A Pilot Study of Intralymphatic Immunotherapy for House Dust Mite, Cat, and Dog Allergies.
Several recent clinical trials reported that intralymphatic immunotherapy (ILIT) for some allergens, such as cat dander and pollen, induce tolerance more rapidly than conventional subcutaneous or sublingual immunotherapy, have a comparable duration of effect after only 3 injections, and do not provoke serious local or systemic reactions. However, the efficacy and safety of ILIT are using Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dp), and dog, which are indoor allergens that are commonly found globally, need to be evaluated. Furthermore, use of multiple allergens in ILIT should be investigated. We assessed the clinical efficacy and adverse effects of ILIT using aqueous Df, Dp, dog, and cat allergens or mixtures thereof in patients with allergic rhinitis. A total of 11 subjects with AR sensitized to Df, Dp, cat, and/or dog allergens received 3 intralymphatic inguinal injections of sensitized allergen extract (HollisterStier, New Orleans, LA, USA). Clinical parameters were assessed before ILIT, and 4 months and 1 year after the first injection. Rhinitis symptoms were alleviated and quality of life was improved 4 months after ILIT (P=0.012 and P=0.007, respectively), and these improvements lasted for 1 year after ILIT (P=0.047 and P=0.009, respectively). However, we observed 2 cases of anaphylaxis, one case of a moderate-to-severe systemic hypersensitivity reaction and the other case of a severe local reaction at the injection site after ILIT. In conclusion, ILIT can rapidly improve allergy symptoms and quality of life, and this effect lasts for 1 year. In hypersensitized patients, however, ILIT can provoke severe systemic and/or local hypersensitivity reactions when performed using aqueous allergen extracts.


Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in ataxin-3 (ATX3; MJD1) protein. In biochemical experiments, we demonstrate that mutant ATX3(exp) specifically associated with the type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1), an intracellular calcium (Ca(2+)) release channel. In electrophysiological and Ca(2+) imaging experiments, we show that InsP(3)R1 was sensitized to activation by InsP(3) in the presence of mutant ATX3(exp). We found that feeding SCA3-YAC-84Q transgenic mice with dantrolene, a clinically relevant stabilizer of intracellular Ca(2+) signaling, improved their motor performance and prevented neuronal cell loss in pontine nuclei and substantia nigra regions. Our results indicate that deranged Ca(2+) signaling may play an important role in SCA3 pathology and that Ca(2+) signaling stabilizers such as dantrolene may be considered as potential therapeutic drugs for treatment of SCA3 patients.


Relative risk regression models with inverse polynomials.
The proportional hazards model assumes that the log hazard ratio is a linear function of parameters. In the current paper, we model the log relative risk as an inverse polynomial, which is particularly suitable for modeling bounded and asymmetric functions. The parameters estimated by maximizing the partial likelihood are consistent and asymptotically normal. The advantages of the inverse polynomial model over the ordinary polynomial model and the fractional polynomial model for fitting various asymmetric log relative risk functions are shown by simulation. The utility of the method is further supported by analyzing two real data sets, addressing the specific question of the location of the minimum risk threshold.


Effectiveness of recruitment strategies for a social media literacy E-intervention for young adults with body dissatisfaction: cost, time, diversity, and completion.
Digital interventions are becoming increasingly popular for the treatment of body dissatisfaction and eating disorders. However, participant recruitment to online interventions poses a challenge. This study examined differences between a variety of recruitment strategies to a digital intervention in terms of number of participants recruited, cost, study personnel time, completion rates, and demographic characteristics of participants.Participants (N = 395) aged 18-25 years (79.5% women) were recruited to take part in an online body image intervention and asked how they heard about the program (e.g., through Facebook, a flyer on a university campus). Strategies of recruitment, including researcher time required and cost were recorded throughout the project. Cost and time effectiveness, study and intervention completion rates, and participant demographics for each recruitment approach were explored.Facebook paid advertising recruited n = 241 participants (78.0% women), with $29.81 cost per completer, and researcher time per completer at 2.41 minutes. Facebook unpaid advertising was also effective, recruiting n = 130 participants (78.5% women), with $0.00 external cost per completer, and time per completer at 20.43 minutes. Other strategies, both online and face-to-face, were far less effective in recruiting participants. Men proved difficult to recruit using any strategy.Facebook advertising was an effective tool for recruiting young adults to this online intervention, although further research should identify effective strategies to recruit men for similar interventions.


Torsion of a wandering spleen: an unusual abdominal catastrophe.
Wandering spleen is a rare clinical entity characterised by splenic hypermobility resulting from laxity or maldevelopment of the suspensory gastrosplenic, splenorenal, and phrenicocolic ligaments. Diagnosis is quite difficult, especially in children because of the lack of symptoms and signs until splenic torsion have occurred. An array of investigations is possible but US with color Doppler, CT with intravenous contrast and MRI are frequently being used to diagnose wandering spleen with or without torsion. We present a case of 5 years old child with torsion of wandering spleen to highlight the importance of prompt diagnosis and management.


Chemical analysis and in vitro antiviral and antifungal activities of essential oils from Glechon spathulata and Glechon marifolia.
Glechon spathulata Benth. and Glechon marifolia Benth. (Lamiaceae, Mentheae) are aromatic plants used in traditional medicine for the treatment of viral infections. The chemical composition and antiviral and antifungal activities of Glechon spathulata and Glechon marifolia essential oils were investigated. The oils were obtained by hydrodistillation and analyzed by GC-FID and GC-MS. Anti-herpes virus (HSV-1) activity was examined in Vero cells by yield reduction assay, in doses of 0.0095% v/v and 0.039% v/v, for G. spathulata and G. marifolia oil, respectively. Antifungal activity was carried by the broth microdilution method, in oil concentrations that ranged from 5.2 to 500 µg/mL. β-Caryophyllene (14.2% and 32.2% for G. spathulata and G. marifolia, respectively) and bicyclogermacrene (17.1% and 16.5%, respectively) were the major components of both oils. At noncytotoxic concentrations of the essential oils, the viral titer was reduced by up to 2 log10 for KOS and VR-733 strains. The antifungal activity was observed against Trichophyton rubrum (MIC 10-83 µg/mL) and Epidermophyton floccosum (MIC 83-500 µg/mL). The oil of G. spathulata exhibited activity against the three strains tested (KOS, VR733, and 29-R), whereas G. marifolia oil was active against two strains, KOS and VR733. The chemical composition for G. spathulata and G. marifolia essential oils is very similar. The oil of G. spathulata can be promising as a new antifungal agent against dermatophytes. The findings add important information to the biological activity of Glechon species essential oils, specifically its antiviral and antidermatophytic properties.


Development of a Synthetic Switch to Control Protein Stability in Eukaryotic Cells with Light.
In eukaryotic cells, virtually all regulatory processes are influenced by proteolysis. Thus, synthetic control of protein stability is a powerful approach to influence cellular behavior. To achieve this, selected target proteins are modified with a conditional degradation sequence (degron) that responds to a distinct signal. For development of a synthetic degron, an appropriate sensor domain is fused with a degron such that activity of the degron is under control of the sensor. This chapter describes the development of a light-activated, synthetic degron in the model organism Saccharomyces cerevisiae. This photosensitive degron module is composed of the light-oxygen-voltage (LOV) 2 photoreceptor domain of Arabidopsis thaliana phototropin 1 and a degron derived from murine ornithine decarboxylase (ODC). Excitation of the photoreceptor with blue light induces a conformational change that leads to exposure and activation of the degron. Subsequently, the protein is targeted for degradation by the proteasome. Here, the strategy for degron module development and optimization is described in detail together with experimental aspects, which were pivotal for successful implementation of light-controlled proteolysis. The engineering of the photosensitive degron (psd) module may well serve as a blueprint for future development of sophisticated synthetic switches.


Precautionary effects of Red Liriope platyphylla on NGF secretion and Aβ42 deposition under the preclinical stage of Alzheimer's disease in Tg2576 mice.
Red Liriope platyphylla (RLP) has been manufactured from Liriope platyphylla (L. platyphylla, LP) roots using steaming process and investigated as a curative agent for treatment of diabetes, obesity and neurodegenerative disorders. To examine the precautionary effects of aqueous extract RLP (AEtRLP) on the preclinical stages of Alzheimer's Disease (AD), alterations of the key factors influencing AD were investigated in Tg2576 mice after AEtRLP7 treatment for 4 months. Aβ-42 peptides level was significantly decreased in the brain of AEtRLP7-treated Tg2576 mice compared to vehicle-treated Tg2576 mice, although significant differences on improving behavioral defects were not observed in the same group. The concentration of nerve growth factor (NGF) in serum was also higher in AEtRLP7-treated Tg2576 mice than vehicle-treated Tg2576 mice. However, the phosphorylation of TrkA and Erk among the downstream effectors of the high affinity NGF receptor was significantly lower in AEtRLP7-treated Tg2576 mice. A similar pattern was observed in the expression level of downstream effectors within low affinity NGF receptor. Overall, these results suggest that AEtRLP7 can contribute to preventing the production and deposition of Aβ-42 peptides during the early progression stage of AD in the brain of Tg2576 mice through increased NGF secretion.


Generation of heterohybridomas capable of releasing swine monoclonal antibody specific to porcine growth hormone.
An effort was made to generate stable swine hybridomas capable of releasing monoclonal antibodies (MAb) with antigenic specificity. Crossbred pigs were immunized with recombinant porcine growth hormone (r-pGH) and the splenic cells were harvested from these animals. B lymphocytes enriched by gradient centrifugation and nylon wool adherence were briefly stimulated in vitro with r-pGH prior to hybridization with murine SP2/0 myeloma cells. The fused hybrids were screened for their ability to produce anti-pGH antibody and the positive ones were subcloned by a limiting dilution procedure. The stable cell lines were maintained by serial passages in cultures for further analysis. One such hybridoma, designated PM20/20, was found to secrete swine IgM. It recognized not only the immunizing r-pGH but also the native pGH extracted from the swine pituitary glands, as demonstrated by Western analysis. It also recognized two smaller fragments with m.w. of 10 kD and 5 kD of r-pGH following trypsin digestion. In addition to pGH, PM20/20 immunoreacted with several other GH species including bovine, chicken, and human origins, but not with ovine prolactin nor rat GH binding protein. The binding association rate constant and dissociation rate constant of PM20/20 to pGH were 5.3 x 10(4) M-1 s-1 and 1.0 x 10(-4) s-1, respectively, thus producing a dissociation constant of 1.9 x 10(-9) M. Therefore, stable swine-mouse heterohybridoma lines have been established and shown to continuously release swine mAb in cultures. These mAb may serve as useful alternatives to murine mAb in certain areas of research.


