Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis.
OA is a degenerative joint disease characterized by articular cartilage degradation, osteophyte formation, synovitis, and subchondral bone sclerosis. One of OAs main risk factors is obesity. To date, it is not fully understood how obesity results in OA. Historically, this link was ascribed to excessive joint loading as a result of increased body weight. However, the association between obesity and OA in non-weight-bearing joints suggests a more complex aetiology for obesity-induced OA. In the present review, the link between obesity and OA is discussed. First, the historical view of altered joint loading leading to wear and tear of the joint is addressed. Subsequently, the effects of a disturbed lipid metabolism, low-grade inflammation, and adipokines on joint tissues are discussed and linked to OA. Taken together, inflamed adipose tissue and dyslipidaemia play pivotal roles in obesity-induced OA. It becomes increasingly clear that the link between obesity and OA transcends excessive loading.


Prognostic factors of early sequelae and fatal outcome of Japanese encephalitis.
A clinical case control study to identify prognostic factors present at hospital admission associated with early sequelae and fatal outcome of acute Japanese encephalitis (JE) was carried out in Gusi county, Henan Province, central China from June to September 1991. A total of 70 patients with laboratory-confirmed acute JE were studied, of whom 3 cases died and 33 cases had neurological or psychiatric sequelae at the end of three months follow-up. The results showed that acute JE at younger age, with higher body temperature, high white cell count in CSF, and deep coma present at hospital admission were markers for unfavorable outcomes (sequelae or fatal). A history of the vaccination was not correlated with the early sequelae and fatal outcome of the disease. The paper suggests that early diagnosis and treatment and universal JE vaccination for all susceptible populations are keys for decreasing incidence of sequelae and fatal outcome of acute JE.


Arthroscopic resection of the radial head.
The authors describe arthroscopic radial head resection in patients with post-traumatic arthritis after fractures of the radial head or in patients with rheumatoid arthritis of the elbow joint, as an expanded indication for elbow arthroscopy. Arthroscopic radial head resection allows the surgeon to deal with the intrinsic joint pathology, as well as with accompanying symptoms such as synovitis, capsular contracture, or loose bodies. The portals used are the proximal medial, anterolateral, and the midlateral portal. The anterior three quarters of the radial head and 2 to 3 mm of the radial neck are resected with the stone-cutting abrader in the anterolateral portal and the arthroscope in the proximal medial portal. For resection of the posterior portion of the radial head, the abrader may be transferred to the midlateral portal. This permits resection of the remnants of the radial head posteriorly and also at the proximal radioulnar joint. Arthroscopic treatment allows the patient to begin and maintain an aggressive postoperative physical therapy program immediately after surgery, thus decreasing the risk of anterior scarring and reoccurring contracture of the capsule of the elbow joint.


Thoracoscopic Trans-mitral Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy in the Elderly.
The thoracoscopic trans-mitral approach can not only facilitate exposure of the ventricular septum, mitral valve, and subvalvular apparatus, it also enables the surgeons to perform concomitant mitral valve intervention. This study aimed to determine the safety and efficacy of thoracoscopic trans-mitral septal myectomy in elderly patients with hypertrophic obstructive cardiomyopathy (HOCM). We reviewed the demographic to clinical characteristics and outcomes of patients who underwent thoracoscopic trans-mitral septal myectomy in our center between April 2019 and April 2021. The population was divided into a younger group (<60 years) and an elderly group (≥60 years). There were 46 and 20 patients in the younger and elderly groups, respectively. The majority of patients in the elderly group were female (39.1 vs. 80.0%, P < 0.01). Patients in the elderly group were more likely to be in New York Heart Association Class IV (2.2 vs. 80.0%, P < 0.01). The European System for Cardiac Operation Risk Evaluation II predicted mortality rates were significantly higher (3.97 ± 1.81 vs. 1.62 ± 0.86%, P < 0.01) in the elderly group. In the elderly group, a patient converted to median sternotomy due to left ventricular posterior free wall rupture following septal myectomy and mitral bioprosthetic valve replacement. The patient then underwent double-patch sandwich repair for rupture and mitral mechanical valve replacement and was eventually discharged. All patients in the elderly group were discharged, while one in the younger group died. No patient in the elderly group required permanent pacemaker implantation vs. one in the younger group. Patients in the elderly group were more likely to spend more time in the intensive care unit than those in the younger group (5.44 ± 5.80 days vs. 3.07 ± 2.72, P < 0.05). However, there was no significant intergroup difference in in-hospital mortality or complications. Importantly, the left ventricular outflow tract pressure gradient was significantly decreased from 96.15 ± 32.89 mmHg to 8.2 ± 3.42 mmHg with no residual obstruction in the elderly group. The interventricular septal thickness was significantly decreased from 19.73 ± 3.14 mm to 11.30 ± 2.23 mm. Postoperative mitral regurgitation severity was significantly improved in the elderly group. This study demonstrated that thoracoscopic trans-mitral septal myectomy is a feasible option for selected elderly patients with satisfactory outcomes similar to those of young patients.


Thyrotoxicosis presenting as acute bulbar palsy.
Myopathy chiefly affecting the proximal muscles of the limbs is frequently seen in hyperthyroidism. But isolated acute bulbar palsy without skeletal muscle involvement is rare in thyrotoxicosis. We report the case of a 52 year old man who presented with severe dysphagia, dysphonia and bouts of aspiration. Laboratory testing revealed an underlying Graves' thyrotoxicosis. His symptoms recovered dramatically within 6 weeks with treatment of hyperthyroidism. This case is reported to emphasize that thyrotoxicosis should be considered in the differential diagnosis of dysphagia of obscure etiology.


Microbial oxidation of anabolic steroids.
Microbial transformation of two anabolic steroids, ethylestrenol (1) and nandrolone (2), were carried out. Ethylestrenol (1), when incubated with Rhizopus stolonifer (TSY 0471), yielded two oxidative metabolites named 17alpha-ethyl-3beta,17beta-dihydroxy-19-norndrost-4-ene (3) and 17alpha-ethyl-17beta-hydroxy-19-norandrost-4-en-3-one (4), while incubation of compound 2 with the same fungus yielded two oxidative metabolites, 19-norandrost-4-en-3,17-dione (5) and 6alpha,17beta-dihydroxy-19-norandrost-1,4-dien-3-one (6).


A Case of Anti-Glomerular Basement Membrane Glomerulonephritis Complicated by Type 1 Diabetes Mellitus, Mimicking Urinary Tract Infection.
BACKGROUND Type 1 diabetes mellitus (DM) tends to complicate other autoimmune diseases. When considering renal dysfunction in patients with DM, diabetic nephropathy is a likely diagnosis. By contrast, anti-glomerular basement membrane (GBM) glomerulonephritis, an autoimmune disease, is one cause of rapidly progressive glomerulonephritis. CASE REPORT We report the case of a 44-year-old woman diagnosed with anti-glomerular basement membrane (GBM) glomerulonephritis. The diagnosis was made on the basis of serological test results and pathological findings of a renal biopsy. Five years before admission, she was diagnosed with type 1 DM. At admission, she presented with a fever, chills, nausea, low back pain, and malaise, which were followed by progressive renal dysfunction. The initial presentation mimicked a urinary tract infection, which delayed the correct diagnosis. CONCLUSIONS Our patient's course strongly suggests that rapidly progressive glomerulonephritis should be considered as an early differential diagnosis in cases of progressive renal dysfunction, especially when accompanied by fever, regardless of the underlying disease.


Aerobic fitness determines whole-body fat oxidation rate during exercise in the heat.
The purpose of this study was to determine whole-body fat oxidation in endurance-trained (TR) and untrained (UNTR) subjects exercising at different intensities in the heat. On 3 occasions, 10 TR cyclists and 10 UNTR healthy subjects (peak oxygen uptake = 60 ± 6 vs. 44 ± 3 mL·kg-1·min-1; p < 0.05) exercised at 40%, 60%, and 80% peak oxygen uptake in a hot, dry environment (36 °C; 25% relative humidity). To complete the same amount of work in all 3 trials, exercise duration varied (107 ± 4, 63 ± 1, and 45 ± 0 min for 40%, 60%, and 80% peak oxygen uptake, respectively). Substrate oxidation was calculated using indirect calorimetry. Blood samples were collected at the end of exercise to determine plasma epinephrine ([EPI]plasma) and norepinephrine ([NEPI]plasma) concentrations. The maximal rate of fat oxidation was achieved at 60% peak oxygen uptake for the TR group (0.41 ± 0.01 g·min-1) and at 40% peak oxygen uptake for the UNTR group (0.28 ± 0.01 g·min-1). TR subjects oxidized absolutely (g·min-1) and relatively (% of total energy expenditure) more fat than UNTR subjects at 60% and 80% peak oxygen uptake (p < 0.05). At these exercise intensities, TR subjects also had higher [NEPI]plasma concentrations than UNTR subjects (p < 0.05). In the heat, whole-body peak fat oxidation occurs at higher relative exercise intensities in TR than in UNTR subjects (60% vs. 40% peak oxygen uptake). Moreover, TR subjects oxidize more fat than UNTR subjects when exercising at moderate to high intensities (>60% peak oxygen uptake).


Measuring and analysing social efficiency in the production of maternal health services in Mexico, 2008-15.
'Social efficiency' (SE) denotes the capacity of health systems to ensure equitable access to quality health services at no financial risk to users. Mexico and other low- and middle-income countries have rarely studied the performance of their health systems from an SE perspective. We propose a metric for assessing SE in the production of maternal health services in the public sector among populations without social security, analysing contextual correlates of the demand for these services. Analysis was based on administrative data collected from the 243 health jurisdictions (HJs) in Mexico for the period 2008-15. We defined production inputs as the availability of physical and human resources and social product as the unweighted sum of social sub-products, including an equitable distribution of maternal health resources, the provision of quality maternal health care and financial protection for users. We described the SE scores, the main contextual characteristics as well as those related to the demand for maternal health services. We then performed a variance decomposition analysis of the SE score by component and estimated the SE territorial concentration patterns. Finally, we identified the structural characteristics modelling SE by means of a spatial autoregressive panel data model with fixed effects by year. The SE score rose from 57.7% in 2008 to 71.9% in 2015 (P < 0.01), with its quality component accounting for the largest proportion of variance (30%). SE peaked in HJs with low social marginalization and rurality, and with service demand characterized by low parity and older populations. Different SE levels demonstrated territorial concentration patterns. Analysing SE as a metric for health system performance offers elements that contribute to the achievement of UHC as well as to the design and implementation of effective maternal health interventions intended particularly for the most socially vulnerable sectors of the population.


