Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial.
Autologous grafting, despite some disadvantages, is still considered the gold standard for reconstruction of maxillofacial bone defects. The aim of this study was to evaluate bone regeneration using bone marrow-derived mesenchymal stromal cells (MSCs) in a clinical trial, a less invasive approach than autologous bone grafting. This comprehensive clinical trial included subjects with severe mandibular ridge resorption. The study included 11 subjects aged 52-79 years with severe mandibular ridge resorption. Bone marrow cells were aspirated from the posterior iliac crest and plastic adherent cells were expanded in culture medium containing human platelet lysate. The MSCs and biphasic calcium phosphate granules as scaffolds were inserted subperiosteally onto the resorbed alveolar ridge. After 4-6 months of healing, new bone formation was assessed clinically and radiographically, as were safety and feasibility. Bone at the implant site was biopsied for micro-computed topography and histological analyses and dental implants were placed in the newly regenerated bone. Functional outcomes and patient satisfaction were assessed after 12 months. The bone marrow cells, expanded in vitro and inserted into the defect together with biphasic calcium phosphate granules, induced significant new bone formation. The regenerated bone volume was adequate for dental implant installation. Healing was uneventful, without adverse events. The patients were satisfied with the esthetic and functional outcomes. No side effects were observed. The results of this comprehensive clinical trial in human subjects confirm that MSCs can successfully induce significant formation of new bone, with no untoward sequelae. Hence, this novel augmentation procedure warrants further investigation and may form the basis of a valid treatment protocol, challenging the current gold standard. EudraCT, 2012-003139-50. Registered on 21 August 2013. ClinicalTrials.gov, NCT 02751125 . Registered on 26 April 2016.


Patterns of glomerulonephritis with crescents: Experience at a tertiary medical center in Saudi Arabia.
A series of 78 cases of glomerulonephritis (GN), in which renal biopsy revealed changes of GN associated with crescent formation, were reviewed. Renal pathology findings were correlated with clinical features including patient's age, renal function, and serologic findings. In most of the cases (71.8%), the crescents were due to immune complex-mediated GN. This was followed by pauci-immune GN (20.5%) and anti-glomerular basement membrane antibody (GBM) GN (7.7%). The percentage of glomeruli with crescents was the highest in cases of anti-GBM disease (mean of 93.3%), followed by pauci-immune GBM (mean of 48.2%) and immune complex GN (30.9%). In cases with the pauci- immune GN, there were additional features of glomerular injury including fibrinoid necrosis, disruption of the GBM, and rupture of Bowman's capsule. These changes were generally more pronounced in a subset of pauci-immune GN associated with serum elevation of antineutrophil cytoplasmic antibody (c-ANCA). In biopsies from patient with immune complex disease, systemic lupus erythematosus was the most common cause of crescentic GN.


Bilateral costotransverse and local continuous chemotherapy approach for debridement, fixation, and fusion of contiguous multisegmental thoracic spinal tuberculosis: A retrospective study.
The study aims to evaluate the clinical efficacy of bilateral costotransverse debridement, transpedicular fixation, fusion, and local continuous chemotherapy in 20 patients of contiguous multisegmental thoracic spinal tuberculosis (CMTSTB). We analyzed 20 patients with contiguous thoracic spinal tuberculosis (TB) who underwent surgery via bilateral costotransverse debridement, fusion, posterior instrumentation, and postural drainage with local continuous chemotherapy. The clinical outcomes were evaluated in terms of kyphotic angle, bone fusion, neurologic status, erythrocyte sedimentation rate (ESR), and intraoperative and postoperative complications. All of the patients (8M/12F), averaged 45.8 ± 15.6 years old. The mean duration of postoperative follow-up was 30.7 ± 4.0 months. There was no recurrent TB infection. The values of ESR returned to normal levels at final follow-up. All patients got bony fusion within 8.1 ± 2.3 months after surgery. The average preoperative Cobb angle was 39.9° ± 8.6°, correcting to 9.8° ± 2.3° postoperatively and 10.8° ± 2.3° at the last follow-up. All patients with neurological deficit had dramatic improvement at the final follow-up. Our results showed that bilateral costotransverse surgery and local continuous chemotherapy are feasible and effective procedures in the treatment of CMTSTB. The approach can provide radical debridement, rebuild spinal stability, and cure TB.


Analysis of Risk Alleles and Complement Activation Levels in Familial and Non-Familial Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is a multifactorial disease, in which complement-mediated inflammation plays a pivotal role. A positive family history is an important risk factor for developing AMD. Certain lifestyle factors are shown to be significantly associated with AMD in non-familial cases, but not in familial cases. This study aimed to investigate whether the contribution of common genetic variants and complement activation levels differs between familial and sporadic cases with AMD. 1216 AMD patients (281 familial and 935 sporadic) and 1043 controls (143 unaffected members with a family history of AMD and 900 unrelated controls without a family history of AMD) were included in this study. Ophthalmic examinations were performed, and lifestyle and family history were documented with a questionnaire. Nine single nucleotide polymorphisms (SNPs) known to be associated with AMD were genotyped, and serum concentrations of complement components C3 and C3d were measured. Associations were assessed in familial and sporadic individuals. The association with risk alleles of the age-related maculopathy susceptibility 2 (ARMS2) gene was significantly stronger in sporadic AMD patients compared to familial cases (p = 0.017 for all AMD stages and p = 0.003 for advanced AMD, respectively). ARMS2 risk alleles had the largest effect in sporadic cases but were not significantly associated with AMD in densely affected families. The C3d/C3 ratio was a significant risk factor for AMD in sporadic cases and may also be associated with familial cases. In patients with a densely affected family this effect was particularly strong with ORs of 5.37 and 4.99 for all AMD and advanced AMD respectively. This study suggests that in familial AMD patients, the common genetic risk variant in ARMS2 is less important compared to sporadic AMD. In contrast, factors leading to increased complement activation appear to play a larger role in patients with a positive family history compared to sporadic patients. A better understanding of the different contributions of risk factors in familial compared to non-familial AMD will aid the development of reliable prediction models for AMD, and may provide individuals with more accurate information regarding their individual risk for AMD. This information is especially important for individuals who have a positive family history for AMD.


Both maternally and paternally imprinted genes regulate seed development in rice.
Genetic imprinting refers to the unequal expression of paternal and maternal alleles of a gene in sexually reproducing organisms, including mammals and flowering plants. Although many imprinted genes have been identified in plants, the functions of these imprinted genes have remained largely uninvestigated. We report genome-wide analysis of gene expression, DNA methylation and small RNAs in the rice endosperm and functional tests of five imprinted genes during seed development using Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated gene9 (CRISPR/Cas9) gene editing technology. In the rice endosperm, we identified 162 maternally expressed genes (MEGs) and 95 paternally expressed genes (PEGs), which were associated with miniature inverted-repeat transposable elements, imprinted differentially methylated loci and some 21-22 small interfering RNAs (siRNAs) and long noncoding RNAs (lncRNAs). Remarkably, one-third of MEGs and nearly one-half of PEGs were associated with grain yield quantitative trait loci. Most MEGs and some PEGs were expressed specifically in the endosperm. Disruption of two MEGs increased the amount of small starch granules and reduced grain and embryo size, whereas mutation of three PEGs reduced starch content and seed fertility. Our data indicate that both MEGs and PEGs in rice regulate nutrient metabolism and endosperm development, which optimize seed development and offspring fitness to facilitate parental-offspring coadaptation. These imprinted genes and mechanisms could be used to improve the grain yield of rice and other cereal crops.


Anti-glomerular basement membrane antibody-mediated nephritis complicating transplantation in a patient with Alport's syndrome.
Loss of an allograft caused by anti-GBM antibody-mediated nephritis is a rare complication of renal transplantation in Alport's syndrome. We describe a patient in whom this occurred. He belongs to the subgroup of patients with hereditary nephritis and deafness with an abnormal Goodpasture antigen, and he developed a high level of circulating anti-GBM antibodies within 20 days of transplantation of a kidney with a presumably normal Goodpasture antigen. The antibody titer fell, only to rise again when he developed evidence of acute infection with CMV. Coincident with this second rise in antibody titer he developed an anti-GBM antibody-mediated crescentic nephritis with resultant loss of graft function and transplant nephrectomy. This case provides support for the hypothesis that the abnormality in the basement membrane in some patients with Alport's syndrome involves the Goodpasture antigen, and raises the possibility that viral infection may have triggered autoantibody production.


Symptoms and diagnostic criteria of acquired Megacolon - a systematic literature review.
Acquired Megacolon (AMC) is a condition involving persistent dilatation and lengthening of the colon in the absence of organic disease. Diagnosis depends on subjective radiological, endoscopic or surgical findings in the context of a suggestive clinical presentation. This review sets out to investigate diagnostic criteria of AMC. The literature was searched using the databases - PubMed, Medline via OvidSP, ClinicalKey, Informit and the Cochrane Library. Primary studies, published in English, with more than three patients were critically appraised based on study design, methodology and sample size. Exclusion criteria were studies with the following features: post-operative; megarectum-predominant; paediatric; organic megacolon; non-human; and failure to exclude organic causes. A review of 23 articles found constipation, abdominal pain, distension and gas distress were predominant symptoms. All ages and both sexes were affected, however, symptoms varied with age. Changes in anorectal manometry, histology and colonic transit are consistently reported. Studies involved varying patient numbers, demographics and data acquisition methods. Outcome data investigating the diagnosis of AMC must be interpreted in light of the limitations of the low-level evidence studies published to date. Proposed diagnostic criteria include: (1) the exclusion of organic disease; (2) a radiological sigmoid diameter of ~ 10 cm; (3) and constipation, distension, abdominal pain and/or gas distress. A proportion of patients with AMC may be currently misdiagnosed as having functional gastrointestinal disorders. Our conclusions are inevitably tentative, but will hopefully stimulate further research on this enigmatic condition.