Hypnosis for monitoring intraoperative spinal cord function.
In such procedures as the Harrington operation for idiopathic scoliosis, evaluation of spinal cord function is advisable immediately after the back is straightened. The authors have used hypnosis for this procedure, as an adjunct to anesthetic management. Patients are awakened on the table, given lower extremity tests, and are then reanesthetized. The incidence of postoperative pain and other discomfort is also reduced by hypnosis.


Abnormal facial emotion recognition in depression: serial testing in an ultra-rapid-cycling patient.
Normal subjects use the right insula and bilateral anterior temporal and prefrontal cortices to recognize the emotion expressed in a human face. Mood disorder subjects have a selective deficit in recognizing human facial emotion. Brain imaging studies show that they fail to activate the right insula to the same degree as controls, even when accurately assessing facial emotion. Many issues remain, however, including whether the facial emotion recognition errors in mood disorder subjects are state dependent or persist during normal mood states (and, thus, reflect a trait abnormality). To probe this issue, we repeatedly studied a male bipolar II patient's ability to recognize faces' emotional content. This patient made significantly more errors in facial emotion recognition during the depressed state. He also demonstrated a significant negative bias when he was depressed compared with nondepressed states. This case study demonstrates the state dependency of the defect in human facial emotion recognition.


Nutrition and development: other micronutrients' effect on growth and cognition.
Previous studies have provided strong evidence that protein-energy malnutrition, deficiencies of iron and iodine early on in life led to compromised growth and cognitive functions in young children. Recently, a growing body of knowledge indicated that other micronutrients also play a role in young child development. Severe as well as marginal vitamin A efficiency were shown to lead to an increased risk of morbidity and mortality in children. A meta-analysis of vitamin A intervention trials indicated an overall reduction of 23% in all-cause mortality rate. Delayed growth, especially stunting, was reported in children with clinical signs of vitamin A deficiency. In addition, deficiency of zinc, which is essential for DNA and protein synthesis, leads to growth failure and delayed secondary sexual maturation in man and animals. Preterm infants appear to benefit from zinc administration in terms of growth and development. Supplementation studies in infants and older children revealed that those who manifested overt zinc deficiency through either clinical or biochemical indicators showed an improvement in linear growth and occasionally, an increase in weight gain. Zinc may also play a major role in brain function based on strong evidence from experimental animals. Zinc deficiency gestation in mice, rats, rhesus monkeys caused impaired learning, reduced attention and poor memory in their offspring. Data in humans are few and inconclusive. With respect to brain function alone, other nutrients such as docosahexaenoic acid (DHA, 22:6 n-3 fatty acid) improve visual acuity and mental development in small-for-gestational-age infants, folate supplementation during pregnancy prevents neural tube defect in infants, selenium deficiency in animals affects activities of brain enzymes necessary for brain development and function. Although evidence is accumulating that micronutrients other than iron and iodine may be important for physical growth and brain development in young children, more well-controlled studies in humans are needed. Critical issues to be considered include: single vs multiple limiting nutrients, critical period of deficiency, responsive indicators and variables that may affect the results as environmental, psychological and social factors.


AmLexin, a Standardized blend of Acacia catechu and Morus alba, shows benefits to delayed onset muscle soreness in healthy runners.
Sudden and exhaustive exercise causes muscle damage accompanied by oxidative stress and inflammation, leading to muscle fatigue and soreness. AmLexin contains a standardized blend of extracts from the heartwood of Acacia catechu and the root bark of Morus alba, and is known to possess antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of this proprietary blend supplementation on muscular pain and redox balance in healthy runners, in comparison to a placebo. A double-blind placebo-controlled clinical trial was carried out over 9 weeks in a single center. Thirty physically active male and female subjects within 18-70 years of age were randomized into AmLexin (mean age = 42.92 ± 2.48 and gender 7/5, male/female, respectively) and placebo (mean age = 41.15 ± 3.5 and gender 10/3, male/female, respectively) groups. Subjects were supplemented with 400 mg of AmLexin/day or a look-alike placebo during an 8-week training program, and for one week following a 13.1-mile half-marathon. Twenty-six subjects completed the 9-week supplementation trial. Results showed the AmLexin group experienced significantly lower levels of post-exercise pain on day 1-3 following the half-marathon compared to the placebo group. The AmLexin group also showed lower post-exercise oxidative stress and higher antioxidant capacity on days 1 and 6 following the half-marathon. These results demonstrated the rapid benefits of AmLexin on pain and oxidative stress within 1-6 days post-exercise. Our data suggest that AmLexin could be a safe, effective botanical alternative for delayed onset muscle soreness.


Achromobacter xylosoxidans respiratory tract infections in cystic fibrosis patients.
Achromobacter xylosoxidans is a ubiquitous Gram-negative non-fermenting rod, recently characterized as an emerging pathogen in cystic fibrosis (CF) patients. Its pathogenic potential and prevalent transmission routes are still unclear. This study investigated the PFGE genetic pattern and antimicrobial resistance profile of 42 A. xylosoxidans isolates obtained over 4 years from the respiratory tract of 22 CF patients. By genotypic analysis, 31 isolates were attributed to 8 distinct PFGE patterns (A-H), whereas 11 isolates were not typable because their DNA was not restricted by XbaI and DraI restriction enzymes. The majority of the isolates showed multidrug resistance; imipenem and piperacillin were the most active drugs. During the course of A. xylosoxidans chronic infection forced expiratory volume and body mass index values were not significantly lowered. The demonstration of widespread antibiotic resistance underscores the importance of antibiogram-directed therapy. Our data suggest that in some cases the infection may have been acquired from other patients or from a common contaminated source. Further epidemiological studies may be important for the design and implementation of prophylactic measures in CF centers.


Antiretroviral therapy does not induce HIV type 1-specific neutralizing activity against autologous HIV type 1 isolates.
To determine the ability of antiretroviral treatment (ART) to deter viral replication in the long term, we tested autologous neutralization of HIV-1 primary isolates in sera from six chronically HIV-1-infected patients before and during such treatment. For comparison, heterologous neutralization was tested in the same samples by using a panel of eight primary HIV-1 isolates. Preceding ART, none of the patients' samples contained neutralizing antibodies against autologous HIV-1 isolates. Subsequently, despite successful ART treatment during a 12- to 19-month period and a rise in CD4 T cell counts, the patients' viral neutralizing capacity did not increase significantly. Furthermore, the partial heterologous neutralizing response was not improved in these patients. This outcome signifies the failure of an HIV-1-specific humoral immune response to improve, despite successful ART. Therefore, our results emphasize the need for immunologic intervention before cessation of ART in chronically HIV-1-infected patients to achieve sustainable control of viral replication.


Feasibility and usability of a home monitoring concept based on mobile phones and near field communication (NFC) technology.
Utilization of mobile information and communication technologies in home monitoring applications is becoming more and more common. The mobile phone, acting as a patient terminal for patients suffering from chronic diseases, provides an active link to the caregiver to transmit health status information and receive feedback. In such a concept the usability is still limited by the necessity of entering the values via the mobile phone's small keypad. The near field communication technology (NFC), a touch-based wireless interface that became available recently, may improve the usability level of such applications significantly. The focus of this paper is to describe the development of a prototype application based on this technology embedded in a home monitoring system. The feasibility and usability of this approach are evaluated and compared with concepts used in previous approaches. The high quantifier with respect to overall usability indicates that NFC may be the technology of choice for some tasks in home monitoring applications.


Performance Evaluation of Parametric and Nonparametric Methods When Assessing Effect Measure Modification.
Effect measure modification is often evaluated using parametric models. These models, although efficient when correctly specified, make strong parametric assumptions. While nonparametric models avoid important functional form assumptions, they often require larger samples to achieve a given accuracy. We conducted a simulation study to evaluate performance tradeoffs between correctly specified parametric and nonparametric models to detect effect modification of a binary exposure by both binary and continuous modifiers. We evaluated generalized linear models and doubly robust (DR) estimators, with and without sample splitting. Continuous modifiers were modeled with cubic splines, fractional polynomials, and nonparametric DR-learner. For binary modifiers, generalized linear models showed the greatest power to detect effect modification, ranging from 0.42 to 1.00 in the worst and best scenario, respectively. Augmented inverse probability weighting had the lowest power, with an increase of 23% when using sample splitting. For continuous modifiers, the DR-learner was comparable to flexible parametric models in capturing quadratic and nonlinear monotonic functions. However, for nonlinear, nonmonotonic functions, the DR-learner had lower integrated bias than splines and fractional polynomials, with values of 141.3, 251.7, and 209.0, respectively. Our findings suggest comparable performance between nonparametric and correctly specified parametric models in evaluating effect modification.


Steatotic Hepatocytes Release Mature VLDL Through Methionine and Tyrosine Metabolism in a Keap1-Nrf2-Dependent Manner.
NAFLD is a lipotoxic disease wherein hepatic steatosis and oxidative stress are key pathogenic features. However, whether free amino acids (FAAs) are associated with the oxidative stress response against lipotoxicity has yet to be determined. We hypothesized that an imbalance of FAAs aggravates hepatic steatosis by interfering with the oxidative stress sensor. C57BL/6 mouse immortalized hepatocytes, primary hepatocytes, and organoids were employed. Steatotic hepatocytes treated with oleic acid (OA) were cultured under FAA-modifying media based on the concentrations of FAAs in the hepatic portal blood of wild-type (WT) mice. As in vivo experiments, WT hepatocyte-specific Kelch-like ECH-associated protein 1 (Keap1) knockout mice (Keap1∆hepa ) and Cre- control mice (Keap1fx/fx ) were fed high-fat (HF) diets with modified amino acid content. The correlations were analyzed between the areas of lipid droplets (LDs) around central vein and plasma OA/FAA ratio in 61 patients with NAFLD. Mice fed an HF, Met-restricted, and tyrosine (Tyr)-deficient diet showed the NAFLD-like phenotype in which the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), triglyceride-rich VLDL, and fumarate were decreased in liver, but Keap1∆hepa ameliorated these phenomena. Reactive oxygen species and LDs induced by the deprivation of Met and Tyr were prevented in hepatic organoids generated from Keap1∆hepa . Dimethyl fumarate, an Nrf2 inducer, ameliorated the steatosis and increased the hepatic fumarate reduced by the deprivation of Met and Tyr in vitro. OA/Met or Tyr ratio in peripheral blood was associated with the hepatic steatosis in patients with NAFLD. An imbalance between free fatty acids and Met and Tyr induces hepatic steatosis by disturbing the VLDL assembling through the Keap1-Nrf2 system.