The human allergens of mesquite (Prosopis juliflora).
BACKGROUND: A computerized statistical analysis of allergy skin test results correlating patient reactivities initiated our interest in the cross-reactive allergens of mesquite tree pollen. In-vitro testing with mesquite-sensitized rabbits and a variety of deciduous tree pollens revealed so many cross-reactivities that it became apparent there could be more allergens in mesquite than previously described in the world literature. Our purpose was to examine the allergens of mesquite tree pollen (Prosopis juliflora) which elicit an IgE response in allergic humans so that future research could determine if these human allergens cross-react with various tree pollens in the same manner as did the mesquite antiserum from sensitized rabbits. METHODS: Proteins from commercial mesquite tree pollen were separated by polyacrylamide gel electrophoresis in the presence of sodium-dodecyl-sulphate. These mesquite proteins were subjected to Western blotting using pooled sera from ten mesquite-sensitive patients and goat anti-human IgE. The allergens were detected using an Amplified Opti-4-CN kit, scanned, and then interpreted by Gel-Pro software. RESULTS: Thirteen human allergens of mesquite pollen were detected in this study. CONCLUSION: The number of allergens in this study of mesquite exceeded the number identified previously in the literature. With the increased exposure to mesquite through its use in "greening the desert", increased travel to desert areas and exposure to mesquite in cooking smoke, the possible clinical significance of these allergens and their suggested cross-reactivity with other tree pollens merit further study.


Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.
Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3-oxidoreductase, EC 22.214.171.124) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation. Definition of the primary structure of MCAD and the tissue distribution of its mRNA is of biochemical and clinical importance because of the recent recognition of inherited MCAD deficiency in humans. The MCAD mRNA nucleotide sequence was determined from two overlapping cDNA clones isolated from human liver and placental cDNA libraries, respectively. The MCAD mRNA includes a 1263-base-pair coding region and a 738-base-pair 3'-nontranslated region. A partial amino acid sequence (137 residues) determined on peptides derived from MCAD purified from porcine liver confirmed the identity of the cDNA clone. Comparison of the amino acid sequence predicted from the human MCAD cDNA with the partial protein sequence of the porcine MCAD revealed a high degree (88%) of interspecies sequence identity. RNA blot analysis shows that MCAD mRNA is expressed in a variety of rat (2.2 kilobases) and human (2.4 kilobases) tissues. Blot hybridization of RNA prepared from cultured skin fibroblasts from a patient with MCAD deficiency disclosed that mRNA was present and of similar size to MCAD mRNA derived from control fibroblasts. The isolation and characterization of MCAD cDNA is an important step in the definition of the defect underlying MCAD deficiency and in understanding its metabolic consequences.


Acute thrombosed external hemorrhoids.
From 1981 to 1985, 159 patients with acute thrombosed external hemorrhoids were treated by the author. This condition is relatively common in young persons; the mean age of the 159 patients in the series was 36 years. The condition was often preceded by a bout of constipation. The incidence was higher in male than in female patients, the ratio being 2:1. These hemorrhoids were slightly more prevalent on the left side (51%), whereas ordinary internal hemorrhoids tend to develop more on the right side (61%). I have postulated that the stagnation of blood and trauma to the anal vessels due to strain is the common denominator in the development of thrombosis. Therefore a rational approach to the condition is to eliminate stasis, trauma, and excess strain. Since the excess strain during defecation is usually caused by constipation, softening the stool is the key to preventing excessive strain. The condition is usually self-limiting and subsides in a few days to a week. If the condition fails to respond to conservative treatment, complete surgical excision of the thrombus is necessary.


[Relationship of mitral valve area to hemostatic condition in rheumatic mitral stenosis].
The influence of mitral valve area (MVA) on hemostatic conditions was assessed in patients with rheumatic mitral stenosis (MS) without atrial thrombus who underwent percutaneous mitral valvuloplasty (PMV). The Doppler-derived MVA and hemostatic variables were obtained before and 2-3 months after PMV. Hemostatic tests included measurements of beta-thromboglobulin and platelet factor 4 levels as indexes of platelet activation, fibrinopeptide A and thrombin-antithrombin complex as markers of fibrin generation, and D-dimer and plasmin-alpha 2-plasmin inhibitor complex as indexes of active fibrinolysis. Thirty-three measurements in 17 MS patients were subdivided into three groups: group A, 16 samples when MVA was < 1.5 cm2, group B, 12 samples obtained when MVA was 1.5 - < 2.0 cm2, and group C, 5 samples obtained when MVA was > or = 2.0 cm2. The mean level of beta-thromboglobulin was significantly lower in group C (43.6 +/- 32.4 ng/ml) than in group A (142.5 +/- 132.5 ng/ml) or B (163.8 +/- 179.8 ng/ml) (p < 0.05). The incidence of abnormal beta-thromboglobulin was also significantly lower in group C (20%) than in group A (67%) or B (73%) (p < 0.05). Other mean values or incidence of abnormal values of other hemostatic parameters did not differ between the groups. The hemostatic change induced by PMV was examined in 15 MS patients with no change in cardiac rhythm after PMV therapy. The patients were divided into suboptimal (MVA widening < 0.5 cm2, n = 7) and optimal (> or = 0.5 cm2, n = 8) groups. No favorable hemostatic changes were achieved by PMV in the suboptimal group.(ABSTRACT TRUNCATED AT 250 WORDS)


Surrogate target cells expressing surface anti-idiotype antibody for the clinical evaluation of an internalizing CD22-specific antibody.
SM03, a chimeric antibody that targets the B-cell restricted antigen CD22, is currently being clinically evaluated for the treatment of lymphomas and other autoimmune diseases in China. SM03 binding to surface CD22 leads to rapid internalization, making the development of an appropriate cell-based bioassay for monitoring changes in SM03 bioactivities during production, purification, storage, and clinical trials difficult. We report herein the development of an anti-idiotype antibody against SM03. Apart from its being used as a surrogate antigen for monitoring SM03 binding affinities, the anti-idiotype antibody was engineered to express as fusion proteins on cell surfaces in a non-internalizing manner, and the engineered cells were used as novel "surrogate target cells" for SM03. SM03-induced complement-mediated cytotoxicity (CMC) against these "surrogate target cells" proved to be an effective bioassay for monitoring changes in Fc functions, including those resulting from minor structural modifications borne within the Fc-appended carbohydrates. The approach can be generally applied for antibodies that target rapidly internalizing or non-surface bound antigens. The combined use of the anti-idiotype antibody and the surrogate target cells could help evaluate clinical parameters associated with safety and efficacies, and possibly the mechanisms of action of SM03.


Promoting social inclusion through Unified Sports for youth with intellectual disabilities: a five-nation study.
Although the promotion of social inclusion through sports has received increased attention with other disadvantaged groups, this is not the case for children and adults with intellectual disability who experience marked social isolation. The study evaluated the outcomes from one sports programme with particular reference to the processes that were perceived to enhance social inclusion. The Youth Unified Sports programme of Special Olympics combines players with intellectual disabilities (called athletes) and those without intellectual disabilities (called partners) of similar skill level in the same sports teams for training and competition. Alongside the development of sporting skills, the programme offers athletes a platform to socialise with peers and to take part in the life of their community. Unified football and basketball teams from five countries--Germany, Hungary, Poland, Serbia and Ukraine--participated. Individual and group interviews were held with athletes, partners, coaches, parents and community leaders: totalling around 40 informants per country. Qualitative data analysis identified four thematic processes that were perceived by informants across all countries and the two sports to facilitate social inclusion of athletes. These were: (1) the personal development of athletes and partners; (2) the creation of inclusive and equal bonds; (3) the promotion of positive perceptions of athletes; and (4) building alliances within local communities. Unified Sports does provide a vehicle for promoting the social inclusion of people with intellectual disabilities that is theoretically credible in terms of social capital scholarship and which contains lessons for advancing social inclusion in other contexts. Nonetheless, certain limitations are identified that require further consideration to enhance athletes' social inclusion in the wider community.


Studies towards the development of a PET radiotracer for imaging of the P2Y1 receptors in the brain: synthesis, 18F-labeling and preliminary biological evaluation.
Purine nucleotides such as ATP and ADP are important extracellular signaling molecules in almost all tissues activating various subtypes of purinoreceptors. In the brain, the P2Y1 receptor (P2Y1R) subtype mediates trophic functions like differentiation and proliferation, and modulates fast synaptic transmission, both suggested to be affected in diseases of the central nervous system. Research on P2Y1R is limited because suitable brain-penetrating P2Y1R-selective tracers are not yet available. Here, we describe the first efforts to develop an 18F-labeled PET tracer based on the structure of the highly affine and selective, non-nucleotidic P2Y1R allosteric modulator 1-(2-[2-(tert-butyl)phenoxy]pyridin-3-yl)-3-[4-(trifluoromethoxy)phenyl]urea (7). A small series of fluorinated compounds was developed by systematic modification of the p-(trifluoromethoxy)phenyl, the urea and the 2-pyridyl subunits of the lead compound 7. Additionally, the p-(trifluoromethoxy)phenyl subunit was substituted by carborane, a boron-rich cluster with potential applicability in boron neutron capture therapy (BNCT). By functional assays, the new fluorinated derivative 1-{2-[2-(tert-butyl)phenoxy]pyridin-3-yl}-3-[4-(2-fluoroethyl)phenyl]urea (18) was identified with a high P2Y1R antagonistic potency (IC50 = 10 nM). Compound [18F]18 was radiosynthesized by using tetra-n-butyl ammonium [18F]fluoride with high radiochemical purity, radiochemical yield and molar activities. Investigation of brain homogenates using hydrophilic interaction chromatography (HILIC) revealed [18F]fluoride as major radiometabolite. Although [18F]18 showed fast in vivo metabolization, the high potency and unique allosteric binding mode makes this class of compounds interesting for further optimizations and investigation of the theranostic potential as PET tracer and BNCT agent.