Making Thymus Visible: Understanding T-Cell Development from a New Perspective.
T-cell development is coupled with a highly ordered migratory pattern. Lymphoid progenitors must follow a precise journey; starting from the hematopoietic tissue, they move toward the thymus and then migrate into and out of distinct thymic microenvironments, where they receive signals and cues required for their differentiation into naïve T-cells. Knowing where, when, and how these cells make directional "decisions" is key to understanding T-cell development. Such insights can be gained by directly observing developing T-cells within their environment under various conditions and following specific experimental manipulations. In the last decade, several model systems have been developed to address temporal and spatial aspects of T-cell development using imaging approaches. In this perspective article, we discuss the advantages and limitations of these systems and highlight a particularly powerful in vivo model that has been recently established. This model system enables the migratory behavior of all thymocytes to be studied simultaneously in a noninvasive and quantitative manner, making it possible to perform systems-level studies that reveal fundamental principles governing T-cell dynamics during development and in disease.


Mouse Embryonic Fibroblast Cell Culture and Stimulation.
Culture of mouse embryonic fibroblast (MEF) cells represents a powerful system to test gene function due to their easy accessibility, rapid growth rates, and the possibility of a large number of experiments. Fibroblasts are a group of heterogeneous resident cells of mesenchymal origin that have various locations, diverse appearances and distinctive activities. Because of their ubiquitous distribution as tissue cells, these cells are poised to respond to factors released by newly activated innate immune cells, thus becoming a useful tool to study inflammation and immunity. Here, we describe procedures for mouse embryonic fibroblast cell isolation, primary culture, and stimulation. Specifically, we have optimized a step of serum starvation prior to stimulation. This step is necessary to maintain the quiescent status of these cells before they are exposed to pro-inflammatory stimuli for optimal responses. As shown in our previous studies, these mouse fibroblasts do not express Tnf, Csf2, or Il2 mRNAs at levels readily detectable by routine northern blotting techniques (Lai WS et al., 2006).


Differential effects of atrial natriuretic peptide on the brain water and sodium after experimental cortical contusion in the rat.
Atrial natriuretic peptide (ANP) plays an important role in the regulation of water and sodium in the body via cyclic GMP (cGMP) pathway. Although ANP has been shown to be protective in cerebral ischemia or intracerebral hemorrhage, its role in traumatic brain injury (TBI) has yet to be elucidated. We herein assessed ANP effects on brain water and sodium in TBI. Controlled cortical impact (3 mm depth, 6 m/sec) was used to induce an experimental cortical contusion in rats. Continuous administration of ANP 0.2 (n = 6) or 0.7 microg/kg/24 h (n = 6), cGMP analogue (8-Bromo-cGMP) 0.1 (n = 5) or 0.3 mg/kg/24 h (n = 5), or vehicle (n = 6) was begun 15 minutes after injury, using a mini-osmotic pump implanted into the peritoneal cavity. At 24 hours after injury, ANP significantly exacerbated brain edema in the injured hemisphere in a dose-dependent manner while it reduced brain sodium concentrations in both hemispheres. These ANP effects could be mimicked by a cGMP analogue. In the second series (n = 20), BBB integrity was assessed by evaluating the extravasation of Evans blue dye. ANP or cGMP analogue significantly worsened BBB disruption in the injured hemisphere at 24 hours after injury. These findings suggest that ANP administration exacerbates brain edema after the experimental cortical contusion in rats, possibly because of an increase in the BBB permeability via cGMP pathway, whereas it reduces brain sodium levels.


Seroprevalence Rates of Tick-Borne Pathogens in Cats from Southern Bulgaria.
The aim of the present study was to investigate the prevalence rates of the feline tick-borne pathogens (FTBPs)-Borrelia burgdorferi, Ehrlichia canis, and Anaplasma phagocytophilum in stray cats from Southern Bulgaria. Serum antibodies were used to estimate the prevalence of exposure to FTBPs from blood swabs. Of the 100 cat samples tested with in-clinic assay SNAP 4Dx Plus, the overall FTBP seroprevalence was 3% (3/100); with B. burgdorferi-1% (1/100) and E. canis-2% (2/100). This study provides the first evidence of exposure to B. burgdorferi and E. canis in cats from Bulgaria.


Heparin/heparan sulphate interactions with complement--a possible target for reduction of renal function loss?
Current management of end-stage renal failure is based on renal replacement therapy by dialysis or transplantation. Increased occurrence of renal failure in both native and transplanted kidneys indicates a need for novel therapies to stop or limit the progression of the disease. Acute kidney injury and proteinuria are major risk factors in the development of renal failure. In this regard, innate immunity plays an important role in the pathogenesis of renal diseases in both native and transplanted kidneys. The complement system is a major humoral part of innate defense. Next to the well-known complement activators, quite a number of the complement factors react with proteoglycans (PGs) both on cellular membranes and in the extracellular compartment. Therefore, these interactions might serve as targets for intervention. In this review, the current knowledge of interactions between PGs and complement is reviewed, and additionally the options for interference in the progression of renal disease are discussed.


Nickel(0)-catalyzed asymmetric hydrocyanation of 1,3-dienes.
1,2-Bis-diarylphosphinites are excellent ligands for the Ni(0)-catalyzed hydrocyanation of certain types of 1,3-dienes. 1-Phenyl-1,3-butadiene, 1-vinyl-3,4-dihydronaphthalene, and 1-vinylindene undergo highly regioselective hydrocyanation under ambient conditions to give exclusively the 1,2-adducts in good to excellent yields. Using bis-1,2-diarylphosphinites derived from d-glucose, the highest enantioselectivities to-date for asymmetric hydrocyanation of 1,3-dienes (70-83% ee's) have been obtained.


Mixed ovarian germ cell tumor composed of immature teratoma, yolk sac tumor and embryonal carcinoma.
We report the case of a 19-year-old woman experiencing lower abdominal distension and pain. Laboratory tests indicated elevated serum levels of Alpha-Fetoprotein (AFP) and human Chorionic Gonadotropin (hCG). A large mass was detected in the abdomen by physical examination and by transvaginal ultrasonography. Exploratory laparotomy was performed, and a smooth-surfaced, spherical, solid tumor was found on the left ovary, measuring 11.5 x 9.9 x 6.9 cm. Histological evaluation revealed that the tumor consisted of a combination of immature teratoma, Yolk Sac Tumor, and embryonal carcinoma; this is a very rare combination in mixed germ cell tumors.


Updated Minimally Invasive Surgery for Sleep-Related Breathing Disorders.
Sleep-related breathing disorders (SRBD) consist of a variety of clinical entities, ranging from primary snoring to severe obstructive sleep apnoea at the opposite extreme. Although it has no official definition, minimally invasive surgery infers surgery where the procedure is clinically less aggressive and may involve a much smaller incision or none at all. It also implies that such procedures may result in a quicker recovery and reduced morbidity, and that they are often conducted under local anaesthesia as day cases. Minimally invasive surgery in SRBD may be performed on its own or may be conducted in conjunction with other surgical procedures or in association with non-surgical treatment modalities such as oral appliances. Indeed, it may be considered in patients experiencing difficulty tolerating treatment with continuous positive airway pressure. This is with a view to improving the upper airway dimensions and thus reducing the pressure requirement with this type of treatment modality, hence improving its compliance and efficacy. Here we address the role of minimally invasive surgery in SRBD within various anatomical regions of the upper airway, namely the nose, soft palate, and the tongue.


Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism.
The alkylating anticancer agent cyclophosphamide (CP) is a prodrug that undergoes a complex metabolism in humans producing both active and inactive metabolites. In parallel, unchanged CP is excreted via the kidneys. The aim of this study was to investigate the influence of dose escalation on CP pharmacokinetics and relative contribution of activating and inactivating elimination pathways. Pharmacokinetics of CP were assessed in 12 patients with high-risk primary breast cancer who received an adjuvant chemotherapy regimen that included four courses of conventional-dose CP (500 mg/m2 over 1 hour every 3 weeks) followed by one final course of high-dose CP (100 mg/kg over 1 hour). Plasma concentrations of CP were analyzed by high-performance liquid chromatography (HPLC), 24-hour urinary concentrations of CP, and its inactive metabolites (carboxyphosphamide, dechloroethylcyclophosphamide [dechlorethylCP], ketocyclophosphamide [ketoCP]) were determined by 31-phosphorus-nuclear magnetic resonance (31P-NMR)-spectroscopy. There was no difference in dose-corrected area under the concentration-time curve (AUC) (216 v 223 [mumol.h/[mL.g]), elimination half-life (4.8 v 4.8 hours), systemic clearance (79 v 77 mL/min) and volume of distribution (0.49 v 0.45 L/kg) of CP between conventional- and high-dose therapy, respectively. However, during high-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P < .01) and in the formation clearance of carboxyphosphamide (7 v 12 mL/min; P < .05) and dechloroethylCP (3.2 v 4.2 mL/min; P < .05), whereas metabolic clearance to ketoCP remained unchanged (1.3 v 1.2 mL/min). Consequently, metabolic clearance to the remaining (reactive) metabolites decreased from 52 to 38 mL/min (P < .001). The relative contribution of the different elimination pathways to overall clearance of CP demonstrated wide interindividual variability. Overall pharmacokinetics of CP are apparently not affected during eightfold dose escalation. However, there is a shift in the relative contribution of different clearances to systemic CP clearance in favor of inactivating elimination pathways, thereby indicating saturation of bioactivating enzymes during dose escalation. Besides individual enzyme capacity, hydration and concomitant medication with dexamethasone modulated CP disposition.


Teacher Characteristics, Knowledge and Use of Evidence-Based Practices in Autism Education in Ireland.
Autism evidence-based practices (EBPs) are those with demonstrated improved outcomes for students with autism across a range of skill areas, yet issues persist in adopting these in classroom settings- particularly in general education (GE) settings. This research aimed to identify teacher training, years of experience, access to allied professionals and knowledge and use of autism EBPs in GE settings in Ireland. 369 mainstream primary school teachers reported their characteristics and their knowledge and use of EBPs. Results indicated that the majority of teachers received little initial teacher education training in autism, almost no continuous professional development (CPD) before educating a child with autism, and received little support from allied professionals. Knowledge and use of EBPs differed significantly across teacher characteristics, with findings discussed in relation to teacher training.


Structure and Biosynthesis of Hectoramide B, a Linear Depsipeptide from the Marine Cyanobacterium Moorena producens JHB Discovered via Co-culture with Candida albicans.
The tropical marine cyanobacterium Moorena producens JHB is a prolific source of secondary metabolites with potential biomedical utility. Previous studies of this strain led to the discovery of several novel compounds such as the hectochlorins and jamaicamides; however, bioinformatic analyses of its genome suggested that there were many more cryptic biosynthetic gene clusters yet to be characterized. To potentially stimulate the production of novel compounds from this strain, it was co-cultured with Candida albicans. From this experiment, we observed the increased production of a new compound that we characterize here as hectoramide B. Bioinformatic analysis of the M. producens JHB genome enabled the identification of a putative biosynthetic gene cluster responsible for hectoramide B biosynthesis. This work demonstrates that co-culture competition experiments can be a valuable method to facilitate the discovery of novel natural products from cyanobacteria.