Ankle-foot orthoses for preambulatory children with spastic diplegia.
We evaluated the effect of articulating and solid ankle-foot orthoses (AFOs) on the transitional movement of sit-to-stand for 15 children aged 2-5 years with spastic diplegia and dynamic equinus. Kinematic and kinetic data were collected for each child. The time to reach stable standing was determined by using a force plate. Seven children were comparable to age-matched normals while barefoot and were slowed by the use of AFOs. Eight patients were more than 1 standard deviation slower than normals while barefoot. All were significantly (p < 0.003) improved by the use of articulating AFOs. The clinical difference between these groups was the presence of equinus during stable standing while barefoot for patients aided by AFOs, whereas the second group remained plantigrade barefoot. We conclude that children with spastic diplegia with uncontrolled dynamic equinus benefit from the use of articulating AFOs for the movement of sit-to-stand.


Microscopic esophagitis in gastro-esophageal reflux disease: individual lesions, biopsy sampling, and clinical correlations.
Patients with non-erosive reflux disease may show microscopic damage. This study is aimed to describe distribution, sensitivity, and specificity of histological lesions (i.e., basal cell hyperplasia-BH, papillae elongation-PE, dilatation of intercellular spaces-DIS, intraepithelial eosinophils-IE, neutrophils, and erosions) and sampling criteria. Four groups were identified on the basis of symptoms, endoscopy, and pH monitoring: (1) erosive esophagitis (n = 48), (2) non-erosive esophagitis with abnormal pH (n = 59), (3) non-erosive esophagitis with normal pH (n = 12), and (4) controls (n = 20). Biopsies were taken at the Z-line and 2 and 4 cm above it. BH, PE, DIS, IE, neutrophils, and erosions were assessed. A global severity score was calculated on the basis of the above parameters and allowed the distinction of patients from controls with 80% sensitivity and 85% specificity. Lesions were more severe at Z-line than proximally and more expressed in erosive than in non-erosive disease, although more than 70% of latter patients still showed histological damage. Esophageal biopsy seems very attractive in non-erosive disease where it may contribute to diagnosis and play a role in the comparative evaluation of different therapies.


Spatial persistence and survival probabilities for fluctuating interfaces.
We report the results of numerical investigations of the steady-state (SS) and finite-initial-conditions (FIC) spatial persistence and survival probabilities for (1+1) -dimensional interfaces with dynamics governed by the nonlinear Kardar-Parisi-Zhang equation and the linear Edwards-Wilkinson (EW) equation with both white (uncorrelated) and colored (spatially correlated) noise. We study the effects of a finite sampling distance on the measured spatial persistence probability and show that both SS and FIC persistence probabilities exhibit simple scaling behavior as a function of the system size and the sampling distance. Analytical expressions for the exponents associated with the power-law decay of SS and FIC spatial persistence probabilities of the EW equation with power-law correlated noise are established and numerically verified.


Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG-CoA reductase inhibitors: a kinetic consideration of its mechanism.
Because the plasma exposure levels of rosuvastatin in Asians are generally twice those in Caucasians, the starting dose for Asians in the United States is set to half of that for non-Asians. However, the precise role of ethnicity in the clearance of rosuvastatin has not yet been clarified. This review focuses on ethnic variability in the clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) and angiotensin II receptor antagonists. The mechanisms of such variability are discussed quantitatively, with building a hypothetical model for pravastatin, and validated against other statins. Our analyses suggest that the ethnic variability in the plasma exposure of statins cannot be explained only by the difference in the allele frequencies of organic anion-transporting polypeptide (OATP)1B1 and breast cancer resistance protein (BCRP), and the intrinsic ethnic variability in the activity of OATP1B1 (the ratio of Japanese/Caucasians is 0.584) must be considered. Further work and validation with additional data will clarify the applicability of this model to other OATP1B1 substrates.


Plasma insulin and glucose in suckling and ruminating lambs after peroral administration of glucose and propionate.
An identical volume of water solutions: 1) glucose 5.56 mmol/kg b.w., or 2) sodium propionate 5.56 mmol/kg b.w., was given perorally to sucklings (6 weeks) and weaned lambs (10 weeks). The maximum increase of glycemia and the highest insulin concentrations were observed 60-90 min after glucose administration in both groups of lambs. Plasma insulin of suckling and weaned lambs was increased within 60 min after propionate infusion. It can be concluded that propionate is a potent insulin secretagogue in sucklings as well as in ruminating ones. However, glucose is probably the most effective stimulus for insulin release in both groups of lambs.


The elicitation effect of pathogenic fungi on trichodermin production by Trichoderma brevicompactum.
The effects of six species of phytopathogenic fungi mycelia as elicitors on trichodermin yield by Trichoderma brevicompactum were investigated. Neither nonviable nor viable mycelia of Botrytis cinerea, Alternaria solani, Colletotrichum lindemuthianum, and Thanatephorus cucumeris demonstrated any elicitation on the accumulation of trichodermin. However, the production of trichodermin was increased by the presence of viable/nonviable Rhizoctonia solani and Fusarium oxysporum mycelia. The strongest elicitation effect was found at the presence of nonviable R. solani. At the presence of nonviable R. solani, the maximum yield of trichodermin (144.55 mg/L) was significantly higher than the Control (67.8 mg/L), and the cultivation time to obtain the maximum yield of trichodermin decreased from 72 h to 60 h. No difference of trichodermin accumulation was observed by changing the concentration of nonviable R. solani from 0.1 to 1.6 g/L. It was observed that the optimum time for adding nonviable R. solani is immediately after inoculation. The diameter of T. brevicompactum mycelial globule after 72 h cultivation with nonviable R. solani elicitor was smaller than that of the Control.


Increased risk of comorbid rheumatic disorders in vitiligo patients: A nationwide population-based study.
Vitiligo is a common acquired depigmentation disorder. Previous studies have shown that vitiligo is associated with a variety of autoimmune disorders. However, a large-scale epidemiological study focused on comorbid rheumatic disorders has not been undertaken. To clarify the associations between vitiligo and various rheumatic disorders, we performed a cross-sectional study using data from the Korean National Health Insurance claims database. Between 2009 and 2013, totals of 86 210 patients with vitiligo and 172 420 age- and sex-matched controls without vitiligo were enrolled in this study. Vitiligo patients were found to be at increased risk of systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome and rheumatoid arthritis, but no significant association was found between vitiligo and dermatomyositis/polymyositis, Behçet's disease or ankylosing spondylitis. Subgroup analysis showed an increased risk of dermatomyositis/polymyositis in male and ankylosing spondylitis in female vitiligo patients. The risks of dermatomyositis/polymyositis or ankylosing spondylitis were higher in young vitiligo patients. Our study confirms a significant association between vitiligo and rheumatic disorders. Differences in comorbid rheumatic disorders by age group and sex suggest the need for patient-specific approaches. Careful consideration of rheumatic disorders is required for the proper management of comorbidities in vitiligo patients.


Long-term follow up of intractable chronic short lasting unilateral neuralgiform headache disorders treated with occipital nerve stimulation.
Background Occipital nerve stimulation is a potential treatment option for medically intractable short-lasting unilateral neuralgiform headache attacks. We present long-term outcomes in 31 patients with short-lasting unilateral neuralgiform headache attacks treated with occipital nerve stimulation in an uncontrolled open-label prospective study. Methods Thirty-one patients with intractable short-lasting unilateral neuralgiform headache attacks were treated with bilateral occipital nerve stimulation from 2007 to 2015. Data on attack characteristics, quality of life, disability and adverse events were collected. Primary endpoint was change in mean daily attack frequency at final follow-up. Results At a mean follow-up of 44.9 months (range 13-89) there was a 69% improvement in attack frequency with a response rate (defined as at least a 50% improvement in daily attack frequency) of 77%. Attack severity reduced by 4.7 points on the verbal rating scale and attack duration by a mean of 64%. Improvements were seen in headache-related disability and depression. Adverse event rates were favorable, with no electrode migration or erosion reported. Conclusion Occipital nerve stimulation appears to offer a safe and efficacious treatment for refractory short-lasting unilateral neuralgiform headache attacks with significant improvements sustained in the long term. The procedure has a low adverse event rate when conducted in highly specialised units.


Local caspase activation interacts with Slit-Robo signaling to restrict axonal arborization.
In addition to being critical for apoptosis, components of the apoptotic pathway, such as caspases, are involved in other physiological processes in many types of cells, including neurons. However, very little is known about their role in dynamic, nonphysically destructive processes, such as axonal arborization and synaptogenesis. We show that caspases were locally active in vivo at the branch points of young, dynamic retinal ganglion cell axonal arbors but not in the cell body or in stable mature arbors. Caspase activation, dependent on Caspase-3, Caspase-9, and p38 mitogen-activated protein kinase (MAPK), rapidly increased at branch points corresponding with branch tip addition. Time-lapse imaging revealed that knockdown of Caspase-3 and Caspase-9 led to more stable arbors and presynaptic sites. Genetic analysis showed that Caspase-3, Caspase-9, and p38 MAPK interacted with Slit1a-Robo2 signaling, suggesting that localized activation of caspases lie downstream of a ligand receptor system, acting as key promoters of axonal branch tip and synaptic dynamics to restrict arbor growth in vivo in the central nervous system.