Endogenous neurogenesis and neovascularization in the neocortex of the rat after focal cerebral ischemia.
The present study was designed to examine whether endogenous neurogenesis and neovascularization occur in the neocortex of the ischemic rat brain after unilateral middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into six groups (n = 29): one control group (n = 4) and five groups composed of animals sacrificed at increasing times post-MCAO (2 days and 1, 2, 4, and 8 weeks; n = 5 per group). To determine the presence of neurogenesis and neovascularization in the ischemic brain, nestin, Tuj1, NeuN, GFAP, Tie2, RECA, and 5-bromo-2'-deoxyuridine (BrdU) were analyzed immunohistochemically. In addition, nestin, GFAP, and Tie2 expression was determined by Western blotting. Triple-labeling of nestin, BrdU, and laminin was performed to visualize the interaction between endogenous neurogenesis and neovascularization. The number of BrdU- and nestin-colabeled cells increased markedly in the neocortex and border zone of the ischemic area up to 1 week after MCAO and decreased thereafter. Western blot analysis revealed that the expression of nestin, Tie-2, and GFAP was amplified in the ipsilateral hemisphere 2 days after MCAO and peaked 1 week after MCAO, compared with that in the normal brain. After ischemic injury, nestin- and BrdU-colabeled cells were observed in the vicinity of the endothelial cells lining cerebral vessels in the ipsilateral neocortex of the ischemic brain. Endogenous neurogenesis and neovascularization were substantially activated and occurred in close proximity to one other in the ipsilateral neocortex of the ischemic rat brain.


IL-2, a lectin with specificity for high mannose glycopeptides.
Utilizing a solid phase binding assay, we have demonstrated that rIL-2 binds with high affinity to the human urinary glycoprotein uromodulin. This binding is specifically inhibited by the saccharides diacetylchitobiose and Man(alpha 1-3)(Man(alpha 1-6]Man-O-methyl and by the high mannose glycopeptides Man5GlcNAc2-R and Man6GlcNAc2-R, but not by Man9GlcNAc2-R. rIL-2 also binds OVA, a glycoprotein which contains approximately 50% high mannose chains at a single glycosylation site, and to yeast mannan. This binding is inhibited by the same battery of saccharides which inhibit the binding to uromodulin. The conclusion that rIL-2 is a lectin is further supported by the observation that the sequence of IL-2 shares 27% homology with a 33-residue sequence of the carbohydrate-binding domain of human mannose-binding protein. The potential physiologic relevance of the carbohydrate binding activity is further elucidated by studies which show that 1) binding of soluble rIL-2 to immobilized uromodulin is enhanced at a pH of 4 to5 in the presence of divalent cations, and 2) neither uromodulin nor the high mannose glycopeptide Man5GlcNAc2Asn blocks the binding of rIL-2 to the IL-2R. Thus the carbohydrate-binding site of rIL-2 is distinct from the cell surface receptor-binding site, and might function preferentially in acidic microenvironments.


Action for better brain health among people living with HIV: protocol for a randomized controlled trial.
Lifestyle changes can protect or improve brain health in older adults. However, sustained lifestyle change is difficult for everyone and may be more difficult for those with executive dysfunction, including some people living with HIV. Thus, the key question is how we can improve adherence to the most promising interventions among people living with HIV experiencing cognitive difficulties. Goal management training is a cognitive rehabilitation program that targets executive dysfunction by teaching goal-directed behaviour and self-management. It is a promising means to improve adherence to lifestyle interventions. To estimate the extent to which goal management training before a healthy lifestyle program is associated with greater adherence to health recommendations, achievement of health-related goals, and better brain health and health outcomes compared to the healthy lifestyle program alone among people living with HIV. Brain Health Now cohort participants with cognitive difficulties or are not aging successfully are eligible. All participants will be given health resources, a health coach, a goal-setting digital application, and access to an online goal-setting workshop. The intervention group will participate in nine 2-h goal management training sessions and then will enter the healthy lifestyle program. Control participants will enter the healthy lifestyle program directly. A total sample of 100 participants will participate for 12 months. The main outcome is adherence to the healthy lifestyle program, defined as the number of weeks where physical activity adherence targets were met (150 min per week, measured with an activity monitor). Weekly social activities will be captured via self-report with confidential photo validation. We will send weekly health state reports to the participants. Downstream outcomes include cognitive ability, health-related quality of life, mobility, vascular risk profile, and social network size. We will analyze the data using a linear regression model. This project is the first to test whether goal management training can augment adherence to health recommendations among individuals with cognitive difficulties. If successful, behavioural interventions such as goal management training could be implemented as an adjunct to lifestyle interventions in other clinical populations. This trial was registered on clinicaltrials.gov (NCT04345484) on April 14, 2020, https://clinicaltrials.gov/ct2/show/NCT04345484?term=NCT04345484&draw=2&rank=1 .


[Progress of international and national researches on disease burden of echinococcosis].
As a neglected tropical disease defined by the World Health Organization (WHO), echinococcosis causes a huge public health burden. Understanding the disease burden due to echinococcosis facilitates the progress towards elimination of the disease. This review analyzes the advances in disease and economic burdens of echinococcosis, describes the status quo disease burden due to echinococcosis in different areas of the world, compares the difference between international and national studies on disease and economic burdens of echinococcosis, and discusses the shortcomings of the current international and national studies on disease burden of echinococcosis. Currently, the studies on disease burden of echinococcosis suffer from problems of few field survey data and lack of authoritative disability weights for echinococcosis, while the studies on economic burden of echinococcosis suffer from problems of lack of comprehensive study populations and indicators.


[Cystic polyposis of the stomach (fundic gland polyps)--relationship to the absence of Helicobacter pylori infection and a therapy with drugs suppressing gastric acidity].
Cystic gastric polyps (fundic gland polyps) have been diagnosed relatively frequently in recent years. The aim of the study was to assess their incidence and relation to possible etiological factors reported in the literature. Over a 5 year period, we have endoscopically and histologically proved cystic polyps in 32 patients. All were examined for Helicobacter pylori infection using either the invasive rapid test, histological examination or 13C urea breath test. Cystic gastric polyps were found significantly more frequently in women (27) than in men (5). All patients were treated with long-term medication suppressing gastric acidity (26 patients with proton pump inhibitors, and 6 with H2 receptor blockers). Helicobacter pylori infection was not detected in either of the patients with proven cystic gastric polyps. Cystic gastric polyps have not the typical clinical picture and they are largely found incidentally during gastroscopic examination, especially in patients with reflux esophagitis or functional dyspepsia. The results confirm evidence in the literature of a close relation between cystic gastric polyps and intensive suppressive treatment of gastric acidity, particularly in combination with the current absence of Helicobacter pylori infection. Precise explanation of this relation and the etiology of cystic gastric polyps is still missing. Important is the fact that the literature reports do not indicate a risk of malignant transformation.


GPER1 Signaling Initiates Migration of Female V-SVZ-Derived Cells.
In the rodent ventricular-subventricular zone (V-SVZ) neurons are generated throughout life. They migrate along the rostral migratory stream (RMS) into the olfactory bulb before their final differentiation into interneurons and integration into local circuits. Estrogen receptors (ERs) are steroid hormone receptors with important functions in neurogenesis and synaptic plasticity. In this study, we show that the ER GPER1 is expressed in subsets of cells within the V-SVZ of female animals and provide evidence for a potential local estrogen source from aromatase-positive astrocytes surrounding the RMS. Blocking of GPER1 in Matrigel cultures of female animals significantly impairs migration of V-SVZ-derived cells. This outgrowth is accompanied by regulation of phosphorylation of the actin-binding protein cofilin by GPER1 signaling including an involvement of the p21-Ras pathway. Our results point to a prominent role of GPER1 in the initiation of neuronal migration from the V-SVZ to the olfactory bulb.


In-situ tool wear monitoring and its effects on the performance of porcine cortical bone drilling: a comparative in-vitro investigation.
Drilling is one of the most widely used process in orthopaedic surgical operation and the same drill bit is used a number of times in hospitals. Using the same drill bit a several times may be the cause of osteosynthesis and osteonecrosis. In the present work, the effect of repeated orthopaedic surgical twist drill bit on the tool wear, force, torque, temperature and chip morphology during porcine cortical bone drilling is studied. Results were compared with rotary ultrasonic drilling (RUD) on the same bone using a hollow drill tool coated with diamond grains. A sequence of 200 experiments (100 with each process, RUD and CD) were performed with constant process parameters. Wear area on the drill bit is significantly increased as the drill bit is used repeatedly in CD, whereas no attritious wear was found on the diamond coated grains in RUD. Comparative results showed that cutting force, torque and temperature increased as a function of tool wear in CD as the same drill bit was used a number of times. No significant variation in the cutting force and torque was observed in RUD as the number of drilled holes increased.