Antioxidant activity and phenolic content of Oregon caneberries.
Five types of caneberries [evergreen blackberries (Rubus laciniatus), marionberries (Rubus ursinus), boysenberries (Rubus ursinus x idaeus), red raspberries (Rubus idaeus), and black raspberries (Rubus occidentalis)] were analyzed for antioxidant activity by measuring their oxygen radical absorbance capacity (ORAC). In addition, the berries were analyzed for total phenolics, anthocyanins, procyanidins, and ellagic acid content. All of the berries had high ORAC activity ranging from 24 to 77.2 micromol of Trolox equiv/g of fresh berries. Anthocyanin content ranged from 0.65 to 5.89 mg/g, and phenolics ranged from 4.95 to 9.8 mg/g. Black raspberries had the highest ORAC and anthocyanin and phenolic contents. Only red raspberries had detectable amounts of procyanidin oligomers (monomer, dimers, and trimers). All berries had high levels of ellagic acid (47-90 mg/g), but boysenberries had the highest level prior to hydrolysis. The results from this study indicate that these caneberries were high in antioxidant activity and were rich sources of anthocyanins and phenolics.


Boater preferences for beach characteristics downstream from Glen Canyon Dam, Arizona.
Release flow decisions are increasingly being influenced by an array of social values, including those related to river-based recreation. A substantial portion of past recreation research on downstream impacts of dams has focused on variability of instream flows. This study complements past research by assessing user preferences for beach characteristics affected by long-term impacts of flow regimes. Based upon a study of three recreational user groups (private trip leaders, commercial passengers, and river guides) of the Colorado River in Grand Canyon, preferences for beach size, presence of shade on beach, and presence of vegetation on beach are examined. Results indicate that large size beaches with shade from trees are setting characteristics with highly reliable and strong user preferences. The multinomial regression models developed for each user group indicate that 80% of all respondents would choose beach campsites 800 m(2); results were the same regardless of respondents' past boating experience, boat type (i.e. oar or motorized), or group size. In addition, size of beach was consistently reported to be a trip feature of moderate importance to respondents' river trip. Implications of this research are related to future prospects for controlled floods (i.e. spike flows) released from Glen Canyon Dam.


Patients' Perceptions of Atrial Fibrillation, Stroke Risk, and Oral Anticoagulation Treatment: An International Survey.
Background Global differences exist in the management of atrial fibrillation (AF), and cultural differences may influence patients' expectations and perceptions of healthcare. This survey investigated whether country-specific differences in patients' perceptions of AF and oral anticoagulation (OAC) exist and if recent stroke influences these perceptions. Methods Cross-sectional survey of 937 adults with nonvalvular AF receiving OAC for stroke prevention was conducted across United States, Canada, Germany, France, and Japan. Thirty-minute online interviews conducted between April and November 2015 included AF patients with recent stroke, and newly diagnosed AF and established AF, both without recent stroke. Results U.S. patients and those with recent stroke perceived AF as more serious (54.0 and 55.2%, respectively) and were more concerned about stroke (50.0 and 68.0%, respectively). Japanese patients were more likely to perceive AF as not serious (41.0%), but 50.4% were frequently concerned about stroke. Patients in the United States, Canada, and Germany and those without recent stroke preferred to be involved in OAC treatment decisions (either shared decision making or patient's choice), while French and Japanese patients and those with recent stroke preferred their doctor to choose. For all country groups, stroke prevention was the most important factor when choosing OAC. Conclusion In this international cohort of AF patients, country-specific differences exist in patients' perceptions of AF, concerns about stroke, and preference for involvement in OAC treatment decisions; recent experience of stroke significantly influenced patients' values and preferences regarding AF and treatment. Stroke prevention was rated as the most important factor when choosing OAC treatment.


Functional, morphological, and phenotypical differences between rat alveolar and interstitial macrophages.
Alveolar macrophages (AM) and interstitial macrophages (IM) from rat lungs were characterized with respect to morphology, phagocytosis, adhesion properties, and phenotype. AM were recovered by lung lavage and IM by treatment of the lung tissue with DNAse and collagenase. The AM were enzyme treated in the same way as the IM. The IM were smaller than AM and had a higher nuclear to cytoplasm ratio. They had markedly lower phagocytic capacity. The attachment of particles to the cell surface was significantly lower in IM than in AM, but the capacity to ingest the particles was the same. Adherence to vitronectin- as well as fibronectin-coated surfaces was significantly higher in AM. The phagolysosomal pH was similar in IM and AM, around pH 5, indicating that dissolution of inorganic particles can take place effectively also in IM. Five surface receptors were studied, and the expression differed significantly in all five between AM and IM. The expression of OX-1 (CD 45), a common leukocyte antigen, was significantly higher on AM as was the expression of CD 71 (transferrin receptor). The receptor density for OX-42 was higher on a fraction of IM. This might be compatible with a stronger interaction between these cells and, for example, matrix components. IM had more surface antigen expressing MHC class Ia (OX-6) and CD 54. Both receptors are important for the antigen presentation capacity of macrophages. These findings show profound differences in phenotype between AM and IM and indicate that IM is a highly immunocompetent cell and should not be regarded only as a precursor to AM.


Noise, physiology, and human performance: the potential role of effort.
Thirty-three male college students ages 18-31 were assigned to 2 levels of noise exposure and worked at 2 levels of effort while calculating the Norinder arithmetic task (M. Frankenhaeuser & U. Lundberg, 1977). As hypothesized, noise increased heart rate, norepinephrine, and cortisol only under high effort. Blood pressure did not change significantly. Reaction time slowed significantly under noise only when effort was low. Both self-report and epinephrine level confirmed the effort manipulation and showed that it was orthogonal to noise levels. These data support the adaptive costs hypothesis and have practical implications for industry. These implications include trade-offs of productivity and worker health, which may be dependent on management style.


Dietary cholesterol stimulates hepatic biosynthesis of triglyceride and reduces oxidation of fatty acids in the rat.
Experiments were conducted in the intact rat and in the isolated, perfused rat liver to investigate the possibility that the increase in the concentration of hepatic triglyceride and increase in the secretion of the very low density lipoprotein (VLDL)-triglyceride (TG) resulting from addition of cholesterol to the diet are due to stimulation of synthesis of triglyceride, reduced fatty acid oxidation, or both. Male rats were fed for 7 days with either a cholesterol-free diet to which 5% (w/w) corn oil was added, or with the same diet supplemented with 0.5% cholesterol. Fed animals received [1-14C]oleic acid via the tail vein, as a complex with rat serum, and were killed 2 h later. Feeding cholesterol for 7 days increased hepatic triglyceride and cholesteryl ester (CE) concentrations, moderately elevated free cholesterol, but did not affect phospholipid (PL) levels, as we had previously observed after a feeding period of 3 weeks. Incorporation of [1-14C]oleic acid into hepatic and plasma triglyceride increased significantly (60 and 48%, respectively) with cholesterol feeding. Incorporation of [1-14C]oleic acid into hepatic and plasma cholesteryl esters increased by 63 and 79%, respectively, while incorporation into phospholipid was unaffected. Increasing the fat (corn oil) content of the diet to 20% (w/w) did not change these effects of dietary cholesterol. Studies using isolated, perfused rat livers were carried out in vitro after rats were fed the 5% corn oil diet for 3 weeks. [Perfusions lasted 4 h. The perfusion medium contained 3% bovine serum albumin and 30% washed bovine erythrocytes in Krebs-Henseleit-HCO3 buffer.(ABSTRACT TRUNCATED AT 250 WORDS)


Tobacco use: ending the epidemic.
Nurses should encourage leaders in their health care systems to provide effective tobacco-use treatment and follow up. Nurses also need to support the policy and community interventions that motivate tobacco users to try to quit, create a supportive environment, and provide more intensive interventions for those needing them.


Rapid maturation of gastric relaxation in newborn infants.
We studied gastric volume, wall compliance, sensory perception, and receptive relaxation during the first postnatal 80 h in 17 healthy term infants, using a computer-driven air pump and simultaneously measuring pressure and volume within a latex balloon placed through the oropharynx into the stomach. To evaluate gastric compliance, we measured pressures while we infused air into the intragastric balloon at different rates (10, 20, and 60 mL/min) in random sequence. In all infants, there was a linear relationship between intragastric pressure and volume to the maximum pressure tested, 30 mm Hg. Gastric compliance ranged from 0.2 mL/mm Hg to 3.8 mL/mm Hg. Different infusion rates had no effect on compliance. We calculated gastric receptive relaxation by measuring the volume needed to maintain a constant pressure of 10 mm Hg within the balloon for 5 min. Gastric receptive relaxation ranged from 0.5 mL/min to 54 mL/min. Gastric compliance and receptive relaxation increased with postnatal age (r = 0.70, p < 0.005; r = 0.79, p < 0.001, respectively) and with number of feedings (r = 0.80, r = 0.88, respectively, both p < 0.001). There was no correlation between weight or type of feeding (breast versus formula) and either gastric compliance or relaxation. In conclusion, these results may explain the small feedings that neonates ingest in the first days of life. During the first 3 postnatal d, the newborn stomach becomes more compliant and develops more receptive relaxation, associated with a larger volume capacity.


Natural history of optic pathway gliomas in a cohort of unselected patients affected by Neurofibromatosis 1.
Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.