Preoperative radiographically guided wire marking of nonpalpable breast lesions.
In 37 women with possibly malignant lesions detected at radiography of the breast, 42 excisional biopsies were performed using preoperative guide wire marking at radiography. The wire transfixed or missed the lesion by less than one cm in 95 per cent of the cases, and in all but three cases a precise localization was obtained with only one wire. Full removal of the lesion was obtained at the first excision in 40 procedures and a second excision was necessary in only two patients. Minor wound complications occurred in two patients. The malignancy rate was 13.5 per cent and metastatic lymph node involvement was not observed in any of the patients. The localization method described is easy to perform and highly recommendable.


Effects of Aspergillus fumigatus on glucocorticoid receptor and β2-adrenergic receptor expression in a rat model of asthma.
Conventional inhaled corticosteroids or β2-adrenergic receptor agonists do not work well in some asthmatic populations while empirical antifungal therapy has obvious impact on those patients. The study was designed to investigate whether short-term exposure to Aspergillus fumigatus (A. fumigatus) could decrease glucocorticoid receptor (GCR) and β2-adrenergic receptor (ADRB2) expression in lung tissue of asthmatic rats. A rat model of chronic asthma was first established by ovalbumin sensitization and challenge. Rats with chronic asthma were then exposed to short-term application of A. fumigatus spores. Airway hyper-responsiveness, eosinophil ratio in bronchoalveolar lavage (BAL) fluid and total IgE in serum were counted in these experimental animals. GCR and ADRB2 expression in the lung were detected and analyzed. Furthermore, the levels of toll-like receptors (TLRs) 2, 3 and 4 in lung tissue were measured. Short-term exposure to A. fumigatus could down-regulate the expression of GCR, aggravate airway hyper-responsiveness and increase the level of TLR2 in rats with asthma. There were no obvious changes in the levels of ADRB2 expression, recruited eosinophils, total IgE, TLR3 and TLR4 after application of A. fumigatus in asthmatic rats. These findings indicate that A. fumigatus exposure may be involved in glucocorticoids unresponsiveness by down-regulating the expression of GCR in asthmatics. The possibility of A. fumigatus colonization or infection should not be ignored in patients of steroid-resistant asthma.


Application of an artificial neural network and genetic algorithm for determination of process orbits in the koji making process.
In order to estimate alpha-amylase, glucoamylase, acid proteinase, and acid carboxypeptidase activities in koji from the process variables and initial conditions of the koji making process, artificial neural network (ANN) models (ANN-10, -11, -15, and -21) were constructed with 10, 11, 15, and 21 input variables, respectively. These models could estimate the enzyme activities with high accuracy. Temperature and humidity orbits were then acquired by a genetic algorithm searching in the reverse direction using ANN-10, -11, -15, and -21 (GA-10, -11, -15, and -21). The orbits acquired by GA-15 and -11 were almost identical to the actual orbits, but those acquired by GA-21 and -10 were different. Enzyme activities acquired by GA-15 had 1.3% errors compared with the target values, while those acquired by GA-11 had 9.7% errors. GA-15 was, therefore, selected as the most suitable algorithm and was used to determine temperature and humidity orbits for target enzyme activities. Test koji making was then carried out according to the orbits acquired. As a result, the enzyme activities of the koji produced were almost the same as the target values.


Correlation between first-trimester maternal serum markers, second-trimester uterine artery doppler indices and pregnancy outcome.
The aim of this study was to assess the correlation between first trimester maternal serum free beta-human chorionic gonadotropin (fBHCG), pregnancy-associated plasma protein A (PAPPA), second-trimester uterine artery (UA) Doppler measurements and adverse pregnancy outcomes. Serum levels of PAPPA and fBHCG were determined at the first trimester, and patients underwent bilateral UA Doppler assessments at 20-25 weeks of gestation. A serum PAPPA level <0.4 MoM was termed as low and the abnormal Doppler findings were the presence of bilateral notches and RI >0.52 (mean) or unilateral notch and RI >0.66 (90th percentile). Mean PAPPA level was significantly lower in cases with unilateral or bilateral notches (1.09; 0.79 and 0.80 MoM for 0, 1 and 2 notches, p < 0.001). Fifty-two cases (12.8%) had a low PAPPA level; in this group the incidence of abnormal Doppler was significantly higher (34.6 vs. 18.4%, p = 0.011). In the presence of abnormal Doppler in a case with a low serum PAPPA the risk of pregnancy-induced hypertension (OR = 4.56, p = 0.0067), low birth weight (OR = 6.8, p = 0.0002) and the risk of at least one complication (OR = 7.6, p = 0.00001) were significantly high. Combination of first- and second-trimester findings might improve the efficiency of screening for pregnancy complications.


OPP Labeling Enables Total Protein Synthesis Quantification in CHO Production Cell Lines at the Single-Cell Level.
Accurate measurement of global and specific protein synthesis rates is becoming increasingly important, especially in the context of biotechnological applications such as process modeling or selection of production cell clones. While quantification of total protein translation across whole cell populations is easily achieved, methods that are capable of tracking population dynamics at the single-cell level are still lacking. To address this need, we apply O-propargyl-puromycin (OPP) labeling to assess total protein synthesis in single recombinant Chinese hamster ovary (CHO) cells by flow cytometry. Thereby we demonstrate that global protein translation rates slightly increase with progression through the cell cycle during exponential growth. Stable CHO cell lines producing recombinant protein display similar levels of total protein synthesis as their parental CHO host cell line. Global protein translation does not correlate with intracellular product content of three model proteins, but the host cell line with high transient productivity has a higher OPP signal. This indicates that production cell lines with increased overall protein synthesis capacity can be identified by our method at the single-cell level. In conclusion, OPP-labeling allows rapid and reproducible assessment of global protein synthesis in single CHO cells, and can be multiplexed with DNA staining or any type of immunolabeling of specific proteins or markers for organelles.


Fluctuation-induced collective motion: a single-particle density analysis.
In a system of noisy self-propelled particles with interactions that favor directional alignment, collective motion will appear if the density of particles increases beyond a certain threshold. In this paper, we argue that such a threshold may depend also on the profiles of the perturbation in the particle directions. Specifically, we perform mean-field, linear stability, perturbative, and numerical analyses on an approximated form of the Fokker-Planck equation describing the system. We find that if an angular perturbation to an initially homogeneous system is large in magnitude and highly localized in space, it will be amplified and thus serves as an indication of the onset of collective motion. Our results also demonstrate that high particle speed promotes collective motion.


Stereoselective Chlorination and Bromination of Enamides and Enamines via an Electrostatic Attraction Effect Using (1,1-Diacetoxyiodo)benzene and a Halide Source.
The direct chlorination and bromination of (E)-enamines and (Z)-enamides to the corresponding (Z)-configurated α-chloroenamines, α-bromoenamines, and α-chloroenamides have been realized using NiCl2·6H2O or tetrabutyl ammonium bromide as a halide source and (1,1-diacetoxyiodo)benzene as an oxidant. The high stereoselective reactions which produce products with only (Z)-configurations can be attributed to the structure of the intermediates, the conformations of which are controlled by the electrostatic attractions between the positively charged nitrogen atoms and the oxygen atoms of the carbonyl group. This type of electrostatic effect has never been reported in olefin halogenations. For this reason, the three-membered bromonium ion is only a minor intermediate in the enamine bromination pathway. These methods open pathways to prepare α-chloroenamines and α-chloroenamides, which are not accessible via the currently used methods.


The Roles of Chronic Disease Complexity, Health System Integration, and Care Management in Post-Discharge Healthcare Utilization in a Low-Income Population.
Economically disadvantaged individuals with chronic disease have high rates of in-patient (IP) readmission and emergency department (ED) utilization following initial hospitalization. The purpose of this study was to explore the relationships between chronic disease complexity, health system integration (admission to accountable care organization [ACO] hospital), availability of care management interventions (membership in managed care organization [MCO]), and 90-day post-discharge healthcare utilization. We used de-identified Medicaid claims data from two counties in western New York. The study population was 114,295 individuals who met inclusion criteria, of whom 7,179 had index hospital admissions in the first 9 months of 2013. Individuals were assigned to three disease complexity segments based on presence of 12 prevalent conditions. The 30-day inpatient (IP) readmission rates ranged from 6% in the non-chronic segment to 12% in the chronic disease complexity segment and 21% in the organ system failure complexity segment. Rehospitalization rates (both inpatient and emergency department [ED]) were lower for patients in MCOs and ACOs than for those in fee-for-service care. Complexity of chronic disease, initial hospitalization in a facility that was part of an ACO, MCO membership, female gender, and longer length of stay were associated with a significantly longer time to readmission in the first 90 days, that is, fewer readmissions. Our results add to evidence that high-value post-discharge utilization (fewer IP or ED rehospitalizations and early outpatient follow-up) require population-based transitional care strategies that improve continuity between settings and take into account the illness complexity of the Medicaid population. © 2016 Wiley Periodicals, Inc.


The influence of stimulation regimes and luteal phase support on the outcome of IVF.
Successful in-vitro fertilization (IVF) requires the generation of a number of healthy embryos and adequate priming and maintenance of a receptive endometrium. Both of these factors are influenced by ovarian stimulation regimes and are responsive to endocrine manipulation. Detailed analysis of follicular phase patterns of hormone secretion have established an inverse relationship between luteinizing hormone (LH) and egg/embryo quality which is not discernible on microscopic examination. The advent and extensive use of LHRH agonists in ovarian stimulation has gone some way towards optimizing embryo fitness by suppressing LH secretion and this has exposed the endometrial contribution to a failure of implantation to closer examination. The supraphysiological production of oestradiol and progesterone from the large numbers of follicles developed during ovarian stimulation cannot be without effect on the endometrium. Data presented in this brief review show how our understanding of ovarian stimulation and its influence on the outcomes of IVF has advanced and highlights the opportunities for manipulation of the endometrium to encourage implantation.