Prevalence and Perceptions of Musculoskeletal Disorders Among Hospital Nurses in Pakistan: A Cross-sectional Survey.
Nursing is a professionally demanding job, and nurses are prone to develop musculoskeletal disorders. However, no data is available regarding its prevalence among Pakistani nurses. This study was conducted to document the pattern of work-related musculoskeletal disorders (WRMDs) in Pakistani nurses and their perceptions about contributing factors and management of WRMDs. A questionnaire-based, cross-sectional survey was conducted in six hospitals in Lahore and Rawalpindi, which were selected using a convenient sampling technique. A four-part questionnaire comprised of demographic data, experience of musculoskeletal disorders, and perception of management and contributing factors of WRMDs was distributed among 150 nurses. One hundred and seventeen nurses returned completed forms. Data was analyzed using SPSS Statistics v20 (IBM, Armonk, New York, USA). Ethics review committee approval was obtained by CMH Lahore Medical College and the Institute of Dentistry, and informed consent was obtained. The prevalence of musculoskeletal disorders over a 12-month period was 31.6%, with the most common site being the low back (32%) followed by the shoulder (20%), upper back, and knees (10%). Among those affected, 60.6% sought professional help. Married nurses were more prone to WRMDs (p=0.0001). Regarding management, most (94%) agreed that rest is required to get better, neglecting problems of this kind can cause permanent health problems (89.7%), and physical activity should be avoided (38.7%). Working in the same positions for long periods (93.1%), attending an excessive number of patients in one day (81.2%), and working in awkward and cramped positions (78.6%) were the most commonly perceived risk factors for WRMDs. About one-third of Pakistani nurses in this cohort reported work-related musculoskeletal disorders with the low back most commonly affected. There is a need to increase awareness regarding ergonomics and posture maintenance to reduce WRMDs and improve patient care. This can be achieved by workshops and seminars on ergonomics and WRMDS.


Jaundice and Elevated Beta-Human Chorionic Gonadotropin in a Female: Duodenal Choriocarcinoma, Not Pregnancy.
A 29-year-old woman with developmental delay presented with 2.5 weeks of jaundice of the skin with accompanying microcytic anemia (hemoglobin 6.8 g/dL, mean corpuscular volume 70.5 fL), elevated liver enzymes (aspartate aminotransferase 77 U/L, alanine aminotransferase 95 U/L, alkaline phosphatase 362 U/L), total bilirubin (9.5 mg/dL; 4.4 mg/dL direct), lipase (325 U/L), and cancer antigen 19-9 (68 U/mL). The patient had no prior gastrointestinal or liver disease. CT of the chest/abdomen/pelvis found a large lobulated non-fully obstructing mass in the second and third part of the duodenum, with endoscopic biopsies yielding an invasive, well-differentiated adenocarcinoma positive for cytoplasmic-stained cells to antibody to beta-human chorionic gonadotropin (hCG) antigen, suggesting a duodenal choriocarcinoma. Treatment included biliary drainage with a percutaneous transhepatic catheter and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy, but a repeat CT scan five months later revealed an increase in tumor size and invasion; the patient died shortly thereafter. Beta-hCG-secreting choriocarcinomas are rare, rapidly growing, highly invasive malignant tumors and are uncommonly present at extragonadal sites.


Making a bridge between general hospital and specialised community-based treatment for alcohol use disorder-A pragmatic randomised controlled trial.
To investigate if more patients in the intervention group attended specialized alcohol treatment compared with a treatment-as-usual group (TAU). Pragmatic randomized controlled trial where consecutive patients, admitted to somatic hospitals, filled out a lifestyle questionnaire with the Alcohol Use Disorder Identification Test (AUDIT) embedded. Patients scoring 8+ on AUDIT were included in the study. Included patients were randomized to either a Danish screening brief intervention and referral to treatment (SBIRT) called the Relay model or TAU depending on date of admission. The Relay group was offered a brief alcohol intervention by an outreach alcohol therapist. Patients scoring 16 points and above on the AUDIT test also received referral to alcohol treatment. Outcome was attendance at specialized outpatient alcohol treatment centres after discharge from hospital. Information on patients was gathered from municipal databases at 18 months follow-up. A total of 3534 patients completed the questionnaire, and 609 patients (17%) scored AUDIT 8+. 48 patients were lost to follow-up, and the final sample had 561 patients. Only 33 patients (6%) attended outpatient treatment at 18-months follow-up, but significantly more patients in the Relay group sought alcohol treatment than in the TAU group (OR = 2.5 [1.2;5.2] (p = 0.017)). Number needed to treat (NNT) was 20 [95% CI 11.2;112.3]. The Relay intervention was associated with more patients attending specialized treatment, but further research is needed to establish if general hospitals are an excellent platform for performing SBIRT.


Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure etiology and correlates to clinical variables.
Downregulation of β(1)- adrenergic receptors (β(1)-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established. Another unresolved question is the incidence of these compensatory mechanisms depending on heart failure etiology and treatment. To analyze these questions, we quantified the mRNA/protein expressions of six ARs (α(1A), α(1B), α(1D), β(1), β(2), and β(3)) and three GRKs (GRK2, GRK3, and GRK5) in left (LV) and right ventricle (RV) from four donors, 10 patients with ischemic cardiomyopathy (IC), 14 patients with dilated cardiomyopathy (DC), and 10 patients with nonischemic, nondilated cardiopathies (NINDC). We correlated the changes in the expressions of ARs and GRKs with clinical variables such as left ventricular ejection fraction (LVEF) and left ventricular end-systolic and left ventricular end-diastolic diameter (LVESD and LVEDD, respectively). The main findings were 1) the expression of the α(1A)-AR in the LV positively correlates with LVEF; 2) the expression of GRK3 and GRK5 inversely correlates with LVESD and LVEDD, supporting previous observations about a protective role for both kinases in failing hearts; and 3) β(1)-AR expression is downregulated in the LV and RV of IC, in the LV of DC, and in the RV of NINDC. This difference, better than an increased expression of GRK2 (not observed in IC), determines the lower LVEF in IC and DC vs. NINDC.


Treatment outcomes, diagnostic and therapeutic impact: Xpert vs. smear. A systematic review and meta-analysis.
Compared with smear microscopy, Xpert® MTB/RIF has the potential to reduce delays in tuberculosis (TB) diagnosis and treatment initiation, and improve treatment outcomes. We reviewed publications comparing treatment outcomes of drug-susceptible TB patients diagnosed using Xpert vs. smear. Citations (2000-2016) reporting treatment outcomes of patients diagnosed using Xpert compared with smear were selected from PubMed, Scopus and conference abstracts. We conducted a systematic review and meta-analysis. Favorable (cured, completed) and unfavorable (failure, death, loss to follow-up) outcomes were pooled for meta-analysis; we also reviewed the number of TB cases diagnosed, time to treatment and empiric treatment. The Mantel-Haenszel method with a fixed-effect model was used; I² was calculated to measure heterogeneity. From 13 citations, 43 594 TB patients were included and 4825 were with known TB treatment outcome. From the pooled analysis, an unfavorable outcomes among those diagnosed using Xpert compared with smear was 20.2%, 541/2675 vs. 21.9%, 470/2150 (risk ratio 0.92, 95%CI 0.82-1.02). Statistical heterogeneity was low (I² = 0.0%, P = 0.910). Compared with smear, Xpert was reported to be superior in increasing the number of TB patients diagnosed (2/9 citations), increasing bacteriologically confirmed TB (7/9 citations), reducing empiric treatment (3/5 citations), reducing time to diagnosis (2/3 citations), and reducing time to treatment initiation (1/5 citations). Xpert implementation showed no discernible impact on treatment outcomes compared with conventional smear despite reduced time to diagnosis, time to treatment or reduced level of empiric treatment. Further research is required to learn more about gaps in the existing health system.


Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.
Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.


Chronic illness behavior and noncompliance with treatment: pathways to an interactional approach.
The increasing cost of medical overconsumption is partially due to the physicians' neglect in everyday clinical practice of the intrinsic gratification of the sick role in our society. Many health care providers do not seem to realize that their intervention as experts in the patient's personal life inevitably implies they are becoming part of the ongoing learning history of that individual. Chronic somatic complaining and partial or complete refusal to follow therapeutic advice have to be viewed, first and foremost, as a symptom of a dysfunctional interaction between the patient and his/her immediate environment of which the clinician became a significant member. Management of chronic illness behavior and non-compliance with treatment requires both a functional analysis and a strategy inspired by an interactional perspective on the attitudes and behaviors of at least three parties involved in health care: doctor, patient, and family.


The glucagon-like peptide-1 analogue liraglutide promotes autophagy through the modulation of 5'-AMP-activated protein kinase in INS-1 β-cells under high glucose conditions.
Glucagon-like peptide-1 (GLP-1) is a potent therapeutic agent for the treatment of diabetes and has been proven to protect pancreatic β-cells from glucotoxicity; however, its mechanisms of action are not entirely understood. Autophagy is a dynamic lysosomal degradation process that can protect organisms against metabolic stress. Studies have shown that autophagy plays a protective role in the survival of pancreatic β-cells under high glucose conditions. In the present study, we explored the role of autophagy in GLP-1-induced protection of pancreatic β-cells exposed to high glucose. We demonstrated that the GLP-1 analogue liraglutide increased autophagy in rat INS-1 β-cells, and inhibition of autophagy abated the anti-apoptosis effect of liraglutide under high glucose conditions. Our results also showed that activation of 5'-AMP-activated protein kinase (AMPK) reduced liraglutide-induced autophagy enhancement and inhibited liraglutide-induced protection of INS-1 β-cells from high glucose. These data suggest that GLP-1 may protect β-cells from glucotoxicity through promoting autophagy by the modulation of AMPK. Deeper insight into the molecular mechanisms linking autophagy and GLP-1-induced β-cell protection may reveal novel therapeutic targets to preserve β-cell mass.


Microbial growth on C1 compounds. Uptake of [14C]formaldehyde and [14C]formate by methane-grown Pseudomonas methanica and determination of the hexose labelling pattern after brief incubation with [14C]methanol.
1. A study has been made of the incorporation of carbon from [(14)C]formaldehyde and [(14)C]formate by cultures of Pseudomonas methanica growing on methane. 2. The distribution of radioactivity within the non-volatile constituents of the ethanol-soluble fractions of the cells, after incubation with labelled compounds for periods of up to 1min., has been analysed by chromatography and radioautography. 3. Radioactivity was fixed from [(14)C]formaldehyde mainly into the phosphates of the sugars, glucose, fructose, sedoheptulose and allulose. 4. Very little radioactivity was fixed from [(14)C]formate; after 1min. the only products identified were serine and malate. 5. The distribution of radioactivity within the carbon skeleton of glucose, obtained from short-term incubations with [(14)C]methanol of Pseudomonas methanica growing on methane, has been investigated. At the earliest time of sampling over 70% of the radioactivity was located in C-1; as the time increased the radioactivity spread throughout the molecule. 6. The results have been interpreted in terms of a variant of the pentose phosphate cycle, involving the condensation of formaldehyde with C-1 of ribose 5-phosphate to give allulose phosphate.