Prognostic value of the fluctuation in the neutrophil-lymphocyte ratio at 6 weeks of pembrolizumab treatment is specific to the clinical response in metastatic urothelial carcinoma.
Most patients with metastatic urothelial carcinoma experience no objective response to pembrolizumab and have poor overall survival (OS). Here, we investigated the prognostic value of fluctuation in the neutrophil-lymphocyte ratio (NLR) at 6 weeks of pembrolizumab treatment, focusing on its association with the achievement of objective response. The clinical records of 177 metastatic urothelial carcinoma patients treated with pembrolizumab were retrospectively analyzed. The median age was 72 years, and the median OS was 14 months. The objective response rate in the total cohort was 26.5% (47 of 177 patients). Multivariable analysis showed that objective response achievement (hazard ratio 0.3 [95% confidence interval 0.15-0.59], P < 0.001) and decline in NLR from that at baseline at 6 weeks of treatment (0.54 [0.34-0.88], P = 0.013) were independent prognostic factors for improved OS. For 47 (26.5%) patients who achieved an objective response, OS was similar regardless of NLR fluctuation at 6 weeks of treatment (P = 0.723). Intriguingly, of the 130 (73.5%) patients with no objective response, those who showed a decreased NLR at 6 weeks of pembrolizumab treatment (57 patients) from that at baseline had significantly longer OS than those with elevated NLR (73 patients) (14 vs. 6 months, P = 0.007). The fluctuation in NLR from that at baseline at 6 weeks of pembrolizumab treatment may be useful for patients without an objective response. This could potentially aid decision-making for post pembrolizumab therapies.


Topography of the lumbar sympathetic trunk in normal lumbar spines and spines with spondylophytes.
Degenerative processes of the lumbar spine may change the position of the sympathetic trunk which might cause failure of sympathetic blocks owing to inadequate distribution of local anaesthetic. The retroperitoneal spaces of 56 cadavers [24 males and 32 females; 79 (10) yr] embalmed with Thiel's method were investigated by dissection. The course of the lumbar sympathetic trunk (LST) was documented from the diaphragmatic level to the linea terminalis. Topography of the large vessels and the psoas muscle was documented. In the case of spondylophytes, the location or direction of displacement of the trunk was regarded with special interest. The LST entered the retroperitoneal space at the level of the vertebral body of L2 in 70 of the 112 sides and showed the most consistent relationship with the medial margin of the psoas muscle at intervertebral disc level L2/3. On 11 spines with spondylophytes, the sympathetic trunk was dislocated to the most ventrolateral point of the spondylophyte in 12 cases, in six cases dorsolaterally, and in one case ventromedially. The more the sympathetic chain departed at the vertebral body level, the more the body developed a concavity by loss of height. Spondylophytes influenced the location of the LST and the distribution of the local anaesthetic. The local anaesthetic should wash around the spondylophyte to reach all possible locations of the chain. The medial margin of the psoas muscle was confirmed to be a consistent reference point at intervertebral disc level L2/3.


Lead Foot Progression Angle in Baseball Pitchers: Implications to Ball Velocity and Upper-Extremity Joint Moments.
The instant of foot contact is an important transition point during the pitch cycle between the linear portion of the pitch, as a pitcher strides down the mound and the rotational portion of the pitch. Understanding the implications of lead foot angle at foot contact is an essential information needed to assist pitching coaches in their work with individual pitchers. Therefore, the purpose of this study was to determine the association between lead foot progression angle at foot contact and ball velocity, elbow varus moment, and pelvic rotation. Kinematic and kinetic data were collected from 99 collegiate pitchers and analyzed using a random intercept, mixed-effects regression model. Significant associations were found between lead foot progression angle at foot contact and elbow varus moment (P = .004), as well as pelvic rotation throughout the pitching motion (P < .001). The data indicate that increased lead foot internal rotation at foot contact is associated with increases in the elbow varus moment but is not associated with ball velocity. This study provides scientific evidence that the rotational positioning of the lead foot can affect both pelvic motion and upper-extremity joint moments.


Effects of endothelin and nitric oxide on organ injury, mesenteric ischemia, and survival in experimental models of septic shock.
The development of potent drugs to treat cardiopulmonary failure in sepsis, such as antibiotics and new immunomodulatory therapeutic approaches have not prevented sepsis from being a major health problem. Dysfunction of the vascular endothelium is an early event in septic shock. The recognition of endothelium-derived substances, such as nitric oxide and endothelin, important mediators of systemic inflammatory response syndrome, led to the proposal that pharmacological inhibition of nitric oxide and endothelin production could represent a useful strategy in the treatment of septic shock. Splanchnic ischemia and translocation of endotoxin from the gut to the circulation contributes significantly to the high mortality rate in sepsis-related syndromes. This vasoconstriction in the splanchnic circulation can be partially blocked by inducible nitric oxide synthase inhibitor aminoguanidine or endothelin receptor antagonist bosentan in experimental models of septic shock. It can be suggested that endothelin and nitric oxide may affect survival. Although septic shock is a highly complex pathophysiological state, the course of septic shock has different phases with different characteristics which need different (special) treatment strategy. The inhibition of nitric oxide production during hyperdynamic, earlier phase of sepsis combined with the blockade of endothelin receptors at a later stage during the hypodynamic, late phase appears to be a novel promising strategy for the therapy of septic shock. The aim of this review is to discuss the role of nitric oxide and endothelin in sepsis and the potential therapeutic implications of blockade of nitric oxide and endothelin as a target in treatment of human septic shock. Briefly the importance of timing of intervention is also emphasized.


A Challenging Yet Motivating Journey: The Experiences of Young Adult Parents With Serious Mental Health Conditions in the USA.
In recent decades the average age of becoming a parent has increased, the rate of teen pregnancies has decreased, and a new developmental period of emerging adulthood is marked by diverse pathways into adulthood. Today, those who become parents in young adulthood (18-24 years old) and their children may be vulnerable to poor outcomes observed in teen parents (13-19 years old) of previous generations. Young adults with serious mental health conditions (SMHC) who encounter additional challenges navigating young adulthood and tend to parent earlier than their peers may be at particularly increased risk of poor outcomes. To date, little research has been done to understand the experiences of young adult parents, especially those with SMHC. This study describes themes from qualitative interviews with 18 young adults with SMHC in the United States who became parents before the age of 25. Life story narrative interviews, conducted mostly by young adults with lived experience, asked participants to describe their parenting and mental health experiences and their school, training, and work experiences. Participants described the challenges of simultaneously parenting young children and managing a mental health condition, experiences of discrimination, and fear of future discrimination related to their mental health condition. However, parents also expressed that their children motivated them to maintain recovery and build a good life for their family. This is the first study to qualitatively explore the experiences of young adult parents with SMHC. While many of these findings align with prior qualitative research on mothers with mental illness, by exclusively focusing on individuals who become parents earlier than their peers and including father experiences, this research adds to our understanding of how individuals simultaneously navigate parenting and managing a serious mental health condition. These findings should inform larger-scale research studies on the experiences and outcomes of young adults with SMHC who become parents in their late teens or early twenties. A better understanding of their experiences should inform public mental health services that incorporate parenting as an important element of an individual's personal recovery model.


Self-diffusion mechanisms based defect complexes in MoSi2.
MoSi2is widely concerned due to excellent electrical conductivity, oxidation resistance as a typical transition metal silicide. The high-temperature diffusion behavior is one of the important factors for the degradation of MoSi2coatings. However, the diffusion mechanism in MoSi2is still unclear. Prior theoretical work mostly focused on defect formation energy, but these are not consistent with the self-diffusion experiments because the migration behaviors were not considered. Therefore, the purpose of this work was to investigate the microscopic diffusion mechanisms of Mo and Si atoms in MoSi2using density functional theory and the CI-NEB method. We confirmed that the temperature-dependent vibrational contribution has a significant impact on the defect formation free energy. The isolated point defects in MoSi2will tend to aggregate to form defect complexes, which participate in the atomic diffusion as mediators. The defect migration behaviors of atoms for vacancy mediated, vacancy complex mediated, and antisite assisted jumps were obtained based on electronic structures analysis. The results show that Si diffusion is mediated by intrasublattice jumps of the nearest neighbor Si vacancies. Moreover, the destroyed covalent Mo-Si bonds by Si vacancies and the non-directional weak metal bonds formed by the Mo antisites and Mo atoms could improve the mobility of the Mo atom which results in the low migration barrier. The agreement between our calculations and the reported experimental results indicates that the dominant diffusion mechanism for Mo atoms is mediated by vacancy complex mediated jumps and antisite assisted jumps. It is concluded that the Si vacancy-based defect complexes are likely the diffusion mediators for Mo atom self-diffusion in MoSi2. This work provides a deeper insight into the connection between the atomic mechanism and the macroscopic behavior for the diffusion in the MoSi2, and establishes the basis for further optimizing high-temperature coating materials.


Leptin: the prototypic adipocytokine and its role in NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, whose pathogenesis begins with the accumulation of liver fat and is followed by the development of necro-inflammation and fibrosis. Recent evidence indicates that adipocytokines, polypeptides secreted by the adispose tissue, might play an important role in the pathogeneic process and progression of NAFLD. In this review, we explore the role of leptin, and in part of other adipocytokines, in the interference with hepatic injury associated with fatty infiltration, in the modulation of steatosis and fibrosis, in both experimental models of the disease and in the clinical practice. We also discuss the potential use of leptin as non-invasive marker for differentiating simple fatty liver from NAFLD, and the possible novel therapeutic strategies aimed at interfering with the leptin axis to dampen chronic liver inflammation and NAFLD.


Role of dynamic contrast-enhanced MRI in predicting severe acute radiation-induced rectal injury in patients with rectal cancer.
To explore the potential of dynamic contrast-enhanced MRI (DCE-MRI) quantitative parameters in predicting severe acute radiation-induced rectal injury (RRI) in rectal cancer. This retrospective study enrolled 49 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and rectal MRI including a DCE-MRI sequence from November 2014 to March 2021. Two radiologists independently measured DCE-MRI quantitative parameters, including the forward volume transfer constant (Ktrans), rate constant (kep), fractional extravascular extracellular space volume (ve), and the thickness of the rectal wall farthest away from the tumor. These parameters were compared between mild and severe acute RRI groups based on histopathological assessment. Receiver operating characteristic curve analysis was performed to analyze statistically significant parameters. Forty-nine patients (mean age, 54 years ± 12 [standard deviation]; 37 men) were enrolled, including 25 patients with severe acute RRI. Ktrans was lower in severe acute RRI group than mild acute RRI group (0.032 min-1 vs 0.054 min-1; p = 0.008), but difference of other parameters (kep, ve and rectal wall thickness) was not significant between these two groups (all p > 0.05). The area under the receiver operating characteristic curve of Ktrans was 0.72 (95% confidence interval: 0.57, 0.84). With a Ktrans cutoff value of 0.047 min-1, the sensitivity and specificity for severe acute RRI prediction were 80% and 54%, respectively. Ktrans demonstrated moderate diagnostic performance in predicting severe acute RRI. Dynamic contrast-enhanced MRI can provide non-invasive and objective evidence for perioperative management and treatment strategies in rectal cancer patients with acute radiation-induced rectal injury. • To our knowledge, this study is the first to evaluate the predictive value of contrast-enhanced MRI (DCE-MRI) quantitative parameters for severe acute radiation-induced rectal injury (RRI) in patients with rectal cancer. • Forward volume transfer constant (Ktrans), derived from DCE-MRI, exhibited moderate diagnostic performance (AUC = 0.72) in predicting severe acute RRI of rectal cancer, with a sensitivity of 80% and specificity of 54%. • DCE-MRI is a promising imaging marker for distinguishing the severity of acute RRI in patients with rectal cancer.