Temporal dynamics of whole body residues of the neonicotinoid insecticide imidacloprid in live or dead honeybees.
In cases of acute intoxication, honeybees often lay in front of their hives for several days, exposed to sunlight and weather, before a beekeeper can take a sample. Beekeepers send samples to analytical laboratories, but sometimes no residues can be detected. Temperature and sun light could influence the decrease of pesticides in bee samples and thereby residues left for analysis. Moreover, samples are usually sent via normal postal services without cooling. We investigated the temporal dynamics of whole-body residues of imidacloprid in live or dead honeybees following a single-meal dietary exposure of 41 ng/bee under various environmental conditions, such as freezing, exposure to UV light or transfer of individuals through the mail system. Immobile, "dead" looking honeybees recovered from paralysis after 48 hours. The decrease of residues in living but paralysed bees was stopped by freezing (= killing). UV light significantly reduced residues, but the mode of transport did not affect residue levels. Group feeding increased the variance of residues, which is relevant for acute oral toxicity tests. In conclusion, elapsed time after poisoning is key for detection of neonicotinoids. Freezing before mailing significantly reduced the decrease of imidacloprid residues and may increase the accuracy of laboratory analysis for pesticides.


Coexistent parathyroid adenomas and Hurthle cell tumors: failure of full detection by subtraction method.
Tc-99m sestamibi and I-123 sodium iodide studies were performed on two patients, one with a neck mass and another with suspected hyperparathyroidism. Subtraction images, detected what proved to be Hurthle cell tumors in each case, but coexisting parathyroid adenomas, which were found at surgery, were not visualized. The findings indicate that both types of lesions can occur simultaneously, and that studies are needed to determine whether detailed assays of rate of washout could distinguish between the lesions.


Peptidoglycan Compositional Analysis of Enterococcus faecalis Biofilm by Stable Isotope Labeling by Amino Acids in a Bacterial Culture.
Peptidoglycan (PG) is a major component of the cell wall in Enterococcus faecalis. Accurate analysis of PG composition provides crucial insights into the bacterium's cellular functions and responses to external stimuli, but this analysis remains challenging because of various chemical modifications to PG-repeat subunits. We characterized changes to the PG composition of E. faecalis grown as planktonic bacteria and biofilm by developing "stable isotope labeling by amino acids in bacterial culture" (SILAB), optimized for bacterial cultures with incomplete amino acid labeling. This comparative analysis by mass spectrometry was performed by labeling E. faecalis in biofilm with heavy Lys (l-[13C6,2D9,15N2]Lys) and planktonic bacteria with natural abundance l-Lys, then mixing equal amounts of bacteria from each condition, and performing cell wall isolation and mutanolysin digestion necessary for liquid chromatography and mass spectrometry. An analytical method was developed to determine muropeptide abundances using correction factors to compensate for incomplete heavy Lys isotopic enrichment (98.33 ± 0.05%) and incorporation (83.23 ± 1.16%). Forty-seven pairs of PG fragment ions from isolated cell walls of planktonic and biofilm samples were selected for SILAB analysis. We found that the PG in biofilm showed an increased level of PG cross-linking, an increased level of N-deacetylation of GlcNAc, a decreased level of O-acetylation of MurNAc, and an increased number of stem modifications by d,d- and l,d-carboxypeptidases.


Functionalized Acupuncture Needle as Surface-Enhanced Resonance Raman Spectroscopy Sensor for Rapid and Sensitive Detection of Dopamine in Serum and Cerebrospinal Fluid.
It is a challenge to develop a robust sensor for simple, rapid operation and sensitive detection of neurotransmitters in complex specimens. Herein, ferric citrate functionalized gold nanoparticles (CA-FeIII /Au NPs) are utilized to develop a facile sensor based on surface-enhanced resonance Raman spectroscopy (SERRS) for sensitive detection of dopamine (DA). The sensor is prepared by decorating the acupuncture needle with Au NPs, which enables sufficient surface-enhanced Raman spectroscopy enhancement. The CA-FeIII structure is highly sensitive and selective for DA due to the formation of the CA-FeIII -DA resonant structure; this indicates the advantages of capturing, carrying, and separating DA molecules from complicated samples in a simple operation. Furthermore, the practical application of the fabricated sensor is validated by the detection of DA in pretreated serum and cerebrospinal fluid of acupuncture-treated mice with detection limits of 0.1 and 2.5 nm DA, respectively. The developed active acupuncture needle sensor has potential benefits for sensitive detection and qualitative identification of DA molecules from biological samples.


Nicotine and smokeless tobacco effects on gingival and peripheral blood mononuclear cells.
The pathogenesis of tobacco-related periodontal diseases is not well understood. The purpose of this study was therefore to investigate smokeless tobacco extract (ST) and nicotine effects on prostaglandin E2 (PGE2) and interleukin-1beta (IL-1beta) secretion by peripheral blood mononuclear cells (PBMC, consisting of monocytes and lymphocytes) and gingival mononuclear cells (GMC). Both peripheral blood and gingival tissue adjacent to the alveolar crest were taken from non-smoking adult periodontitis patients. Gingival tissue was treated with collagenase and deoxyribonuclease and GMC and PBMC were isolated by Ficoll-Hypaque centrifugation. GMC and PBMC (100,000 cells/200 microl) were cultured for 24 hours in supplemented RPMI 1640 alone (control), or in supplemented RPMI 1640 containing 1% ST, 100 microg/ml nicotine, 1 microg/ml Porphyromonas gingivalis LPS, or 1 microg/ml P. gingivalis LPS and either 100 microg/ml nicotine or 1% ST. Enzyme immunoassays were used to quantify PGE2 and IL-1beta. Treatments were compared by repeated measures ANOVA. 100 microg/ml nicotine (7-fold, p<0.02) and 1% ST (3.5-fold, p<0.004) significantly increased secretion of PGE2 by PBMC relative to control cultures. 100 microg/ml nicotine and 1% ST, however, had no effect on IL-1beta secretion by PBMC. Enhanced PGE2 secretion also was seen when PBMC were treated with P. gingivalis LPS+ 100 microg/ml nicotine relative to P. gingivalis LPS alone (p<0.007). In contrast, 100 microg/ml nicotine significantly downregulated IL-1beta secretion by GMC relative to medium alone (p<0.008) and had no effect on PGE2 secretion by GMC. These data indicate that while nicotine and ST can stimulate PBMC to secrete PGE2, they cannot activate further mononuclear cells extracted from gingiva, possibly due to maximal previous stimulation in the periodontitis lesion.


[The application of biomed-informatics in cardiovascular research--data and knowledge].
With the development of biotechnology, especially the projects which lead to high throughout experimental results, lots of data have been jammed in every related fields, and broke the balance between data and knowledge in these fields. It is urgent to refine these data, and let them be more productive. To avoid these data being decaying into rubbish, technology and theory such as database, statistics, data mining, knowledge management, and artificial intelligence had been applied into biologic and medical study fields. So, a new standalone research subject--biomed-informatics has been formed. This paper reviewed the application of biomed-informatics in cardiovascular research, and gave the view for the future development of this subject.


Role of the Furosemide Stress Test in Renal Injury Prognosis.
Risk stratification and accurate patient prognosis are pending issues in the management of patients with kidney disease. The furosemide stress test (FST) has been proposed as a low-cost, fast, safe, and easy-to-perform test to assess tubular integrity, especially when compared to novel plasma and urinary biomarkers. However, the findings regarding its clinical use published so far provide insufficient evidence to recommend the generalized application of the test in daily clinical routine. Dosage, timing, and clinical outcomes of the FST proposed thus far have been significantly different, which further accentuates the need for standardization in the application of the test in order to facilitate the comparison of results between series. This review will summarize published research regarding the usefulness of the FST in different settings, providing the reader some insights about the possible implications of FST in clinical decision-making in patients with kidney disease and the challenges that research will have to address in the near future before widely applying the FST.


Contribution of molecular modeling and site-directed mutagenesis to the identification of two structural residues, Arg-220 and Asp-227, in aminopeptidase A.
Aminopeptidase A is a zinc metalloenzyme involved in the formation of brain angiotensin III, which exerts a tonic stimulatory action on the central control of blood pressure. Thus, central inhibitors of aminopeptidase A constitute putative central antihypertensive agents. Mutagenic studies have been performed to investigate organization of the aminopeptidase A active site, with a view to designing such inhibitors. The structure of one monozinc aminopeptidase (leukotriene A(4) hydrolase) was recently resolved and used to construct a three-dimensional model of the aminopeptidase A ectodomain. This new model, highly consistent with the results of mutagenic studies, showed a critical structural interaction between two conserved residues, Arg-220 and Asp-227. Mutagenic replacement of either of these two residues disrupted maturation and subcellular localization and abolished the enzymatic activity of aminopeptidase A, confirming the critical structural role of these residues. In this study, we generated the first three-dimensional model of a strict aminopeptidase, aminopeptidase A. This model constitutes a new tool to probe further the active site of aminopeptidase A and to design new inhibitors of this enzyme.


What binds biosociality? The collective effervescence of the parent-led conference.
Questions of community are central to many research settings in the social sciences. Rabinow argued that, in the wake of the Human Genome Project, an increasingly important form of collectivity would be biosociality. Biosociality recognises a central role for biomedical knowledge in constructing genetic identities and producing and reproducing social relationships. Accordingly, it is often imagined as a new form of social solidarity. We draw on observations of parent-led conferences to explore the way in which biosociality is expressed at events organised around a particular genetic syndrome - 22q11 deletion syndrome. The parent-led conferences took place within the United Kingdom between 2007 and 2010 and were observed as part of a multi-sited ethnographic study. By bringing together a geographically dispersed group of people together within the same physical location, conferences offer an ideal platform to empirically examine sociality. Durkheim used the term collective effervescence to describe the collective expression of heightened emotion. We suggest that in the case of the 22q11 deletion syndrome activities discussed in this paper, collective effervescence is a mechanism through which individuals become a collective. We argue that parent-led conferences gather individuals in one location on the basis of common biological factors, but it is the shared emotional experience of being together that consolidates and renews the connection between members.