Intratumoral cisplatin/epinephrine-injectable gel as a palliative treatment for accessible solid tumors: a multicenter pilot study.
Intratumoral injections of cisplatin/epinephrine-injectable gel were administered weekly for 4 weeks in 45 patients with malignant tumors of various histologic types. Tumors were located on the skin and subcutaneous tissue primarily of the head, neck, and trunk, and on the tongue, oral pharynx, and esophagus. Patients were not candidates for surgery, radiation, or systemic chemotherapy. Each of the treated tumors (n = 82) was evaluated 2, 4, 8, and 12 weeks after the final injection. The initial dose of cisplatin was 1 mg/cm3 tumor volume, with escalation to 6 mg/cm3 allowed, depending on observed toxicities. The mean cumulative dose per patient for the four treatments ranged from 0.56 to 380 mg cisplatin. No dose-limiting cisplatin-related toxicities, such as nephrotoxicity, neurotoxicity, or ototoxicity, were observed. The overall objective tumor response rate was 50% (41 of 82), with 40% (33 of 82) complete responses and a median response duration of 160 days. Complete responses for adenocarcinoma and squamous cell carcinoma were 58% (21 of 36) and 38% (12 of 32), respectively. These results justified further clinical trials to evaluate the role of local chemotherapy with intratumoral cisplatin/epinephrine-injectable gel in the palliative treatment of patients with selected accessible solid tumors.


Prediagnosis pathway benchmarking audit in patients with Duchenne muscular dystrophy.
To describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement. A multicentre retrospective national audit. Nine tertiary neuromuscular centres across the UK and Ireland. A prior single-centre UK audit of 20 patients with no DMD family history provided benchmark criteria. Patients with a definitive diagnosis of DMD documented within 3 years prior to December 2018 (n=122). Mean age (months) at four key stages in the DMD diagnostic pathway and mean time (months) of presentational and diagnostic delay, and time from first reported symptoms to definitive diagnosis. Type of symptoms was also recorded. Overall, mean age at definitive diagnosis, age at first engagement with healthcare professional (HCP) and age at first reported symptoms were 53.9±29.7, 49.9±28.9 and 36.4±26.8 months, respectively. The presentational delay and time to diagnosis were 21.1 (±21.1) and 4.6 (±7.9) months, respectively. The mean time from first reported symptoms to definitive diagnosis was 24.2±20.9. The percentages of patients with motor and/or non-motor symptoms recorded were 88% (n=106/121) and 47% (n=57/121), respectively. Majority of data mirrored the benchmark audit. However, while the time to diagnosis was shorter, a presentational delay was observed. Failure to recognise early symptoms of DMD could be a contributing factor and represents an unmet need in the diagnosis pathway. Methods determining how to improve this need to be explored.


Avoided crossings in three coupled oscillators as a model system of acoustic bubbles.
The resonance frequencies and oscillation phases of three acoustically coupled bubbles are examined to show that avoided crossings can appear in a multibubble system. Via a simple coupled oscillator model, we show that if at least three bubbles exist, it is possible for their resonance frequencies as functions of the separation distances between the bubbles to experience an avoided crossing. Furthermore, by focusing our attention on the oscillation phases and based on analysis of the transition frequencies [M. Ida, Phys. Lett. A 297, 210 (2002); J. Phys. Soc. Jpn. 71, 1214 (2002)] of the coupled bubbles, we show that a distinct state exchange takes place between the bubbles at a point in the avoided crossing region, where a resonance frequency of the triple-bubble system crosses with a transition frequency not corresponding to the resonance frequencies.


Primary cutaneous zygomycosis due to Saksenaea vasiformis and Apophysomyces elegans.
We report three cases of primary cutaneous zygomycosis due to either Saksenaea vasiformis (two patients) or Apophysomyces elegans (one patient). Extensive surgical debridement helped two patients recover from their infections. The underlying disease in the one patient who died was diabetes mellitus. We reviewed the literature on primary cutaneous zygomycosis and found that S. vasiformis and A. elegans were the etiologic agents in 16 and 13 earlier cases, respectively.


Carboxamido steroids inhibit the opening properties of transient receptor potential ion channels by lipid raft modulation.
Transient Receptor Potential (TRP) cation channels, like the TRP Vanilloid 1 (TRPV1) and TRP Ankyrin 1 (TRPA1), are expressed on primary sensory neurons. These thermosensor channels play a role in pain processing. We have provided evidence previously that lipid raft disruption influenced the TRP channel activation, and a carboxamido-steroid compound (C1) inhibited TRPV1 activation. Therefore, our aim was to investigate whether this compound exerts its effect through lipid raft disruption and the steroid backbone (C3) or whether altered position of the carboxamido group (C2) influences the inhibitory action by measuring Ca2+ transients on isolated neurons and calcium-uptake on receptor-expressing CHO cells. Membrane cholesterol content was measured by filipin staining and membrane polarization by fluorescence spectroscopy. Both the percentage of responsive cells and the magnitude of the intracellular Ca2+ enhancement evoked by the TRPV1 agonist capsaicin were significantly inhibited after C1 and C2 incubation, but not after C3 administration. C1 was able to reduce other TRP channel activation as well. The compounds induced cholesterol depletion in CHO cells, but only C1 induced changes in membrane polarization. The inhibitory action of the compounds on TRP channel activation develops by lipid raft disruption, and the presence and the position of the carboxamido group is essential.


A national survey of ethnic differences in knowledge and understanding of supplementary health insurance.
Knowledge and understanding of what health insurance covers is an important public health issue. In Israel, whereas national health insurance covers all residents, optional supplemental health insurance (SHI) can be purchased from the healthcare providers, for additional, special services. The purpose of this study was to identify disparities between Jews and Arabs in their knowledge and understanding of SHI. National, cross-sectional, telephone survey using a structured questionnaire, among random samples of 814 Jews and 800 Arabs. Knowledge and understanding of health insurance was assessed by a score based on correct answers to 8 questions. Log-linear regression was used to estimate association between health insurance knowledge and population group, after controlling for potential confounding independent variables. Ninety one percent of Jews and 62% of Arabs reported owning SHI. Among both groups, knowledge levels were low on a 0-8 scale. However, the average score for Jews was statistically higher (Mean = 3.50, S.D = 1.69) as compared with Arabs (Mean = 2.78, S.D = 1.70) (p < 0.001). The adjusted health insurance knowledge score was significantly higher among Jews than Arabs (Prevalence ratio = 1.10; 95% CI = 1.06-1.13), indicating that differences remain even after controlling for socio-demographic characteristics and SHI ownership. There is a large gap between the public's understanding of what is covered by SHI and the services that it covers in practice. Low SHI knowledge and understanding may lead to frustration, and limit access to additional health care among populations that suffer from socio-economic inequalities. These findings emphasize the need to provide clearer and more culturally sensitive information on health insurance coverage.


Conformational stability of B cell epitopes on group I and group II Dermatophagoides spp. allergens. Effect of thermal and chemical denaturation on the binding of murine IgG and human IgE antibodies.
The conformational stability of B cell epitopes on the 25-kDa group I and 14-kDa group II mite allergens was compared by using heat-treated or chemically denatured allergens to inhibit the binding of native 125I allergens to murine mAb or to human IgE antibodies. Structural changes after treatment were assessed by SDS-PAGE and circular dichroism spectroscopy. Heating for 1 h at greater than 75 degrees C, treatment at pH 2.0 or pH 12.0, or with 6M guanidine or 6M urea, reduced the binding of the group I allergens to mAb or IgE antibodies by 10- to 1000-fold. The group II allergens were heat stable and even after prolonged heat treatment (5 h at 75 degrees C or 30 min at 100 degrees C) their antibody binding activity was reduced by less than twofold. The group II allergens were also resistant to pH and to denaturation with 6M guanidine. However, after reduction and alkylation, antibody binding sites on both the group I and group II allergens were destroyed. Reduction of disulfide bonds with 2-ME caused a marked shift in the molecular mass of group I allergens on SDS-PAGE, from 25 kDa to 28-31 kDa. Reduction and alkylation also generated two high m.w. forms of Der p I and Der f I. After heating (100 degrees for 30 min), both Der f I and Der f II retained significant secondary structure, as judged by circular dichroism spectroscopy, but on reduction they showed the typical spectra of fully denatured proteins (greater than 85% random structure). The results show clear differences between the susceptibility of B cell epitopes on the group I and group II allergens to denaturation. Despite these differences in stability, both allergens are equally potent immunogens for IgE antibody responses in man. The results support the view that the physical properties of allergens (low m.w. and solubility), limiting low dose exposure (1 to 10 ng/day), and host genetic and immunoregulatory processes, are more important than gross structural features in the induction and maintenance of IgE antibody responses.


Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept.
Botulinum neurotoxins (BoNTs) cause muscle paralysis by selectively cleaving core components of the vesicular fusion machinery within motoneurons. Complex gangliosides initially bind into a pocket that is conserved among the seven BoNTs and tetanus neurotoxin. Productive neurotoxin uptake also requires protein receptors. The interaction site of the protein receptor within the neurotoxin is currently unknown. We report the identification and characterization of the protein receptor binding site of BoNT/B and BoNT/G. Their protein receptors, synaptotagmins I and II, bind to a pocket at the tip of their H(CC) (C-terminal domain of the C-terminal fragment of the heavy chain) that corresponds to the unique second carbohydrate binding site of tetanus neurotoxin, the sialic acid binding site. Substitution of amino acids in this region impaired binding to synaptotagmins and drastically decreased toxicity at mouse phrenic nerve preparations; CD-spectroscopic analyses evidenced that the secondary structure of the mutated neurotoxins was unaltered. Deactivation of the synaptotagmin binding site by single mutations led to virtually inactive BoNT/B and BoNT/G when assayed at phrenic nerve preparations of complex-ganglioside-deficient mice. Analogously, a BoNT B mutant with deactivated ganglioside and synaptotagmin binding sites lacked appreciable activity at wild-type mouse phrenic nerve preparations. Thus, these data exclude relevant contributions of any cell surface molecule other than one ganglioside and one protein receptor to the entry process of BoNTs, which substantiates the double-receptor concept. The molecular characterization of the synaptotagmin binding site provides the basis for designing a novel class of potent binding inhibitors.