The use of harmonic scalpel for free flap dissection in head and neck reconstructive surgery.
Surgeons conventionally use electrocautery dissection and surgical clip appliers to harvest free flaps. The ultrasonic Harmonic Scalpel is a new surgical instrument that provides high-quality dissection and hemostasis and minimizes tissue injury. The aim of this study was to evaluate the effectiveness and advantages of the ultrasonic Harmonic Scalpel compared to conventional surgical instruments in free flap surgery. This prospective study included 20 patients who underwent head and neck reconstructive surgery between March 2009 and May 2010. A forearm free flap was used for reconstruction in 12 patients, and a fibular flap was used in 8 patients. In half of the patients, electrocautery and surgical clips were used for free flap harvesting (the EC group), and in the other half of the patients, ultrasonic dissection was performed using the Harmonic Scalpel (the HS group). The following parameters were significantly lower in the HS group compared to the EC group: the operative time of flap dissection (35% lower in the HS group), blood loss, number of surgical clips and cost of surgical materials. This study demonstrated the effectiveness of the Harmonic Scalpel in forearm and fibular free flap dissections that may be extended to other free flaps.


Eosinophilic pustular folliculitis in infancy: not a distinctive inflammatory disease of the skin.
In the standard literature of dermatology and dermatopathology "eosinophilic pustular folliculitis in infancy" is presented as a distinctive inflammatory disease of the skin, to wit, a variant of "Ofuji's eosinophilic folliculitis". Assessment critically of the first publication devoted to the subject revealed a potpourri of findings clinical and histopathologic, with no clear criteria being set forth by the authors to enable diagnosis, with precision. Our review of all articles dedicated to the matter of "eosinophilic pustular folliculitis in infancy" shows that criteria for diagnosis are found with great difficulty. The majority of patients reported on had neither "eosinophilic folliculitis," nor did they present themselves clinically in any way similar to what was originally described by Ofuji. The findings histopathologic told of most commonly were dense and diffuse infiltrates in the dermis that contained many eosinophils, sometimes with periadnexal distribution. We think that the findings reported on in several articles suggest that the patients more likely had a variety of different diseases, among them scabies, insect bites, impetigenized nummular dermatitis, and linear IgA-dermatosis. For clarification of terminology, we suggest that "eosinophilic folliculitis" is better defined as a pattern histopathologic than as a distinctive disease entity. It may be encountered in a variety of conditions (eg, Ofuji's disease, arthropod bites, scabies, or dermatophytosis). In sum, no clear criteria have been established for diagnosis of "eosinophilic pustular folliculitis of infancy" and there is no convincing evidence, at present, that "eosinophilic pustular folliculitis of infancy" qualifies as a distinctive inflammatory disease of the skin.


Mycosis Fungoides Exhibits the Features of Skin Tags: A Case Report.
We present the case of a 37-year-old male diagnosed with Mycosis fungoides (MF) after gradually developing multiple skin tags and brownish lichenoid papules. The patient had pre-existing erythema over his entire body, especially his face, upper extremities, and trunk, for over 1.5 years. Microscopic examination of the papule and the skin tag (ST) exhibited similar features mainly characterized by superficial dense band-like lymphoid infiltrates and epidermotropism of atypical lymphocytes (Pautrier's micro-abscesses). Immunohistochemistry further revealed the lymphoid infiltrates predominantly expressed LCA, CD3, CD4, and CD45RO but lacked CD7, CD8, CD30, CD20, and CD79a. The finding of this study that reports MF characterized by unusual STs suggests that some causes and effects have not been previously described in MF.


[Expression of bcl-2, c-erbB2, and p53 protein in cervical epithelial carcinogenesis].
Less research of molecular biology have been reported on cervical carcinogenesis. So the authors designed this study to evaluate the expression and clinical significance of antiapoptosis gene bcl-2, oncogene c-erbB2, and tumor suppressor gene p53 in the progression of this kind of cancer. Using S-P immunohistochemical technique, the authors examined the expression of bcl-2, c-erbB2, and p53 in 48 squamous cell carcinoma of the cervix, 42 cervical intraepithelial neoplasia (CIN), and 20 normal cervical tissues. The expression rates of bcl-2, c-erbB2, and p53 were 72.9%(35/48), 60.4% (29/48), and 58.3% (28/48) in carcinomas, 61.9% (26/42), 38.1% (16/42), and 26.2% (11/42) in CIN, 20.0% (4/20), 0.0% (0/20), and 0.0% (0/20) in normal cervices, respectively. The overexpression of bcl-2 protein in carcinomas and in CIN was remarkably higher than that in normal cervices (P< 0.01), and the difference between carcinomas and CIN was not significant (P>0.05). There were significant differences for c-erbB2 and p53 between carcinomas and CIN and normal cervices, respectively (P< 0.05). There were significant differences for bcl-2, c-erbB2, and p53 between CIN3 and CIN1-2, respectively (P< 0.05). Expression of bcl-2 and p53 were correlated with histological type, tumor grades, and clinical stages (P< 0.05). Expression of bcl-2 was lower keratinized than nonkeratinized and was lower as tumor grades and clinical stages increased (P< 0.05). It was not associated with lymph node metastasis (P >0.05). However, the expression of p53 was contrary with bcl-2. Expression of c-erbB2 was not associated with histological type, tumor grades, clinical stages, and lymph node metastasis (P >0.05). In cervical carcinogenesis, the overexpression of bcl-2 protein may be activated in the early stage of pathogenesis of cervical carcinoma. Expression of c-erbB2 was the signal of cell malignant change. Expression of p53 was associated with the pathogenesis and development of cervical carcinoma.


[Effect of multidrug resistant associated protein 4 overexpression on lipopolysaccharide-induced vascular endothelial hyperpermeability and its mechanism].
To investigate the effect of multidrug resistance protein 4 (MRP4) overexpression on lipopolysaccharide (LPS)-induced vascular endothelial hyperpermeability of rat pulmonary micro-vascular endothelial cells (PMVECs) and its molecule mechanism. Three to six passages of PMVECs were cultured in vitro, and they were divided into three groups: the cells in LPS group were only challenged by LPS 10 μg/mL after being cultured in serum-free medium for 24 hours; the cells in Ad-shRNA and Ad-MRP4 groups were infected with the empty virus control or recombinant adenovirus expressing MRP4 for 2 hours, and then were cultured in serum-free medium for 24 hours followed by stimulation of LPS 10 μg/mL. Endothelial permeability was assayed by the Transwell chamber models at 2, 6, 12, and 24 hours after LPS stimulation. Intracellular cyclic adenosine monophosphate (cAMP) levels were detected by enzyme-linked immunosorbent assay (ELISA). The morphological characteristics and distribution of F-actin was determined by laser confocal fluorescence microscope. The protein expressions of MRP4, β-catenin, vascular endothelium-cadherin (VE-cad) and ZO-1 were measured by Western Blot. (1) After LPS stimulation, endothelium permeability and intracellular cAMP levels in PMVECs were significantly increased, peaked at 12 hours, and then decreased after 24 hours. Compared with LPS group and Ad-shRNA group, PMVECs of Ad-MRP4 group were exhibited a significant increase in endothelial permeability [12-hour permeability (A value): 1.88±0.06 vs. 1.12±0.17, 1.10±0.18] and a significant decrease in intracellular cAMP level [12-hour cAMP (μg/L): 2.39±0.02 vs. 2.97±0.01, 3.00±0.02, all P < 0.05]. There was no significant difference in endothelium permeability and intracellular cAMP levels at all time points between the LPS group and the Ad-shRNA group (all P > 0.05). (2) Under laser confocal fluorescence microscope, after LPS stimulation, the stress fiber formation was induced in three groups. But there were pronounced irregular aggregation of fiber in PMVECs of Ad-MRP4 group. (3) Furthermore, compared with LPS group and Ad-shRNA group, protein expression of MRP4 in Ad-MRP4 group was dramatically increased (gray value: 0.76±0.03 vs. 0.44±0.02, 0.43±0.02, both P < 0.05), and the protein expressions of β-catenin, VE-cad, and ZO-1 were significantly decreased [β-catenin (gray value): 0.14±0.03 vs. 0.23±0.04, 0.23±0.03); VE-cad (gray value): 0.21±0.01 vs. 0.34±0.02, 0.35±0.04; ZO-1 (gray value): 0.14±0.02 vs. 0.37±0.06, 0.33±0.07, all P < 0.05]. There was no significant difference in all protein expressions between the LPS group and Ad-shRNA group (all P > 0.05). MRP4 overexpression can decrease intracellular cAMP levels, reduce intercellular junction protein expression, and then exaggerate LPS-induced vascular endothelial hyperpermeability.


Effects of thoracic or abdominal strapping on exercise performance.
In eleven young healthy subjects, vital capacity was reduced by 30% by thoracic or abdominal strapping and the effects of this on maximal work capacity, ventilation and circulation were examined. During exercise as well as at rest, tidal volume and stroke volume were reduced and respiratory frequency and heart rate were increased with both types of strapping. Cardiac output appeared to be decreased. Thoracic strapping was slightly but significantly more impeding than abdominal strapping: residual volume, tidal volume and maximal work capacity were smaller. In both instances, the decrease in maximal performance was apparently due to ventilatory as well as circulatory limitation.