Associations between fruit and vegetable consumption and psychological distress: results from a population-based study.
Several studies observed associations of various aspects of diet with mental health, but little is known about the relationship between following the 5-a-day recommendation for fruit and vegetables consumption and mental health. Thus, we examined the associations of the Swiss daily recommended fruit and vegetable intake with psychological distress. Data from 20,220 individuals aged 15+ years from the 2012 Swiss Health Survey were analyzed. The recommended portions of fruit and vegetables per day were defined as 5-a-day (at least 2 portions of fruit and 3 of vegetables). The outcome was perceived psychological distress over the previous 4 weeks (measured by the 5-item mental health index [MHI-5]). High distress (MHI-5 score ≤ 52), moderate distress (MHI-5 > 52 and ≤ 72) and low distress (MHI-5 > 72 and ≤ 100) were differentiated and multinomial logistic regression analyses adjusted for known confounding factors were performed. The 5-a-day recommendation was met by 11.6 % of the participants with low distress, 9.3 % of those with moderate distress, and 6.2 % of those with high distress. Consumers fulfilling the 5-a-day recommendation had lower odds of being highly or moderately distressed than individuals consuming less fruit and vegetables (moderate vs. low distress: OR = 0.82, 95 % confidence interval [CI] 0.69-0.97; high vs. low distress: OR = 0.55, 95 % CI 0.41-0.75). Daily intake of 5 servings of fruit and vegetable was associated with lower psychological distress. Longitudinal studies are needed to further determine the causal nature of this relationship.


An open trial of climatotherapy at the Dead Sea for patch-stage mycosis fungoides.
Climatotherapy at the Dead Sea (CDS) is a well-established therapeutic modality for moderate to severe psoriasis vulgaris, resulting in sustained remissions. It has also been found to be effective for atopic dermatitis, another T-cell-mediated dermatosis. We sought to prospectively evaluate the efficacy of CDS in patch-stage mycosis fungoides. A total of 12 patients with patch-stage mycosis fungoides (6 with stage IA and 6 with stage IB) were treated with CDS as monotherapy for 28 consecutive days according to the protocol for psoriasis, ie, a gradual increase of sun exposure to a maximum of 3 hours daily. A total of 9 patients achieved a complete clinical response (CCR), defined as no disease activity present; 2 achieved an almost CCR, defined as the reduction by more than 90% of disease activity; and 1 achieved a partial response, ie, reduction by more than 50% of disease activity. A CCR was achieved in all the patients with stage IA disease and in 3 of the 6 patients with stage IB disease. Of the 9 with a CCR, 6 also showed histopathologic clearing. Duration of the remissions, during which no therapy was allowed except for emollients, lasted from 2 to 9 months (mean: 5 months). No serious short-term side effects were recorded. CDS appears to be an effective, well-tolerated therapy for patch-stage mycosis fungoides.


Trends in sarcoidosis mortality rate in Japan from 2001 to 2020: A population-based study.
The sarcoidosis mortality rate has increased over the years, which contributes to the health care burden. Although epidemiological studies of sarcoidosis mortality in aging societies are essential, none have been published since 1989 in Japan. We aimed to investigate the trends in crude and age-adjusted sarcoidosis-associated mortality rates per 1,000,000 population in Japan from 2001 to 2020 using national death certificate data among older adults aged over 50 years. The data were analysed using the joinpoint regression models to estimate long-term trends and average annual percentage changes (AAPCs). A total of 3094 sarcoidosis-associated deaths were recorded from 2001 to 2020 in Japan; women constituted 65.3% of these, with a female:male ratio of 1.89. Nearly 80% of deaths were over the age of 65 years, of which 32% were over the age of 80 years. The trend in crude mortality of those aged ≥80 years markedly increased from 0.81 to 9.68 per 1,000,000 population in men and from 2.38 to 12.87 in women, respectively. The overall age-adjusted sarcoidosis mortality rate increased 2.46-fold during the study period, with an AAPC of 5.1%. This study revealed that sarcoidosis-associated deaths in Japan have significantly increased over the past two decades, especially among the older population with a female predominance. Given the rising mortality rate and susceptibility of the older population, sarcoidosis will require more attention from health care providers in terms of a multidisciplinary approach to address the specific needs of the older population.


Structure of pectate lyase A: comparison to other isoforms.
Pectate lyase A is a virulence factor secreted by the plant-pathogenic bacteria Erwinia chrysanthemi. The enzyme cleaves the glycosidic bond of pectate polymers by a calcium-dependent beta-elimination mechanism. The crystal structure of pectate lyase A from E. chrysanthemi EC16 has been determined in two crystal forms, monoclinic C2 to 1.8 A and rhombohedral R3 to 2.1 A. The protein structure is compared with two other pectate lyase isoforms from E. chrysanthemi EC16, pectate lyase C and pectate lyase E. Pectate lyase A is unique as it is the only acidic pectate lyase and has end products that are significantly more varied in length in comparison to those of the other four major pectate lyase isozymes. Differences and similarities in polypeptide trace, size and volume of the active-site groove and surface electrostatics are discussed.


[Blood supply of free skin flaps].
This article discusses the factors which determine the blood supply of free skin flaps. The method of free transfer consists of three steps, namely, the elevation of the flap, its transfer to the target area with microvascular anastomosis, and the healing of the flap on the recipient site. During the first two steps the flaps meet with a diminished blood supply and, in addition, their tissues undergo a period of ischemia. The flaps are usually able - within certain limits - to tolerate these disturbances of blood circulation. The healing of the flap begins with the proliferation of capillaries in the recipient site, which is stimulated by the relative hypoxia of the transferred tissues. The first capillary links between the recipient site and the flap can usually be observed on the third day after the transfer. On the sixth day after the operation, the anastomoses are quite numerous and can take over the blood supply to the flap. The progress of this dynamic process depends on the functional ability of the anastomosed vascular pedicle. The development of a new blood supply to the flap leads to profound remodelling of its original vascular system and the axial character of the flap is usually lost.


Developmental regulation of alpha 1A-adrenoceptor function in rat brain oligodendrocyte cultures.
In this study, we examined the effect of norepinephrine (NE) on phosphatidylinositol-4,5-bisphosphate (PI) hydrolysis in progenitors and differentiated oligodendrocytes. NE caused a time- and concentration-dependent increase in total inositol phosphate (IP(t)) formation. The magnitude of this response increased as oligodendrocytes matured and was accompanied with an increase in alpha(1)-adrenoceptor (alpha(1)-AR) levels. To pharmacologically characterize the alpha(1)-AR subtype mediating PI hydrolysis in 12-day differentiated oligodendrocytes, various selective antagonists were used. Prazosin, the non-selective 1-AR antagonist, blocked NE-mediated IP(t) formation. Similarly, the alpha(1A)-AR selective competitive antagonists, 5-methyl urapidil (5-MU) and WB4104, were potent blockers of NE-mediated IP(t) formation. In contrast, the alpha(1B)- and alpha(1D)-AR antagonist, chloroethylclonidine and the alpha(1D)-AR antagonist, BMY 7378, had no effect. These results suggest that NE-induced PI hydrolysis in differentiated oligodendrocytes was mediated through the alpha(1A)-AR. Furthermore, this response was prevented by EGTA and CdCl(2), suggesting a requirement for extracellular calcium. The presence of alpha(1)-AR subtypes in oligodendrocytes was confirmed by reverse transcriptase coupled polymerase chain reaction and by immunoprecipitation, with subtype specific antibodies. The results indicated that mRNA and protein for the alpha(1A)-, alpha(1B)- and alpha(1D)-AR subtypes were expressed. In conclusion, our findings show that oligodendrocytes express all three alpha(1)-AR subtypes but that only the alpha(1A)-AR was involved in NE-mediated IP(t) formation.


Promoters largely determine the efficiency of repressor action.
Operator sequence and repressor protein regulate the activity of the lac promoter over a greater than 1000-fold range. Combinations of the lac operator with other promoter sequences, however, differ vastly in the level of repression. The data presented show that the extent of repression is determined largely by the rates of complex formation of the competing systems operator-repressor and promoter-RNA polymerase and by the rate at which RNA polymerase clears the promoter. Moreover, up to 70-fold differences in the level of repression were found when the operator was placed in different positions within the promoter sequence. A kinetic model is proposed that explains the observed effects and that allows predictions on promoters controlled by negatively acting elements.


Partitioning of thioridazine and mesoridazine in human blood fractions.
The partitioning of 3H-thioridazine and 3H-mesoridazine in fresh human whole blood was studied. The packed red blood cells were solubilized using the New England Nuclear protocol for whole blood solubilization. The plasma fraction was further fractionated into protein bound and free drug by molecular ultrafiltration. All solutions were counted in Biofluor LSC cocktail and corrected for quenching. Greater than 99% of the labeled drug was bound to the red blood cells and plasma protein. For thioridazine, 59% is bound to RBC, 41% is bound to plasma protein and 0.7% is free; for mesoridazine, 63% is bound to RBC, 37% is bound to plasma protein and 0.9% is free. Though substantial overlap is found in the bound percentage for mesoridazine and thioridazine, more mesoridazine binds to RBC than thioridazine (p less than 0.01). There is no statistically significant relationship between the amount of drug bound to the RBC or to plasma protein and the percent free drug. Though the total drug concentration is the same (1 microgram/ml) the percent free drug is quite variable across subjects by as much as a factor of three. Since free drug is the pharmacologically active portion and therefore determinant of clinical response, the reported variation in free drug concentration at the same total blood concentration invalidates the measurements of total serum or plasma drug concentration as predictive of clinical response.


Identification of class 1 and 2 integrons from clinical and environmental Salmonella isolates.
The indiscriminate use of antimicrobials has selected for the emergence of resistant strains. Many mechanisms contribute to the spread of antimicrobial-resistant genes, and integrons play a key role in this process. The aim of this study was to describe the serotypes and resistance profiles, and to characterize the presence of integrons in Salmonella strains isolated from Dourados, Mato Grosso do Sul, Brazil. Thirty-six isolates from different sources were used. To evaluate the resistance profiles, the determination of minimum inhibitory concentrations together with polymerase chain reaction were used to screen for the presence of class 1 and class 2 integrons. The Infantis serotype of Salmonella was the most frequently isolated serotype. Minimum inhibitory concentrations showed that out of the 36 isolates, 11 (30.5%) were resistant to all the antimicrobials tested. These resistant isolates were separated into three groups: 4 clinical isolates (36.4%), 3 food isolates (36.4%), and 4 water isolates (27.2%). Class 1 integrons occurred in 31 (86.1%) isolates and were found in all 11 resistant isolates (35.5 %) and in 20 (64.5%) of the non-resistant isolates. Class 2 integrons were found in 3 (8.3%) isolates, which were all non-resistant. The presence of an integron did not necessarily confer resistance. Future studies will seek to identify the mechanism behind integron-mediated antimicrobial resistance.