Skeletal growth in experimental uremia.
Although in recent years experimental work on growth in uremia has clarified many issues, many key questions cannot be answered with available experimental data. In our own studies on subtotally nephrectomized rats, uremic animals consumed less food and grew less. However, although low energy intake diminishes growth, it has not been established that high protein energy intake will normalize growth. We showed that uremia reduced growth (and net protein synthesis) even under conditions of controlled food intake. In renal failure the optimal dietary protein level for growth or for efficiency of utilization has not been established, particularly since protein intake has an independent injurious effect on long-term renal function. Calcium and vitamin D supplements improved growth in uremic rats, but the data cannot easily be extrapolated to humans. The growth-promoting action of 1,25(OH)2D3 was not superior to that of equipotent doses of vitamin D3. Correction of anemia and physical exercise did not improve growth. Diminished stimulation of growth cartilage cyclic AMP with PTH and augmented stimulation with calcitonin was noted in uremic animals. Growth hormone in supraphysiological doses improved growth and raised IGF carrier protein in uremic animals. Spermine, a potential uremic toxin, inhibited growth cartilage 3H-thymidine incorporation, but only in concentrations higher than that encountered in uremia.


Digitally synthesized high purity, high-voltage radio frequency drive electronics for mass spectrometry.
Reported herein is development of a quadrupole mass spectrometer controller (MSC) with integrated radio frequency (rf) power supply and mass spectrometer drive electronics. Advances have been made in terms of the physical size and power consumption of the MSC, while simultaneously making improvements in frequency stability, total harmonic distortion, and spectral purity. The rf power supply portion of the MSC is based on a series-resonant LC tank, where the capacitive load is the mass spectrometer itself, and the inductor is a solenoid or toroid, with various core materials. The MSC drive electronics is based on a field programmable gate array (FPGA), with serial peripheral interface for analog-to-digital and digital-to-analog converter support, and RS232/RS422 communications interfaces. The MSC offers spectral quality comparable to, or exceeding, that of conventional rf power supplies used in commercially available mass spectrometers; and as well an inherent flexibility, via the FPGA implementation, for a variety of tasks that includes proportional-integral derivative closed-loop feedback and control of rf, rf amplitude, and mass spectrometer sensitivity. Also provided are dc offsets and resonant dipole excitation for mass selective accumulation in applications involving quadrupole ion traps; rf phase locking and phase shifting for external loading of a quadrupole ion trap; and multichannel scaling of acquired mass spectra. The functionality of the MSC is task specific, and is easily modified by simply loading FPGA registers or reprogramming FPGA firmware.


The benefits of post-surgical orthodontic treatment.
Orthodontic therapy is best carried out in a normal skeletal and soft tissue environment. In patients requiring orthognathic surgery, it is suggested that there are advantages in correcting the skeletal and soft tissue elements as early as possible, and to orthodontically control the occlusion post-operatively. This results in a shorter overall treatment time due to more biologically favourable tooth movement, more predictable occlusal results and better management by the orthodontist. The clinical benefits of post-operative orthodontics are outlined.


Multimethod latent class analysis.
Correct and, hence, valid classifications of individuals are of high importance in the social sciences as these classifications are the basis for diagnoses and/or the assignment to a treatment. The via regia to inspect the validity of psychological ratings is the multitrait-multimethod (MTMM) approach. First, a latent variable model for the analysis of rater agreement (latent rater agreement model) will be presented that allows for the analysis of convergent validity between different measurement approaches (e.g., raters). Models of rater agreement are transferred to the level of latent variables. Second, the latent rater agreement model will be extended to a more informative MTMM latent class model. This model allows for estimating (i) the convergence of ratings, (ii) method biases in terms of differential latent distributions of raters and differential associations of categorizations within raters (specific rater bias), and (iii) the distinguishability of categories indicating if categories are satisfyingly distinct from each other. Finally, an empirical application is presented to exemplify the interpretation of the MTMM latent class model.


A novel hydrothermal process to produce hydroxyapatite powders.
A novel hydrothermal process has been developed various hydroxyapatite(HA) powder. The HA powder was investigated in different calcination temperatures over the range of 200 degrees C-800 degrees C. TG/DTA and XRD analysis revealed that at temperatures of 700-800 degrees C the decomposition processes and phase changes took place. It is due to the appearance of TCP phase substituting the HA phase. FESEM observation showed that the produced hydroxyapatite powder was extraordinarily fine with nanosize primary particles and almost evenly spherical in shaped. Its high purity proved that the powder fulfills medical requirement.


The effect of music listening on older adults undergoing cardiovascular surgery.
The purpose of this study was to determine the effect of music listening on postoperative anxiety and intubation time in patients undergoing cardiovascular surgery. Coronary artery disease and valvular heart disease affect approximately 15 million Americans and 5 million persons in the U.K. annually, with the majority of these patients being older adults. The anxiety experienced before, during and after surgery increases cardiovascular workload, thereby prolonging recovery time. Music listening as a nursing intervention has shown an ability to reduce anxiety. The study used a randomized control trial design. Sixty adults older than 65 years were randomly assigned to the control and the experimental groups. The experimental group listened to music during and after surgery, while the control group received standard postoperative care. The Spielberger State Trait Anxiety Inventory was administered to both groups before surgery and 3 days postoperatively. The mean of the differences between scores was compared using analysis of variance. Differences in mean intubation time were measured in both groups. Older adults who listened to music had lower scores on the state anxiety test (F = 5.57, p = .022) and had significantly fewer minutes of postoperative intubation (F = 5.45, p = .031) after cardiovascular surgery. Older adults undergoing cardiovascular surgery who listen to music had less anxiety and reduced intubation time than those who did not.


Sarcopenia correlates with systemic inflammation in COPD.
Muscle wasting and chronic inflammation are predominant features of patients with COPD. Systemic inflammation is associated with an accelerated decline in lung function. In this study, the prevalence of sarcopenia and the relationships between sarcopenia and systemic inflammations in patients with stable COPD were investigated. In a cross-sectional design, muscle strength and muscle mass were measured by handgrip strength (HGS) and bioelectrical impedance analysis in 80 patients with stable COPD. Patients (≥40 years old) diagnosed with COPD were recruited from outpatient clinics, and then COPD stages were classified. Sarcopenia was defined as the presence of both low muscle strength (by HGS) and low muscle mass (skeletal muscle mass index [SMMI]). Levels of circulating inflammatory biomarkers (IL-6 and high-sensitivity TNFα [hsTNFα]) were measured. Sarcopenia was prevalent in 20 (25%) patients. Patients with sarcopenia were older, had lower body mass index, and a higher percentage of cardiovascular diseases. In addition, they had significantly higher modified Medical Research Council scores and lower 6-minute walk distance than those without sarcopenia. HGS was significantly correlated with age, modified Medical Research Council score, and COPD Assessment Test scores. Both HGS and SMMI had associations with IL-6 and hsTNFα (HGS, r=-0.35, P=0.002; SMMI, r=-0.246, P=0.044) level. In multivariate analysis, old age, lower body mass index, presence of cardiovascular comorbidities, and higher hsTNFα levels were significant determinants for sarcopenia in patients with stable COPD. Sarcopenia is very common in patients with stable COPD, and is associated with more severe dyspnea-scale scores and lower exercise tolerance. Systemic inflammation could be an important contributor to sarcopenia in the stable COPD population.


SPERM DISPLACEMENT WITHOUT SPERM TRANSFER IN DROSOPHILA MELANOGASTER.
In this paper we show that when Drosophila melanogaster females are mated twice, the semen of the second male causes a reduction of the effective number of resident sperm from the previous mating. This is demonstrated by two different kinds of experiments. In one set of experiments, mated females were remated to two different kinds of sterile males, one with normal semen and the other with deficient semen. The effect on the resident sperm was determined from the number of remaining progeny after mating to the sterile male, with the result that the normal semen reduced the amount of resident sperm in comparison with matings to the males with deficient semen. The second set of experiments employed interrupted matings. These experiments were based on the observation that semen is delivered before sperm during the first 5 min of copulation. The second matings were interrupted instantly, 2 min, and 4 min after the initiation of copulation. Compared to the instant interruptions, the two later interruptions had the effect of reducing the amount of resident sperm. The results of these two experiments clearly indicate that a sperm-incapacitation process plays a role in the well-documented phenomenon of sperm displacement (last-male advantage) in this species. Such a process could play a role in sperm displacement in the many cases where the mechanism is unknown.


Clinics in diagnostic imaging (69). Bilateral developmental dysplasia of the hip.
Developmental dysplasia of the hip (DDH) is a condition encompassing a spectrum of abnormality. The ultrasonography features of DDH in a male infant is illustrated. Follow-up after treatment with a Pavlik harness shows resolution of the DDH. In the neonatal period, ultrasonography (US) is the modality of choice used to evaluate babies with suspected developmental dysplasia of the hip. The unossified cartilaginous femoral head and much of the acetabulum can be visualised on US. When the femoral head begins to ossify, pelvic radiographs can be used to follow-up patients with developmental dysplasia of the hips.