Clinical study of a steel cable fixation for distal tibiofibular syndesmosis injury.
In order to overcome the shortcomings of common surgical fixation methods for Distal Tibiofibular Syndesmosis (DTS) injuries, which include the inability to exercise early, significant surgical trauma, and the risk of loosening and breakage of implants, we have designed and implemented a new technique using steel cable fixation to treat DTS injuries. Twenty-six patients treated with steel cable fixation for DTS injury between March 2013 and March 2019 in the Second Hospital of Tangshan City trauma department were followed up to monitor the efficacy of treatment. There were 16 males and 10 females between the ages of 19 and 64, with a mean age of 41.81 ± 9.54 years. All patients were examined by X-ray and CT for 3 days before and after surgery. The patients were then reexamined by X-ray 6 and 9 weeks postoperatively, and by CT 1 year later. The treatment results were evaluated by comparing the distal tibiofibular anterior, middle, and posterior gap changes and the Baird-Jackson score. The 26 patients attained good postoperative repositioning, with a fracture healing time of 2.5 to 3 months. and the Baird-Jackson score was 96 ± 2.78. After surgery, the DTS gaps observed in the CT scans taken 3 days and 1 year postoperatively in all patients were significantly reduced compared to the preoperative measurements, with statistical significance (P < .05). However, when comparing the CT scans taken 1 year postoperatively to those at 3 days postoperatively, there was no significant change in the anterior gap. The middle and posterior gaps of DTS showed a slight increase with statistical significance (P < .05), but all measurements remained within the normal range. Steel cable fixation for DTS injury has the advantages of reliable fixation, early functional exercise, and reduction in the number of operations, and no adverse effects or complications were found.


Theoretical investigation of the dissociation dynamics of vibrationally excited vinyl bromide on an ab initio potential-energy surface obtained using modified novelty sampling and feedforward neural networks. II. Numerical application of the method.
A previously reported method for conducting molecular dynamics simulations of gas-phase chemical dynamics on ab initio potential-energy surfaces using modified novelty sampling and feedforward neural networks is applied to the investigation of the unimolecular dissociation of vinyl bromide. The neural network is fitted to a database comprising the MP4(SDQ) energies computed for 71 969 nuclear configurations using an extended basis set. Dissociation rate coefficients and branching ratios at an internal excitation energy of 6.44 eV for all six open reaction channels are reported. The distribution of vibrational energy in HBr formed in three-center dissociation is computed and found to be in excellent accord with experimental measurements. Computational requirements for the electronic structure calculations, neural network training, and trajectory calculations are given. The weight and bias matrices required for implementation of the neural network potential are made available through the Supplementary Material.


Cardiovascular and renal action of dopaminergic prodrugs.
The possibility of exploiting the cardiovascular and renal action of dopamine for therapeutic purposes is enhanced by its conversion into orally active prodrugs. Following an outline of the medicinal chemistry bases of the development of these prodrugs, laboratory and clinical pharmacology of ibopamine, levodopa, gludopa, and TA-870 are reviewed, pointing out the interesting indications of various preliminary studies in heart failure, essential hypertension, and renal failure on the one hand, and the extensive therapeutic experience with ibopamine as an "inodilator" in the chronic treatment of congestive heart failure on the other hand. New experimental results are also reported for ibopamine and for the novel prodrug Sim 2055, i.e., epinine-4-O-phosphate. The latter is shown to act as a selective renal vasodilator on oral administration in dogs and it is therefore proposed for clinical investigation in renal failure and in essential hypertension.


Abnormalities in the metabolism of acetaminophen in patients infected with the human immunodeficiency virus (HIV).
The urinary concentration of acetaminophen and its glucuronide, sulphate, cysteine, and mercapturate conjugates was measured by high-performance liquid chromatography in 32 healthy volunteers, 9 untreated symptom-free HIV-seropositive subjects, and 19 patients with AIDS after a single oral dose of 1.5 g of acetaminophen. The concentration of the glucuronide conjugate was significantly lower in AIDS patients when simultaneously compared with concentrations found in healthy individuals and symptoms-free HIV-seropositive subjects. Differences between healthy volunteers and symptom-free HIV seropositives were not encountered. By contrast, urinary concentrations of sulphate and oxidation pathway-derived metabolites were significantly higher in AIDS patients as compared with the other two groups. When AIDS patients treated with zidovudine were compared with those not given this medication, differences in the urinary excretion of acetaminophen and its metabolites were not observed. However, the urinary concentration of mercapturic acid was significantly higher in those given enzyme inducers, such as rifampicin or phenytoin, than in AIDS patients not treated with these drugs. In summary, patients with advanced HIV infection showed reduced acetaminophen glucuronidation and increased formation of the hepatotoxic oxidation metabolites, which was independent of zidovudine therapy.


Diagnostics and treatment of spontaneous intracranial hypotension.
Intracranial hypotension is a frequently misdiagnosed syndrome which is caused by reduced intracranial cerebrospinal fluid (CSF) pressure due to spontaneous spinal CSF leakage. We present our series of intracranial hypotension regarding especially the required diagnostic imaging and the treatment. A retrospective analysis was performed on 8 patients (5 males, 3 females, mean age 49 years) with postural and non-postural headache due to spinal CSF collection. Cranial MRI showed diffuse pachymeningeal gadolinium enhancement in all cases. CSF leakage detected by gadolinium-enhanced MR cisternography could be either diffuse (n=5) or precisely located around a dural tear (n=3). All but one leakages were located at the thoracic spine. In 6 patients 40-65 mL of blood were injected through epidurally placed drainages. In 1 patient, a dural tear was sealed with fibrin glue and fat. One patient refused surgical intervention. One epidural haematoma had to be revised. 5 of 7 patients showed excellent results. Gadolinium-enhanced MR cisternography best revealed CSF leaks. In the majority of patients with spontaneous intracranial hypotension, complete recovery may be achieved via a midthoracic epidural blood patch with minimal complications.


Screening for problem drinkers in a general population survey in Spain by use of the CAGE scale.
The CAGE scale has been used as a screening device for problem drinkers in a general population survey. The study was conducted in the fall of 1992 on 2,500 individuals, aged 14-70 years, who live in the region of Castile and Leon (Spain). Alcohol was consumed at least once a week by 51.3% of those surveyed. A total of 136 drinkers (10.6% of "weekly" drinkers, 5.4% of total sample) had positive CAGE scores, as determined by two or more affirmative answers, 120 men (14.3%) and 16 women (3.6%). Those with CAGE positive scores consumed a daily mean of 57.5 grams of pure alcohol per day. The utility of the CAGE scale in a general population survey and the difficulties in applying it are discussed.


Multimodal Imaging of Laser-Induced Retinal-Choroidal Anastomosis Masquerading as Type 3 Macular Neovascularization.
The use of laser to induce a retinal-choroidal anastomosis (RCA) through photomechanical and photothermal rupture of the retinal pigment epithelium/Bruch's membrane beneath a retinal vein has been performed in eyes with retinal vein occlusion to create an alternate pathway for retinal venous outflow. The authors document the multimodal imaging findings of a 64-year-old female with type 2 diabetes presenting with a parafoveal vascular lesion simulating type 3 macular neovascularization. A review of the medical history and the benign course of the lesion suggested its inadvertent origin from prior focal/grid laser to treat diabetic macular edema. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:244-248.].


[[The Lactéol's laboratory of Dr Boucard (Laboratoire du Dr Boucard].
Shortly before 1910, Dr Boucard creates his laboratory in Paris. It manufactures and sells a drug based on lactic ferments the " Lactéol du Dr Boucard" (Dr's Boucard Lactéol) that will make the fortune of the physician. The article explains Dr Boucard's life and his relationship with the arts (painting and photography), and tells the story of his laboratory until the 2000s, referring to the pharmacists who succeeded them, as well as the various buildings where were elaborated Lactéol's variants.


Treatment of pilonidal disease by phenol application.
The literature indicates various approaches regarding the properties of phenol, the target patient group, and the complication and recurrence rates. Although phenol is most frequently used to treat the fistulated form of the disease, it can also be applied for other types. The overall success and complication rates of the application is reported as 62-95% and 0%-2%, respectively. Phenol treatment in pilonidal disease can be used more frequently as an alternative method with acceptable success, complication, and recurrence rates.


Development of a self-assembling protein nanoparticle vaccine targeting Plasmodium falciparum Circumsporozoite Protein delivered in three Army Liposome Formulation adjuvants.
We have developed FMP014, a vaccine candidate against Plasmodium falciparum malaria, which is comprised of 60 identical monomer protein chains that form an icosahedral shaped self-assembling protein nanoparticle (SAPN). Each monomer contains selected P. falciparum Circumsporozoite Protein (PfCSP) CD4+ and CD8+ epitopes, universal TH epitopes, portions of the α-TSR domain, and 6 repeats of the NANP motifs of the PfCSP. Here we describe the conditions that are required for successful scale-up and cGMP manufacturing of FMP014 with a yield of ≈1.5g of drug substance per 100g of wet bacterial paste. When adjuvanted with an Army Liposomal Formulation (ALF) based adjuvant, the nanoparticle vaccine is highly immunogenic and prevents infection of mice by an otherwise lethal dose of transgenic P. berghei sporozoites expressing the full-length PfCSP.


Brefeldin A promotes the appearance of oligosaccharyl phosphates derived from Glc3Man9GlcNAc2-PP-dolichol within the endomembrane system of HepG2 cells.
We reported an oligosaccharide diphosphodolichol (DLO) diphosphatase (DLODP) that generates dolichyl-phosphate and oligosaccharyl phosphates (OSPs) from DLO in vitro. This enzyme could underlie cytoplasmic OSP generation and promote dolichyl-phosphate recycling from truncated endoplasmic reticulum (ER)-generated DLO intermediates. However, during subcellular fractionation, DLODP distribution is closer to that of a Golgi apparatus (GA) marker than those of ER markers. Here, we examined the effect of brefeldin A (BFA), which fuses the GA with the ER on OSP metabolism. In order to increase the steady state level of truncated DLO while allowing formation of mature DLO (Glc3Man9GlcNAc2-PP-dolichol), dolichyl-P-mannose Man7GlcNAc2-PP-dolichol mannosyltransferase was partially downregulated in HepG2 cells. We show that BFA provokes GA endomannosidase trimming of Glc3Man9GlcNAc2-PP-dolichol to yield a Man8GlcNAc2-PP-dolichol structure that does not give rise to cytoplasmic Man8GlcNAc2-P. BFA also strikingly increased OSP derived from mature DLO within the endomembrane system without affecting levels of Man7GlcNAc2-PP-dolichol or cytoplasmic Man7GlcNAc2-P. The BFA-provoked increase in endomembrane-situated OSP is sensitive to nocodazole, and BFA causes partial redistribution of DLODP activity from GA- to ER-containing regions of density gradients. These findings are consistent with BFA-provoked microtubule-dependent GA-to-ER transport of a previously reported DLODP that acts to generate a novel endomembrane-situated OSP population.