Changes in membrane ionic conductance, but not changes in slip, can account for the non-linear dependence of the electrochemical proton gradient upon the electron-transport rate in chromatophores.
Decrease in the rate of cyclic electron transport (JE) measured from the absorbance changes associated with reaction centre bacteriochlorophyll led to a less than proportionate decrease in the membrane potential (delta psi) measured by electrochromism. In principle this result can be explained either by a delta psi-dependent slip in the H+/e- coupling ratio (nE) or by a delta psi-dependent change in the membrane ionic conductance. Simultaneous measurement of the membrane ionic current (JDIS) did not reveal any significant changes in the H+/e- ratio (JDIS/JE) and showed that conductance changes (JDIS/delta psi) account quantitatively for the curved dependence of delta psi on JE. Simultaneous recordings of JDIS and the extravesicular pH from cresol-red absorbance changes, suggest that protons are the main current-carrying species across the chromatophore membrane at high values of delta psi in the presence and absence of Fo-ATPase inhibitor. At reduced delta psi the flux of other ions outweighs the hydrogen ion current.


Prostaglandin E1 protects coronary microvascular function via the glycogen synthase kinase 3β-mitochondrial permeability transition pore pathway in rat hearts subjected to sodium laurate-induced coronary microembolization.
Prostaglandin E1 (PGE1) is used as a pretreatment for ischemia reperfusion injury in many biological systems. However, its value as a pretreatment for coronary microembolization (CME) is unknown. The goal of this study was to determine whether PGE1 would protect against CME. In a CME rat model, we observed microthrombi and early myocardial ischemia, with endothelium appearing exfoliated and mitochondria having irregular morphology and decreased internal complexity. The level of fibrinogen-like protein 2 prothrombinase was increased and superoxide dismutase and catalase levels were decreased. Moreover, mitochondria copy number and mitochondrial permeability transition pore (mPTP) opening were increased. Pretreatment with PGE1 (1 or 2 μg/kg) significantly improved these cardiological deficits, acting via the glycogen synthase kinase 3β (GSK-3β)-mPTP pathway. Unexpectedly, the phosphorylation of Akt at Ser473 decreased in the PGE1 at high dose. Overall, our findings suggested an important role for PGE1 in pretreatment of coronary microvascular dysfunction.


Effect of n-butyl-2-cyanoacrylate on the tensile strength and pressure resistance of tracheal anastomoses ex vivo.
To investigate the effects of n-butyl-2-cyanoacrylate on tracheal anastomoses in terms of increased tension and intraluminal pressure ex vivo. Ex vivo experimental study. Tertiary referral center (Department of Otolaryngology). Thirty sheep tracheas were used. Four cartilage rings were resected from the tracheas that were 20 cm in length. End-to-end anastomoses were performed by using Vicryl only (group 1), Vicryl and n-butyl-2-cyanoacrylate (group 2), and n-butyl-2-cyanoacrylate only (group 3). The amount of force to break off the anastomosis and the amount of intraluminal pressure to arouse air leakage through the anastomosis were measured. The mean force required to break off was 171.9 ± 29.7 N in group 1, 164.8 ± 26 N in group 2, and 13.52 ± 2 N in group 3. The mean force required to break off in group 3 was significantly lower than those in groups 1 and 2 (P = .008 and P = .008, respectively). The mean pressure required to cause air leakage was 49.6 ± 9.1 mm Hg in group 1, 113 ± 14.4 mm Hg in group 2, and 15 ± 4.2 mm Hg in group 3. Group 2 was found to be more resistant to intraluminal pressure than groups 1 and 3 (P = .008 and P = .008, respectively). n-Butyl-2-cyanoacrylate had no significant effect on tensile strength. However, its application on the suture line provided extra pressure resistance ex vivo. We believe that further studies need to be conducted to investigate its long-term effects and histological impact on tracheal anastomoses in vivo.


In-vitro activity of a new penem FCE 22101.
The in-vitro activity of a new penem FCE 22101 was evaluated in comparison with other antimicrobial agents against 966 aerobic and anaerobic Gram-negative and Gram-positive bacteria. FCE 22101 inhibited 90% of Enterobacteriaceae, Haemophilus influenzae, H. parainfluenzae, H. ducreyi, Neisseria gonorrhoeae, Branhamella catarrhalis, Staphylococcus aureus, Staph. epidermidis and group B streptococcus at concentrations of 0.12-4.0 mg/l. Pseudomonas aeruginosa was resistant with MIC90 of greater than 32 mg/l. Streptococcus faecalis displayed MIC90 of 16 mg/l. Bacteroides fragilis, Clostridium spp., Peptococcus spp. and Peptostreptococcus spp. were inhibited at concentrations of 0.25-2.0 mg/l. beta-Lactamase-producing or methicillin resistant bacteria did not have significantly elevated MICs. FCE 22101 was generally less active than imipenem but more active than other beta-lactam antibiotics examined.


Crystallization and preliminary X-ray analysis of a new crystal form of nitrite reductase from Pseudomonas aeruginosa.
Nitrite reductase from Pseudomonas aeruginosa (EC 126.96.36.199), a redox enzyme synthesized by the bacterium grown in the presence of nitrate, is a soluble dimer of two identical subunits of 60 kDa, each containing one c and one d1 haem as prosthetic groups. A new crystal from of the Ps. aeruginosa nitrite reductase in the oxidized state, suitable for X-ray structure determination, has been obtained by vapour diffusion at 20 degrees C, in the presence of 10% polyethylene glycol 4000, 50 mM Tris-HCl (pH 8.7), 400 mM NaCl and at a protein concentration of 14 mg/ml. The crystals are dark green elongated tetragonal prisms of dimensions 1.5 mm x 0.2 mm x 0.2 mm for the largest ones. These crystals are tetragonal with space group P4(1(3))2(1)2 and cell dimensions a = b = 128.2 A, c = 172.6 A. They diffract at least up to 2.8 A. Assuming a dimer in the asymmetric unit, the VM value is 2.95 A3/Da (58% of solvent).


Identification and management of high-risk patients with Klippel-Feil syndrome.
Patients with Klippel-Feil syndrome are often at high risk for neurological injury. The cervicomedullary junction and cervical spinal cord are especially vulnerable. Twenty-one patients examined and treated over a 20-year period are reviewed. The salient features of the syndrome are identified, and an approach to management is proposed.


The Delayed Neuroprotective Effect of Methylene Blue in Experimental Rat Brain Trauma.
After traumatic brain injury (TBI), an increase in dysfunction of the limbs contralateral to injury focus was observed. Using different behavioral tests, we found that a single intravenous injection of methylene blue (MB, 1 mg/kg) 30 min after the injury reduced the impairment of the motor functions of the limbs from 7 to 120 days after TBI. Administration of methylene blue 30 min after the injury and then monthly (six injections in total) was the most effective both in terms of preservation of limb function and duration of therapeutic action. This therapeutic effect was clearly manifested from the seventh day and continued until the end of the experiment-by the 180th day after TBI. MB is known to possess antioxidant properties; it has a protective effect against TBI by promoting autophagy and minimizing lesion volume in the first two weeks after TBI. Studies of the brains on the 180th day after TBI demonstrated that the monthly treatment of animals with MB statistically significantly prevented an increase in the density of microglial cells in the ipsilateral hemisphere and a decrease in the thickness of the corpus callosum in the contralateral hemisphere in comparison with untreated animals. However, on the 180th day after TBI, the magnetic resonance imaging scan of the animal brains did not show a significant reduction in the volume of the lesion in MB-treated animals. These findings are important for understanding the development of the long-term effects of TBI and expand the required therapeutic window for targeted neuroprotective interventions.


Protective effect of gossypol on lipopolysaccharide-induced acute lung injury in mice.
Gossypol has been reported to have anti-inflammatory properties. The purpose of this study was to evaluate the effect of gossypol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Male BALB/c mice were pretreated with gossypol 1 h before intranasal instillation of LPS. Then, 7 h after LPS administration, the myeloperoxidase in histology of lungs, lung wet/dry ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the BALF were measured by ELISA. The extent of phosphorylation of IκB-α, p65 NF-κB, p46-p54 JNK, p42-p44 ERK, and p38 were detected by western blot. Gossypol markedly attenuated the LPS-induced histological alterations in the lung and inhibited the production of TNF-α, IL-1β and IL-6. Additionally, gossypol reduced the inflammatory cells in BALF, decreased the wet/dry ratio of lungs and inhibited the phosphorylation of IκB-α, p65 NF-κB, p46-p54 JNK, p42-p44 ERK, and p38 caused by LPS. The data suggest that anti-inflammatory effects of gossypol against the LPS-induced ALI may be due to its ability of inhibition of the NF-κB and MAPKs signaling pathways. Gossypol may be a promising potential therapeutic reagent for ALI treatment.


Fixation stability and scotoma mapping for patients with low vision.
To develop a simplified device that performs fundus perimetry techniques such as fixation mapping and kinetic perimetry. We added visual stimulation to a near-infrared retinal imager, the laser scanning digital camera (LSDC). This device uses slit scanning illumination combined with a two-dimensional CMOS (complementary metal oxide semiconductor) detector, with continuous viewing of the retina. The CMOS readout was synchronized with the slit scanning, thereby serving as a confocal aperture to reduce stray light in retinal images. A series of retinal images of 36 degrees was automatically aligned to provide data for fixation maps and quantification of fixation stability. The LSDC and alignment techniques also provided fundus viewing with retinal location correction for scotoma mapping. First, fixation mapping was readily performed in patients with central scotoma or amblyopia. The automatic alignment algorithm allowed quantification of fixation stability in patients with macular pathologies that did not cause scotoma. Second, fixation stability was rapidly and quantitatively assessed by the automatic registration of the series of retina images. There was no significant difference in the fixation stability with automatic versus manual alignment. Kinetic perimetry demonstrated that fundus imaging helped reduce the variability of perimetric data by identifying and preventing false-positives caused by eye motion. We found that the size of the blind spot was significantly larger for dark targets on brighter backgrounds than when the contrast was reversed (p < 0.045). This is consistent with incremental targets being detected partially or wholly because of scattered light falling on more sensitive retinal locations. Fundus perimetry with the LSDC allows for a wide range of fixation and perimetry tasks.