The Role of Imaging in Femoroacetabular Impingement: History, Current Practices, and Future Applications.
Femoroacetabular impingement (FAI) is one of the most common causes of early hip articular cartilage wear and labral damage, and subsequently leads to the onset of hip osteoarthritis. Cam-type FAI impingement lesions can be best identified with a 90° Dunn lateral radiograph and a cross-table lateral radiograph with 15° of internal rotation; the alpha angle and the femoral head-neck offset are the most used predictive radiographic markers. FAI lesions with pincer impingement are associated with acetabular retroversion and are more difficult to identify on traditional radiographic imaging; however, the presence of a crossover sign, an ischial spine sign, and/or a posterior wall sign can be useful radiographic markers. Advanced imaging modalities such as magnetic resonance imaging (MRI) and/or magnetic resonance arthrography (MRA) can also be beneficial in the evaluation of FAI and labral pathology; MRA is more sensitive than MRI in detecting intra-articular pathology. Computer-assisted navigation for preoperative planning and intraoperative surgical assistance are promising technologies; however, additional studies are needed before they can be utilized safely and effectively.


Phenotypic features of BHK-21 cells used for production of foot-and-mouth disease vaccine.
BHK-21 c13 monolayer and suspension cells were investigated with regard to some phenotypic features which could bear on the quality of foot-and-mouth disease virus (FMDV) antigen produced in them. Despite good viability, suspension cells differed from monolayer cells in fundamental features of susceptibility to FMDV. Most important, FMD virus particles grown in suspension cells at high passage levels were shown to be largely degraded following inactivation with an aziridine compound. Suspension cells were characterised by a downregulation in the surface expression of both alpha 5 and alpha V integrin chains. According to the results of binding assays, both integrins could act as FMDV receptors on BHK-21 c13 cells. Reduced surface expression of integrins was correlated with disappearance of actin stress fibres, which would play a role in regular encapsidation of viral RNA and hence in stability of virus particles. With regard to FMD vaccine production, practical suggestions are put forward to evaluate the quality of BHK-21 c13 cells and FMDV Ag, which must prove stable during downstream processing.


Draft genome sequence of Arctic marine Bacterium Pseudoalteromonas issachenkonii PAMC 22718.
The psychrotolerant Pseudoalteromonas issachenkonii PAMC 22718 was isolated for its higher chitinase and protease activities from cold seawater in the Kara Sea, Arctic. Here, we present the draft genome sequence of PAMC 22718 to provide further information for the ecological function of the genus Pseudoalteromonas in a cold marine environment.


The sediment-water flux of HOCs due to "diffusion" or is there a well-mixed layer? If there is, does it matter?
In most present modeling of the sediment-water flux of hydrophobic organic chemicals (HOCs), the flux due to sediment erosion/deposition is described explicitly by means of a sediment transport model, while the remaining components of the flux (molecular diffusion, bioturbation, and groundwater flow) are lumped together and modeled as a "diffusive" flux. This diffusive flux is usually described by means of a mass transfer approximation with the implicit assumption of a well-mixed contaminant layer of thickness h in the sediments. On the basis of recent experiments and theoretical modeling, the justification forthis assumption and the quantification of this diffusive flux are discussed here. In particular, for HOCs with large partition coefficients, it is argued that a well-mixed layer often may not exist, and, when it does, it is slow to form; that h is difficult to define and even harder to quantify; and that, as far as long-term predictions (up to 100 years) of this diffusive flux are concerned, the exact value for h probably does not matter. What does matter are the magnitudes and time dependencies of each of the components of the flux and the interactions between the diffusive flux and the flux due to erosion/deposition.


Inhibition of deoxyribonucleic acid synthesis and bud formation by nalidixic acid in Hyphomicrobium neptunium.
The relationship between chromosome replication and morphogenesis in the budding bacterium Hyphomicrobium neptunium has been investigated. Nalidixic acid was found to completely inhibit deoxyribonucleic acid synthesis, but not ribonucleic acid synthesis. The antibiotic was bacteriostatic to the organism for the initial 5 h of exposure; thereafter it was bacteriocidal. Observation of inhibited cultures revealed cells that had produced abnormally long stalks, but no buds. These results indicate that bud formation is coupled to chromosome replication in H. neptunium. They do not exclude the possibilities that cross wall formation and bud separation may also be coupled to chromosome replication.


Prospective association of dietary soy and fibre intake with puberty timing: a cohort study among Chinese children.
Dietary phytoestrogens have been suggested to influence puberty timing, a critical stage for well-being in adulthood. We hypothesized that childhood soy intake might prospectively influence puberty timing and that dietary fibre and the key isoflavone metabolite equol might play roles. Cox proportional hazard regression models were performed in 4781 children (2152 girls and 2629 boys) aged 6-8 years old from the Chinese Adolescent Cohort Study for whom a food frequency questionnaire at baseline and information about potential confounders were available. Anthropometry and pubertal status including age at Tanner stage 2 for breast development (B2) or age at the initiation of gonadal growth (G2), and age at menarche (M) or voice break (VB) were assessed annually. Equol excretion was determined by urine samples from 1311 participants. Among girls and boys, higher soy intake was associated with later puberty timing (hazard ratio (HR)-B2: 0.88 (95% CI, 0.80-0.96), p=0.02; HR-M, 0.87 (0.77-0.94), p=0.01; HR-G2, 0.91 (0.82-0.98), p=0.013; HR-VB, 0.90 (0.82-0.9), p=0.02), independent of prepubertal body fatness and fibre intake. These associations were more pronounced among children with a high urinary equol level (pfor-interaction ≤ 0.04) or with a high cereal fibre intake (pfor-interaction ≤ 0.06). Intake of dietary fibre or its subtype was not prospectively associated with puberty onset after adjusting for dietary soy intake (p≥0.06). Higher childhood soy intake is prospectively associated with later puberty timing in both Chinese girls and boys, independent of prepubertal body fatness, and the association is particularly pronounced among individuals with a higher urinary equol level.


Measurement induced entanglement and quantum computation with atoms in optical cavities.
We propose a method to prepare entangled states and implement quantum computation with atoms in optical cavities. The internal states of the atoms are entangled by a measurement of the phase of light transmitted through the cavity. By repeated measurements an entangled state is created with certainty, and this entanglement can be used to implement gates on qubits which are stored in different internal degrees of freedom of the atoms. This method, based on measurement induced dynamics, has a higher fidelity than schemes making use of controlled unitary dynamics.


Proto-oncogene expression and nuclear factor specifically bound to c-myc gene in peripheral blood mononuclear cells from progressive systemic sclerosis patients as the indicator of clinical activity.
In the present study, we examined the expression of various protooncogenes and the specific binding of nuclear factor to c-myc gene in peripheral blood mononuclear cells (PBMC) from progressive systemic sclerosis (PSS) patients. We demonstrated first amplified expression of c-myc and c-myb gene and the existence of a nuclear protein specifically bound to 5'-non-coding fragment of c-myc gene. We then found a positive correlation between the degree of expression and/or affinity for the c-myc gene fragment of the nuclear protein and clinical disease activity. The amount of the factor was significantly reduced along with or prior to the amelioration of clinical symptoms and laboratory abnormalities with treatment. The significance of c-myc and c-myb proto-oncogene expression and nuclear factor specifically bound to c-myc gene is discussed.


Tremorgenic mycotoxins paxilline, penitrem and lolitrem B, the non-tremorgenic 31-epilolitrem B and electromyographic activity of the reticulum and rumen of sheep.
The mycotoxic tremorgens penitrem, paxilline and lolitrem B had profound effects on electromyographic (EMG) activity of smooth muscle of the reticulorumen in conscious sheep, with a similar time course of action to their respective characteristic effects on the induction (1 to 2, 15 to 20 and 20 to 30 minutes) and the duration (1 to 2, 1 to 2 and 8 to 12 hours) of tremoring. Responses to penitrem revealed a greater sensitivity of smooth muscle than skeletal muscle. Effects included an inhibition of the vagally-dependent cyclical A and B sequences of contraction of the reticulorumen, an increase in their amplitude and an excitation of local intrinsic activity contributing to elevated baselines and the occurrence of chaotic activity of the reticulum. The excitatory local effects were partially blocked by atropine, indicating that stimulation of muscarinic cholinoceptors was involved. Increased local activity may mediate a reflex inhibition of cyclical contractions. A non-tremorgenic isomer of lolitrem B (31-epilolitrem B) had no effect on the reticulorumen. The intensity and duration of the effects of lolitrem B, up to 12 hours, indicate that severe disruption of digestion may occur in animals grazing endophyte-infected pasture.


Detection of chicken anemia virus DNA in embryonal tissues and eggshell membranes.
Chicken infectious anemia virus (CIAV) is a ubiquitous and highly resistant virus of chickens that causes anemia and death in chicks less than 3 wk of age and immunosuppression in chickens older than 3 wk of age. The production of specific-pathogen-free eggs free of CIAV is essential for research and vaccine production. Currently, flocks are screened for CIAV by antibody tests to ensure freedom from CIAV infection. Recent evidence, however, indicates that chickens may carry and vertically transmit CIAV DNA independently of their antibody status. In this study, we tested embryos and eggshell membrane residues by nested polymerase chain reaction (PCR) as a sensitive method of detecting CIAV DNA. CIAV DNA could be detected in the blastodisks and semen obtained from antibody-positive and -negative chickens. Examination of different tissues between 18 and 20 days of incubation indicated that many but not all organs of individual embryos were positive. The lymphoid organs and gonads had the highest incidence of CIAV DNA, which was significantly different (P < 0.05) from the incidence in the liver. Eggshell membrane samples from embryos or newly hatched chicks were an excellent noninvasive source for the detection of CIAV DNA, identifying significantly more positive embryos than did pooled lymphoid organs. The use of dexamethasone injections as a method to improve the detection of carrier birds did not result in an increase of vertical transmission or cause seroconversion in the treated hens. A combination of testing eggshell membrane residues at hatch and periodic testing of blood DNA by nested PCR can be used to identify chickens carrying CIAV DNA and may be used to eradicate carrier birds.