Investigation of horizontal gene transfer of pathogenicity islands in Escherichia coli using next-generation sequencing.
Horizontal gene transfer (HGT) contributes to the evolution of bacteria. All extraintestinal pathogenic Escherichia coli (ExPEC) harbour pathogenicity islands (PAIs), however relatively little is known about the acquisition of these PAIs. Due to these islands, ExPEC have properties to colonize and invade its hosts efficiently. Even though these PAIs are known to be acquired by HGT, only very few PAIs do carry mobilization and transfer genes required for the transmission by HGT. In this study, we apply for the first time next-generation sequencing (NGS) and in silico analyses in combination with in vitro experiments to decipher the mechanisms of PAI acquisition in ExPEC. For this, we investigated three neighbouring E. coli PAIs, namely the high-pathogenicity island (HPI), the pks and the serU island. As these PAIs contain no mobilization and transfer genes, they are immobile and dependent on transfer vehicles. By whole genome sequencing of the entire E. coli reference (ECOR) collection and by applying a phylogenetic approach we could unambiguously demonstrate that these PAIs are transmitted not only vertically, but also horizontally. Furthermore, we could prove in silico that distinct groups of PAIs were transferred "en bloc" in conjunction with the neighbouring chromosomal backbone. We traced this PAI transfer in vitro using an F' plasmid. Different lengths of transferred DNA were exactly detectable in the sequenced transconjugants indicating NGS as a powerful tool for determination of PAI transfer.


Peptide mass fingerprinting after less specific in-gel proteolysis using MALDI-LTQ-Orbitrap and 4-chloro-alpha-cyanocinnamic acid.
Peptide Mass Fingerprinting (PMF) of tryptically in-gel digested samples is a well-established protein identification technique for MALDI mass spectrometry but an in-depth PMF evaluation for in-gel digestions of less specific enzymes is still missing. This study demonstrates that the MALDI-LTQ-Orbitrap provides the mass accuracy to gain significant database search results via PMF for the less specific enzymes chymotrypsin and elastase. Additionally, the highly sensitive MALDI matrix ClCCA was compared to the most widely used matrix CHCA by means of the detected peptide number, peptide composition, pI and S/N distribution, sequence coverage, and Mascot score. Therefore, several proteins were in-gel digested by chymotrypsin and elastase. Trypsin and proteinase K were included as references for specific and nonspecific proteases, respectively. Compared to CHCA, ClCCA resulted in a better mapping in all cases of the more complex peptide mixtures generated by less specific enzymes. In summary, the MALDI-LTQ-Orbitrap combined with the matrix ClCCA makes PMF of less specific digests possible in an easy and fast way. Moreover, it opens more possibilities for PMF in the analysis of difficult tasks such as membrane proteins.


Imaging of skeletal metastases in myxoid liposarcoma.
Unlike other soft tissue sarcomas, myxoid/round cell liposarcoma (MRCL) has a tendency to spread to extrapulmonary sites but bone metastases are thought to be uncommon. In case reports, negative bone scintigraphy has been noted in patients with myxoid/round cell liposarcoma and bone metastases but the prevalence and optimal method of diagnosis of bone metastases in this common subtype of liposarcoma are unclear. In an attempt to answer these questions, data were obtained from a prospective database of patients with sarcoma, including MRCL, and the diagnostic imaging used was examined. A variety of imaging tools were used including plain X-rays, bone scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI). Eight patients (4.3%) developed skeletal metastases all of which were positive on MRI. Bone scintigraphy was negative in two out of four cases, CT was negative in six out of seven, and X-rays were negative in four. Radiography and CT measure mainly cortical bone involvement, whereas MRI examines bone marrow. When investigating patients with MRCL for bone pain, negative X-rays and bone scans do not rule out bone metastases. In our experience, MRI provides the most sensitive technique for the diagnosis of bone metastases in MRCL.


The subtlety of simple eyes: the tuning of visual fields to perceptual challenges in birds.
Birds show interspecific variation both in the size of the fields of individual eyes and in the ways that these fields are brought together to produce the total visual field. Variation is found in the dimensions of all main parameters: binocular region, cyclopean field and blind areas. There is a phylogenetic signal with respect to maximum width of the binocular field in that passerine species have significantly broader field widths than non-passerines; broadest fields are found among crows (Corvidae). Among non-passerines, visual fields show considerable variation within families and even within some genera. It is argued that (i) the main drivers of differences in visual fields are associated with perceptual challenges that arise through different modes of foraging, and (ii) the primary function of binocularity in birds lies in the control of bill position rather than in the control of locomotion. The informational function of binocular vision does not lie in binocularity per se (two eyes receiving slightly different information simultaneously about the same objects from which higher-order depth information is extracted), but in the contralateral projection of the visual field of each eye. Contralateral projection ensures that each eye receives information from a symmetrically expanding optic flow-field from which direction of travel and time to contact targets can be extracted, particularly with respect to the control of bill position.


Angles of facial convexity in different skeletal Classes.
The objective of this study was to investigate whether it is possible to use a lateral (profile) photograph to determine the underlying skeletal Class and which reference points of the angle of convexity are most suitable for this purpose. Profile photographs and lateral cephalographs included in the baseline data for 180 orthodontic patients were retrospectively evaluated. The subjects were assigned to skeletal Classes based on Wits values obtained by radiolographic analysis. The Class I subjects were 58 patients (22 males, 36 females) with an average age of 13.63 +/- 2.1 years, the Class II subjects 60 patients (37 males, 23 females) with an average age of 13.60 +/- 2.6 years, and the Class III subjects 62 patients (28 males, 34 females) with an average age of 11.65 +/- 3.3 years. The angles measured were A'OrB' (=POrA'-POrA'), A'N'B', and the angle of convexity with its variants (N'SnPog', N'A'Pog', TrSnPog', TrA'Pog', Gl'SnPog', and Gl'A'Pog'). These angles were statistically evaluated using a two-sided t-test and linear discriminant analysis. Class II and Class III subjects exhibited highly significant differences (P < 0.001) for all angles. Class I and Class III exhibited highly significant differences (P < 0.001) for almost all angles, and significant differences for A'N'B' (P < 0.05). Class I and Class II differed significantly (P < 0.05) only for some angles (N'SnPog', TrA'Pog', Gl'SnPog', and Gl'A'Pog'). The error within the linear discriminant analysis was smallest for N'SnPog', GlA'Pog', and TrA'Pog' angles. However, the method error according to Dahlberg yielded rather high values for all angles (1.07-1.17 degrees). Discrimination between skeletal Class I and Class III was easier than that between Class I and Class II. One of the reasons may be that the subclasses division I and division II were not distinguished within the Class II subjects.


Diagnosing bladder outlet obstruction in women.
There are no universally accepted urodynamic criteria for diagnosing female bladder outlet obstruction. When accepted criteria for men are applied to women, the diagnosis of obstruction may often be missed, which is most likely due to differences in voiding dynamics. We propose video urodynamic criteria for diagnosing obstruction in women, and describe the urodynamic findings in those with and without obstruction. We reviewed the charts of 331 women who underwent multichannel video urodynamics for nonneurogenic voiding dysfunction. Of these women 261 (mean age 55.8 years) had evaluable voiding pressure flow studies with simultaneous video fluoroscopy of the bladder outlet during voiding. At video urodynamics cases were classified as obstructed if there was radiographic evidence of obstruction between the bladder neck and distal urethra in the presence of a sustained detrusor contraction. Strict pressure flow criteria were not used. Maximum flow rate, detrusor pressure at maximum flow rate, post-void residual, bladder capacity and the incidence of detrusor instability were compared between obstructed and unobstructed cases. A total of 76 women met the criteria for obstruction (mean age 57.5 years), while 184 (mean age 55) did not. Causes of obstruction were dysfunctional voiding in 25 cases, cystocele in 21, primary bladder neck obstruction in 12, iatrogenic from incontinence surgery in 11, urethral stricture in 3, uterine prolapse in 2, urethral diverticulum in 1 and rectocele in 1. Obstructed cases had lower mean maximum flow rate (9 versus 20.2 ml. per second, p <0.0001), higher mean detrusor pressure at maximum flow rate (42.8 versus 22.1 cm. water, p <0.0001) and higher mean post-void residual (157 versus 33 ml., p <0.0001). There was no difference in bladder capacity (381 versus 347 ml.) or incidence of detrusor instability (45 versus 41%). Using the proposed video urodynamic criteria obstructed cases had significantly higher voiding pressures, lower flow rates and higher post-void residual than unobstructed cases, as expected. However, absolute values, especially for voiding pressure, are not as dramatic in women as in men. Pressure flow studies alone may fail to diagnose obstruction but simultaneous imaging of the bladder outlet during voiding greatly facilitates diagnosis.


[The assessment of temperament, quality of life and intensity of depressive symptoms in patients with Hodgkin's disease in different stages of the illness].
Hodgkin's disease is an oncology illness of unknown aetiology connected with high risk of psychological disturbances, depressive symptoms and poorer quality of life. The aim of this study was to assess temperamental factors, intensity of depression and quality of life in patients with Hodgkin's disease in the diagnostic period, active oncology treatment and in remission. In this study 50 subjects with a diagnosis of Hodgkin's disease participated, all aged 20-65 years. Temperament was assessed using the Zawadzki and Strelau Temperament Scale, quality of life was measured using the WHO QL scale. The intensity of depressive symptoms was evaluated by the 17-item Hamilton Depression Rating Scale. The results obtained suggested a possibility of changes in temperamental factors of patients with Hodgkin's disease in different stages of the illness, a significant increase of depressive symptoms and the association between intensity of depression and quality of life as well as intensity of temperamental changes. The differences between the results obtained in male and female subjects with Hodgkin's disease indicate different coping mechanisms in male and female patients.


