technology and techniques in healthcare simulation.


Breast cancer aware.
I read with interest the article by carol Davis in the October issue (Nursing Older People.22,8,6). The article summarised the findings of a UK study on age discrimination in breast cancer treatment. I have alerted colleagues in cancer care to the article to raise their awareness of this work. I have suggested that they reflect on their own area of practice and their role in treatment discussions and decisions as part of multiprofessional team meetings.


Interfaces Between Alpha-helical Integral Membrane Proteins: Characterization, Prediction, and Docking.
Protein-protein interaction (PPI) is an essential mechanism by which proteins perform their biological functions. For globular proteins, the molecular characteristics of such interactions have been well analyzed, and many computational tools are available for predicting PPI sites and constructing structural models of the complex. In contrast, little is known about the molecular features of the interaction between integral membrane proteins (IMPs) and few methods exist for constructing structural models of their complexes. Here, we analyze the interfaces from a non-redundant set of complexes of α-helical IMPs whose structures have been determined to a high resolution. We find that the interface is not significantly different from the rest of the surface in terms of average hydrophobicity. However, the interface is significantly better conserved and, on average, inter-subunit contacting residue pairs correlate more strongly than non-contacting pairs, especially in obligate complexes. We also develop a neural network-based method, with an area under the receiver operating characteristic curve of 0.75 and a Pearson correlation coefficient of 0.70, for predicting interface residues and their weighted contact numbers (WCNs). We further show that predicted interface residues and their WCNs can be used as restraints to reconstruct the structure α-helical IMP dimers through docking for fourteen out of a benchmark set of sixteen complexes. The RMSD100 values of the best-docked ligand subunit to its native structure are <2.5 Å for these fourteen cases. The structural analysis conducted in this work provides molecular details about the interface between α-helical IMPs and the WCN restraints represent an efficient means to score α-helical IMP docking candidates.


Core-shell microcapsules: biofabrication and potential applications in tissue engineering and regenerative medicine.
The fabrication of scaffolds that accurately recreate the architecture of living tissues is a major challenge in the field of tissue engineering and regenerative medicine. Core-shell microcapsules hold great potential in this regard, as they can recreate the hierarchical structure of biological systems. The independent modulation of the composition of both core and shell layers allows the design of compartmentalized platforms tailored to the recreation of specific cell niches. Emergent technologies such as superhydrophobic surfaces, microfluidics, electrospray, and layer-by-layer assembly have been successful in producing core-shell microcapsules for the encapsulation of cells and bioactive factors. This review provides an overview of available materials and techniques used in the generation of core-shell microcapsules, while also highlighting some of their potential applications in the design of innovative and effective tissue engineering and regenerative medicine strategies.