Health-care seeking by men in their spouse's pregnancy.
This study compares the health-care seeking by 212 married male members of a health maintenance organization of 36,000 whose wives were pregnant, with a group of 212 " nonexpectant " married men matched for age, number of prior children, and HMO membership. Retrospective, blind chart review was used to examine the number and timing of medical visits and the types of symptoms, diagnoses, testing, and treatments recorded over the 21-month period surrounding and including each wife's pregnancy. Contrary to prior reports, the expectant fathers had a significantly lower group visit rate during the nine months of pregnancy when compared to their visit rates before conception and after delivery (p less than 0.01). The control group had a constant visit rate over the same time intervals. The types of symptoms and diagnoses recorded in the medical record over time were comparable in the two groups. The study suggests that expectant fatherhood, a clearly defined psychosocial event for a male, significantly influences health-care seeking but not the types of symptoms presented or diagnoses made.


Delayed diagnosis of spinal vascular malformations presenting as intermittent myelopathy.
We report our recent experience of three male patients, whose clinical diagnosis and subsequent surgery was delayed for 9.25 and 15 months respectively. Initially, they all presented with vague, either sensory or motor lower limb disturbances and intermittency of symptoms was followed by bladder dysfunction or impotence. Extensive laboratory work-up was unrevealing and the non-specific diagnosis of myelopathy further delayed the recognition of the underlying vascular lesion. Finally spinal magnetic resonance imaging (MRI), supine myelography and selective spinal arteriography indicated the presence of a tumor in the first patient and vascular malformation in the other two. Neurosurgery and histology confirmed one cavernous angioma and two arteriovenous malformations, all thoracic and dural. We believe that both the cryptic nature of these lesions and our technical limitations (spinal arteriography and MRI not readily available), accounted for the delayed diagnosis in our three patients, who nevertheless, when treated by surgery showed a satisfactory outcome in the first case, while further deterioration was prevented in the other two.


Synthesis of a Small-Molecule Library with Skeletal Diversity from Hemslecin A via the Reaction-Discovery Strategy.
An efficient reaction tool box was developed for the synthesis of skeletally diverse and stereochemically complex templates for a small-molecule library based on the common synthon Q, which was prepared from hemslecin A in four steps. The reaction tool box comprises three acid-promoted rearrangements: semipinacol, Wagner-Meerwein, and cyclopropylmethyl cation rearrangements. More importantly, a Mn-mediated C-H oxidation was developed to achieve a high level of complexity, which provides a new entry for C-H functionalization of inert angular methyl groups in the chemistry of triterpenes. Our reaction-discovery strategy based on hemslecin A provides a basis for the inherent chemistry of triterpenes and could be applied for the further transformation of triterpenes.


Assessment and management of pain in the elderly.
Due to the high prevalence of musculoskeletal disorders, cancer, and other medical conditions in elderly patients, pain is a significant concern for this age group and their caregivers. Despite the frequent experience of pain in this population, few assessment and management techniques have been developed and tested to treat pain in the elderly. To provide effective pain relief, medical-surgical nurses must know how to adapt assessment and management techniques for elderly patients.


[The progress of stem cells in the treatment of olfactory dysfunction].
Olfactory dysfunction is one of the common diseases in the Department of Otorhinolaryngology. Although the olfactory nerve has ability to regenerate in human central nervous system, if the damage involves nerve, only a few patients can restore the olfactory function. At present, there is no satisfactory treatment for sensorineural olfactory dysfunction. Therefore, it is urgent to explore new and effective method for treating sensorineural olfactory dysfunction. The progress of stem cells in the treatment of olfactory dysfunction is reviewed in this article.


The Effects of Probiotic Formulation Pretreatment (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) on a Lipopolysaccharide Rat Model.
The role of gut microbiota in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), via the gut-brain axis has recently been demonstrated; hence, modification of the intestinal microbiota composition by probiotic biotherapy could be a therapeutic target for these conditions. The aim of this study was to assess the effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) on inflammatory and memory processes in lipopolysaccharide (LPS)-induced rats, one of the animal models used in peripherally induced neuroinflammation and neurodegeneration. Rats were randomly divided into four groups (Control, LPS, Probiotic + LPS, and Probiotic). All experimental groups were orally administrated maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 14 consecutive days and then were injected with saline or LPS (1 mg/kg, intraperitoneally [i.p.], single dose) 20 hours later. Memory retention ability and systemic and neuroinflammatory markers were assessed 4 hours after the injections. Systemic exposure to LPS resulted in significant elevation of both the circulating and hippocampal levels of proinflammatory cytokines, which decreased remarkably following probiotic pretreatment. Oral bacteriotherapy with a combination of L. helveticus R0052 and B. longum R0175 also attenuated the decremental effect of LPS on memory through brain-derived neurotrophic factor (BDNF) expression at the molecular level; however, this effect was not significant in the passive avoidance test at the behavioral level. These results suggest that the management of gut microbiota with this probiotic formulation could be a promising intervention to improve neuroinflammation-associated disorders such as AD.


Simulating effects of brain atrophy in longitudinal PET imaging with an anthropomorphic brain phantom.
In longitudinal positron emission tomography (PET), the presence of volumetric changes over time can lead to an overestimation or underestimation of the true changes in the quantified PET signal due to the partial volume effect (PVE) introduced by the limited spatial resolution of existing PET cameras and reconstruction algorithms. Here, a 3D-printed anthropomorphic brain phantom with attachable striata in three sizes was designed to enable controlled volumetric changes. Using a method to eliminate the non-radioactive plastic wall, and manipulating BP levels by adding different number of events from list-mode acquisitions, we investigated the artificial volume dependence of BP due to PVE, and potential bias arising from varying BP. Comparing multiple reconstruction algorithms we found that a high-resolution ordered-subsets maximization algorithm with spatially variant point-spread function resolution modeling provided the most accurate data. For striatum, the BP changed by 0.08% for every 1% volume change, but for smaller volumes such as the posterior caudate the artificial change in BP was as high as 0.7% per 1% volume change. A simple gross correction for striatal volume is unsatisfactory, as the amplitude of the PVE on the BP differs depending on where in the striatum the change occurred. Therefore, to correctly interpret age-related longitudinal changes in the BP, we must account for volumetric changes also within a structure, rather than across the whole volume. The present 3D-printing technology, combined with the wall removal method, can be implemented to gain knowledge about the predictable bias introduced by the PVE differences in uptake regions of varying shape.


Comparison of Joint and Muscle Biomechanics in Maximal Flywheel Squat and Leg Press.
The aim was to compare the musculoskeletal load distribution and muscle activity in two types of maximal flywheel leg-extension resistance exercises: horizontal leg press, during which the entire load is external, and squat, during which part of the load comprises the body weight. Nine healthy adult habitually strength-training individuals were investigated. Motion analysis and inverse dynamics-based musculoskeletal modelling were used to compute joint loads, muscle forces, and muscle activities. Total exercise load (resultant ground reaction force; rGRF) and the knee-extension net joint moment (NJM) were slightly and considerably greater, respectively, in squat than in leg press (p ≤ 0.04), whereas the hip-extension NJM was moderately greater in leg press than in squat (p = 0.03). Leg press was performed at 11° deeper knee-flexion angle than squat (p = 0.01). Quadriceps muscle activity was similar in squat and leg press. Both exercise modalities showed slightly to moderately greater force in the vastii muscles during the eccentric than concentric phase of a repetition (p ≤ 0.05), indicating eccentric overload. That the quadriceps muscle activity was similar in squat and leg press, while rGRF and NJM about the knee were greater in squat than leg press, may, together with the finding of a propensity to perform leg press at deeper knee angle than squat, suggest that leg press is the preferable leg-extension resistance exercise, both from a training efficacy and injury risk perspective.


Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.
Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3',5'-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals.


The spliceosomal PRP19 complex of trypanosomes.
In trypanosomes, mRNAs are processed by spliced leader (SL) trans splicing, in which a capped SL, derived from SL RNA, is spliced onto the 5' end of each mRNA. This process is mediated by the spliceosome, a large and dynamic RNA-protein machinery consisting of small nuclear ribonucleoproteins (snRNPs) and non-snRNP proteins. Due to early evolutionary divergence, the amino acid sequences of trypanosome splicing factors exhibit limited similarity to those of their eukaryotic orthologs making their bioinformatic identification challenging. Most of the ~ 60 protein components that have been characterized thus far are snRNP proteins because, in contrast to individual snRNPs, purification of intact spliceosomes has not been achieved yet. Here, we characterize the non-snRNP PRP19 complex of Trypanosoma brucei. We identified a complex that contained the core subunits PRP19, CDC5, PRL1, and SPF27, as well as PRP17, SKIP and PPIL1. Three of these proteins were newly annotated. The PRP19 complex was associated primarily with the activated spliceosome and, accordingly, SPF27 silencing blocked the first splicing step. Interestingly, SPF27 silencing caused an accumulation of SL RNA with a hypomethylated cap that closely resembled the defect observed previously upon depletion of the cyclin-dependent kinase CRK9, indicating that both proteins may function in spliceosome activation.


Microvascular architecture of the enamel organ in the rat-incisor maturation zone. Scanning and transmission electron microscopic studies.
In order to clarify the microvascular architecture and ultrastructural features of the capillary vessels related to transendothelial transport of metabolites, scanning electron microscopy of tissues digested by HCl-collagenase and of vascular corrosion casts as well as thin-section, tracer, and freeze-fracture replications were employed to study the maturation zone of rat-incisor enamel organ. The enamel-organ maturation zone was shown to have a well-developed, dense capillary plexus. The capillary vessels were distributed along furrows formed by the enamel-organ papillary ridges. In central regions they formed a regular, blindlike network; in the peripheral regions, however, they formed an irregular, circular network. Everywhere except in the nuclear and perinuclear regions, the very thin capillary-vessel endothelial walls were pierced with numerous fenestrations. Such fenestrations were evident in endothelial walls facing the ameloblast-layer site. In tracer experiments, intravenously injected horseradish peroxidase passed through the fenestrations in the endothelial walls to diffuse throughout the enamel-organ extracellular spaces. It did not, however, pass through intercellular spaces or transendothelial channels. The dense, regular distribution of highly fenestrated capillaries in the enamel organ is thought to make possible the rapid transcapillary exchange of various metabolites between the vascular system and the ameloblast and papillary layers that is necessary for enamel maturation.