Noise investigation of an electrostatic accelerometer by a high-voltage levitation method combined with a translation-tilt compensation pendulum bench.
A high precision electrostatic accelerometer has widely been employed to measure gravity gradients and detect gravitational waves in space. The high-voltage levitation method is one of the solutions for testing electrostatic accelerometers on the ground, which aims at simultaneously detecting all six-degree-of-freedom movements of the electrostatic accelerometers engineering and flight prototypes. However, the noise performance in the high-voltage levitation test is mainly limited by seismic noise. The combined test of the accelerometer and vibration isolation platform is adopted to improve the detection precision of the high-voltage levitation method. In this paper, a high precision electrostatic accelerometer prototype is developed after designed appropriate mechanical parameters with a test mass weighing 300 g and with an estimated resolution of 2 × 10-12 m/s2/Hz1/2 from 0.01 to 0.4 Hz. Such a prototype is tested by the high-voltage levitation method, its measurement noise on the ground is mainly limited by the seismic noise, which is about 5 × 10-7 m/s2/Hz1/2 around 0.2 Hz and about 4 × 10-8 m/s2/Hz1/2 around 0.1 Hz. A vibration isolation pendulum bench based on the translation-tilt compensation principle is adopted for accelerometer prototype combined tests to suppress the seismic noise, which has a large bench area and the ability to adjust the tilt angle precisely. The measured accelerometer noise of the combined test with the translation-tilt compensation pendulum has reached 3 × 10-9 m/s2/Hz1/2 around 0.2 Hz, and it is about two orders of magnitude lower than the measurement noise on the ground. The combined test method provides technical guidance for further improving the noise level of ground test in the future.


Channels and transporters. Mini-symposium of the Division of Medicinal Chemistry (DMC) of the Swiss Chemical Society (SCS) at the Department of Chemistry, University of Basel, May 27, 2010.
During a half-day symposium, the topic 'Channels and Transporters' was covered with five lectures, including a presentation on 'Introduction and Basics of Channels and Transporters' by Beat Ernst, lectures on structure, function and physiology of channels and transporters ('The Structural Basis for Ion Conduction and Gating in Pentameric Ligand-Gated Ion Channels' by Raimund Dutzler and 'Uptake and Efflux Transporters for Endogenous Substances and for Drugs' by Dietrich Keppler), and a case study lecture on 'Avosentan' by Werner Neidhart. The program was completed by Matthias Hediger who introduced to the audience the National Center of Competence in Research (NCCR)-TransCure in his lecture entitled 'From Transport Physiology to Identification of Therapeutic Targets'.


[Abecedary of the "Annales". Part 6].
The terms included and detailed in the present part are: cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis, proportional hazards (Cox) model, inclusion criteria, endpoints or outcomes.


Risk and protective factors for whoonga use among adolescents in South Africa.
Antiretroviral therapy (ART) is publicly available in South Africa in response to the urgent need to address HIV and AIDS. Off-label use of ARV medication alone or in combination with other substances is known as "whoonga" and "nyaope" in South Africa. Diversion of ARVs for whoonga use is not well understood, especially among adolescents. This secondary analysis explores risk and protective factors for adolescent whoonga use in a community-based HIV endemic setting. Data on whoonga use were derived from a baseline survey of N = 200 adolescents recruited for participation in a randomized controlled trail to reduce adolescent HIV risk behaviors and depression. Risk and protective factors for adolescent whoonga use were explored using an ecological systems framework using one-way ANOVAs, chi-squared tests and hierarchical regression. Individual level factors increased the odds of whoonga use or known use such as child age OR:1.22 (95% CI, 1.03-1.43), hazardous drug use OR:1.62 (95% CI, 1.02-2.59), and hazardous alcohol OR:1.80 (95% CI, 1.05-3.09). Food insecurity appears to have a slightly protective effect on the odds of whoonga use or reports of use among people adolescents knew OR:0.649 (95% CI, 0.541-0.779). Larger epidemiological studies should expand the surveillance of hazardous alcohol use and illicit drug use, specifically for recreational use of prescription medication. Granular data is warranted to characterize the patters of use, especially among highly vulnerable populations. Future surveillance studies that explore these multi-level relationships are warranted to further understand this phenomenon among teens in South Africa.


Neuromuscular hamartoma.
A rare case of neuromuscular hamartoma, a benign tumor composed of well-differentiated skeletal muscle and nerve fibers, is described and compared with four previously reported cases. The tumor arose in the major peripheral nerves. Three of the five tumors were congenital tumors. A biopsy is essential in establishing the diagnosis. However, the tumor may be left alone if it cannot be separated from the nerve with ease, since spontaneous regression has been documented.


Chronic hypercapnic incubation increases relative organ growth and reduces blood pressure of embryonic American alligator (Alligator mississippiensis).
Reptilian nests can experience natural hypoxic and hypercapnic conditions. We incubated alligator eggs at a female-only producing temperature (30°C) in three conditions: 21% O2/0.04% CO2, 21% O2/3.5% CO2 and 21% O2/7% CO2. Alligator embryos chronically incubated in high CO2 were markedly hypotensive (blood pressure reduced by 46%) and had relatively (mass-specific) enlarged hearts (dry mass increased by 20%), lungs (dry mass increased by 17%), and kidneys (dry mass increased by 14%). This study is the first to chronically incubate reptilian eggs in hypercapnia and suggests that high CO2 alters the cardiovascular phenotype of alligator embryos (low blood pressure, relatively enlarged hearts), as well as the relative size of the organs primarily responsible for acid base balance, lungs and kidneys. The lungs and kidneys are largely non-functional during embryonic development, and the embryonic phenotype of increased relative mass may be a predictive-adaptation to metabolic or respiratory acidosis, such as during exercise or high respiratory CO2. This study demonstrates that phenotypic plasticity of alligator embryos incubated in high CO2 may result in either preferential organ growth, or maintenance of organ growth with reduced somatic growth.


Benign breast dysplasia causing hypercalcemia.
An adolescent female had hypercalcemia and massive, bilateral breast enlargement. At neck and mediastinal explorations three parathyroid glands were removed and found to be histologically normal. Following bilateral mastectomy the hypercalcemia resolved within two days and did not recur during a six-year period of followup. Microscopic examination of the excised breast tissue revealed marked dysplasia but no cancer. Those findings suggest that benign, dysplastic breast tissue can release humoral mediators of hypercalcemia.


Improved morphology and performance from surface treatments of naphthalenetetracarboxylic diimide bottom contact field-effect transistors.
We report bottom contact organic field-effect transistors (OFETs) with various surface treatments based on n-channel materials, specifically, 1,4,5,8-naphthalene-teracarboxylic diimides (NTCDIs) with three different fluorinated N-substituents, systematically studied with a particular emphasis on the interplay between the morphology of the organic semiconductor films and the electrical device properties. The morphological origins of the improvements were directly and dramatically visualized at the semiconductor-contact interface. As a result of a series of treatments, a large range of performances of bottom contact side-chain-fluorinated NTCDI OFETs (mobility from 1 x 10(-6) to 8 x 10(-2) cm(2)/(V s), on/off ratio from 1 x 10(2) to 1 x 10(5)) were obtained. The surface treatments enabled systems that had shown essentially no OFET activity without electrode modification activity to perform nearly as well as top contact devices made from the same materials. In addition, for the fresh bottom contact NTCDI device, the effect of gate bias stress on the tens-of-minutes time scale, during which the threshold voltage (V(t)) shifted and relaxed with similar time constants, was observed.


A preclinical study on the combined effects of repeated eltoprazine and preladenant treatment for alleviating L-DOPA-induced dyskinesia in Parkinson's disease.
Eltoprazine, a serotonergic (5-HT)1A/B receptor agonist, is a potential treatment for L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD) but notably compromises the anti-parkinsonian effects of L-DOPA, as seen in rodent and monkey models of PD. Preladenant, a selective adenosine A2a receptor antagonist, mediates modest anti-parkinsonian effects in parkinsonian monkeys. In a recent investigation, combined eltoprazine and preladenant treatment with a sub-threshold dose of L-DOPA acutely attenuated dyskinesia without exacerbating PD disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The aim of this study was to investigate the daily repeated treatment effects of eltoprazine (1mg/kg) alone, and in combination with preladenant (5mg/kg), on the motor symptoms of PD and LID in MPTP-treated macaques. The anti-dyskinetic and -parkinsonian effects of combinative drug administration with a sub-threshold dose of L-DOPA were measured over 14 days. Eltoprazine treatment alone produced a near-complete suppression of dyskinesia but consistently increased parkinsonism. The administration of preladenant with eltoprazine prevented the increased severity of parkinsonian motor symptoms but was unable to maintain a reduced expression of dyskinesia with repeated administration. These data demonstrate the clinical utility of the modulation of the serotonergic and adenosine neurotransmitter systems with selective pharmacological agents for only acute treatment of LID. This multi-targeted approach is unsuitable as a long-term treatment regimen due to unsustainable therapeutic effects on dyskinesia.


Genome Sequence of the Deep-Sea Denitrifier Pseudomonas sp. Strain MT-1, Isolated from the Mariana Trench.
Pseudomonas sp. strain MT-1 was the first deep-sea denitrifier isolated and characterized from mud recovered from a depth of 11,000 m in the Mariana Trench. We report here the genome sequence of this bacterium, which contributes to our understanding of denitrification and bioenergetics in the deep sea.


[Familial intestinal degenerative neuropathy with chronic pseudo-obstruction linked to duplication in chromosome 9].
The so-called Helsingborg Disease is an intestinal degenerative neuropathy discovered in a kindred in South Sweden. Affected subjects develop severe intestinal symptoms, the most common being chronic diarrhea, but abdominal pain, constipation and severe vomiting are common. Chronic intestinal pseudo-obstruction is the end-stage with high mortality from intestinal failure. Two families with affected members were shown by histopathology and genealogy to be one large kindred with the same underlying disease. Genetic analysis shows that this disease, having an autosomal dominant transmission, is strongly linked to a region in the short arm of chromosome 9 and a 1.2 Mb duplication in this region. The duplication includes 22 protein-coding genes, most of them are interferon genes. Family members not carrying the duplication have no increased prevalence of gut diseases. Genetic analysis including gene-dose array should be important for etiologic diagnosis and for genetic guidance in this kindred.


Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6.
Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, Sirt6 or FoxO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice. In summary, our data suggest an important role of hepatic Sirt6 and FoxO3 in the regulation of cholesterol homeostasis.