Balloon atrial septostomy and transition of subcutaneous to intravenous prostacyclin infusion for rescuing advanced right heart failure in idiopathic pulmonary arterial hypertension: a case report.
Intravenous (IV) prostacyclin analogues infusion and balloon atrial septostomy (BAS) are two important treatment options for managing advanced right heart failure in patients with idiopathic pulmonary arterial hypertension (IPAH). References and protocols are rare for dose titrations and transitions between subcutaneous and IV prostacyclin in functional Class IV IPAH patients. Balloon atrial septostomy is rarely done in very few expert centres. A young female with IPAH who had received maximal medication including subcutaneous prostacyclin analogues injection was admitted due to advanced right heart failure. She received ascites drainage twice. Later, we directly switched the administration route of prostacyclin from subcutaneous to IV at a ratio of 1:1 instantly. Such rapid conversion led her into a state of profound hypotension and drowsy consciousness, which was resolved after escalating IV inotropics and reducing prostacyclin dosage. Five days later, she received BAS under the guidance of intracardiac echocardiography. Her urine output increased and dyspnoea improved gradually. Six months later, clinical worsening happened again with increase of ascites and dyspnoea. She underwent 2nd and 3rd session of graded BAS with relief of symptoms again. She received permanent transition to IV prostacyclin analogues infusions via a peripherally inserted central catheter after three sessions of BAS. Balloon atrial septostomy is effective in stabilizing the critical right heart failure in IPAH patients but should be intended as a bridge to lung transplant procedure. Transition from subcutaneous to IV prostacyclin is helpful but needs to be titrated in proper aliquots and time intervals to avoid abrupt haemodynamic changes.


Parathyroidectomy in dialysis patients: Indications, methods, and consequences.
Secondary hyperparathyroidism, characterized by increased PTH synthesis and secretion, is often seen in advanced stages of chronic kidney disease. Excessive proliferation of parathyroid cells leads to the development of diffuse hyperplasia that subsequently progresses to nodular histology. Refractory hyperparathyroidism occurs when parathyroid glands fail to respond to medical therapy. Parathyroidectomy (PTX), surgical resection of parathyroid glands, is usually performed in cases of persistent serum levels of PTH above 1000 pg/mL associated with hypercalcemia or when hyperparathyroidism is refractory to conservative therapy. Parathyroidectomy can be carried out using different procedures: subtotal PTX or total PTX with or without parathyroid autotransplantation. Parathyroid surgery may have undesirable consequences due to PTH oversuppression, such as the development of adynamic bone disease; hungry bone syndrome is quite common after this surgery. However, PTX improves survival and parameters of mineral metabolism. Parathyroidectomy needs to be considered in those patients with severe hyperparathyroidism with a poor response to pharmacological treatment and with distinct undesirable effects of PTH on bone and mineral metabolism parameters.


The Drosophila melanogaster genome.
Drosophila's importance as a model organism made it an obvious choice to be among the first genomes sequenced, and the Release 1 sequence of the euchromatic portion of the genome was published in March 2000. This accomplishment demonstrated that a whole genome shotgun (WGS) strategy could produce a reliable metazoan genome sequence. Despite the attention to sequencing methods, the nucleotide sequence is just the starting point for genome-wide analyses; at a minimum, the genome sequence must be interpreted using expressed sequence tag (EST) and complementary DNA (cDNA) evidence and computational tools to identify genes and predict the structures of their RNA and protein products. The functions of these products and the manner in which their expression and activities are controlled must then be assessed-a much more challenging task with no clear endpoint that requires a wide variety of experimental and computational methods. We first review the current state of the Drosophila melanogaster genome sequence and its structural annotation and then briefly summarize some promising approaches that are being taken to achieve an initial functional annotation.


Synthesis and evaluation of N-alkanoyl-S-benzyl-L-cysteinylglutamic acid esters as glyoxalase I inhibitors and anticancer agents.
Esters of several glutathione analogues have been synthesized in which the glycine moiety was replaced by straight-chain fatty acids and the mercapto group was benzylated . Two of the derivatives (sufficiently water-soluble for the assay) were found to inhibit glyoxalase I to a greater extent than did S-methylglutathione. The two glyoxalase I inhibitors did not inhibit P388 lymphocytic leukemia in mice, however.


Measurement of phantomless thoracic bone mineral density on coronary artery calcium CT scans acquired with various CT scanner models.
To determine the accuracy and precision of thoracic phantomless bone mineral density (BMD) measurements obtained on coronary artery calcium (CAC) computed tomography (CT) scans by using a variety of commercially available CT scanners. The institutional review board approved this Health Insurance Portability and Accountability Act-compliant study. A total of 4126 asymptomatic subjects (2022 [49%] men, 2104 [51%] women; mean age, 63.7 years ± 11.8 [standard deviation]) underwent CAC CT with the use of a quantitative CT calibration phantom for evaluation of subclinical atherosclerosis. Two hundred eighty subjects also underwent CT of the chest, abdomen, and pelvis (C7 through L5). Mean BMD of three consecutive thoracic vertebrae (in the T7-T10 range) was measured in all 4126 subjects. Individual calibration factors for each phantom insert and a general calibration factor for the spine were determined for each CT scanner model. The study population was then divided into three subgroups: All calibration factors were generated from group 1 (n = 1536) and were applied and tested in group 2 (n = 1587), and effects of various image acquisition parameters were assessed in group 3 (n = 1003). Accuracy (bias) and precision of thoracic phantomless BMD measurements across 14 CT scanner models from five manufacturers were determined. Phantomless BMD values correlated highly with standard phantom-based quantitative CT BMD values (r = 0.987, P < .001). Bias was 3.9% ± 1.4 for phantomless BMD measurements, and the mean coefficient of variation for the general calibration factor was 4.9% ± 2.4. Phantomless BMD can be measured accurately on CAC CT scans acquired with a variety of CT scanners without additional radiation exposure.


Nucleic acid synthesis in mustard gas-treated E. coli B.
Following exposure to dilute aqueous solutions of mustard gas, suspensions of E. coli B do not produce DNA although PNA is formed in nearly normal amounts. When the treated cells are infected with virus T(2), DNA is synthesized and RNA is not. The DNA formation continued after the virus titer reached a maximum.


Safety-Net Hospital Status Is Associated With Coronary Artery Bypass Grafting Outcomes at an Urban Academic Medical Center.
Socioeconomic disparities impact outcomes after cardiac surgery. At our institution, cardiac surgery cases from the safety-net, county funded hospital (CH), which primarily provides care for underserved patients, are performed at the affiliated university hospital. We aimed to investigate the association of socioeconomic factors and CH referral status with outcomes after coronary artery bypass grafting (CABG). The institutional Adult Cardiac Surgery database was queried for perioperative and demographic data from patients who underwent isolated CABG between January 2014 and June 2020. The primary outcome was major adverse cardiovascular event (MACE), a composite of postoperative myocardial infarction, stroke, or death. Secondary outcomes included individual complications. Chi-square, Wilcoxon rank-sum, and logistic regression analyses were used to compare differences between CH and non-CH cohorts. We included 836 patients with 472 (56.5%) from CH. Compared to the non-CH cohort, CH patients were younger, more likely to be Hispanic, non-English speaking, and be completely uninsured or require state-specific financial assistance. CH patients were more likely to have a history of tobacco and drug use, liver disease, diabetes, prior myocardial infarction, and greater degrees of left main coronary and left anterior descending artery stenosis. CH cases were less likely to be elective. The incidence of MACE was significantly higher in the CH cohort (16.3% versus 8.2%, P = 0.001). There were no significant differences in 30-d mortality, home discharge, prolonged mechanical ventilation, bleeding, sepsis, pneumonia, new dialysis requirement, cardiac arrest, or multiorgan system failure between cohorts. CH patients were more likely to develop renal failure and less likely to develop atrial fibrillation. On multivariable analysis, CH status (odds ratio 2.39, 95% confidence interval 1.25-4.55, P = 0.008) was independently associated with MACE. CH patients undergoing CABG presented with greater comorbidity burden, more frequently required nonelective surgery, and are at significantly higher risk of postoperative MACE.


[T-rosette test in Wilson's disease].
Twenty-three patients with Wilson's disease were studied. Using the rosette formation test it was found that the count of T-lymphocytes in the peripheral blood of these patients (29,77% +/- 12,58) was lower than in the control group (61,68% +/- 13,14). Using skin tests for demonstration of delayed hypersensitivity it was noted that in the group of patients the frequency of positive reaction with Candida albicans antigen was lower and these patients showed also less frequently positive reactions after DNCB immunization. The obtained results indicate that in Wilson's disease the functions of T-lymphocytes are distrubed. This may be the cause of previously observed hyperactivity of B-lymphocytes.


Deciphering the regulation of P2X4 receptor channel gating by ivermectin using Markov models.
The P2X4 receptor (P2X4R) is a member of a family of purinergic channels activated by extracellular ATP through three orthosteric binding sites and allosterically regulated by ivermectin (IVM), a broad-spectrum antiparasitic agent. Treatment with IVM increases the efficacy of ATP to activate P2X4R, slows both receptor desensitization during sustained ATP application and receptor deactivation after ATP washout, and makes the receptor pore permeable to NMDG+, a large organic cation. Previously, we developed a Markov model based on the presence of one IVM binding site, which described some effects of IVM on rat P2X4R. Here we present two novel models, both with three IVM binding sites. The simpler one-layer model can reproduce many of the observed time series of evoked currents, but does not capture well the short time scales of activation, desensitization, and deactivation. A more complex two-layer model can reproduce the transient changes in desensitization observed upon IVM application, the significant increase in ATP-induced current amplitudes at low IVM concentrations, and the modest increase in the unitary conductance. In addition, the two-layer model suggests that this receptor can exist in a deeply inactivated state, not responsive to ATP, and that its desensitization rate can be altered by each of the three IVM binding sites. In summary, this study provides a detailed analysis of P2X4R kinetics and elucidates the orthosteric and allosteric mechanisms regulating its channel gating.


Medication for hypercholesterolemia and the risk of nonfatal acute myocardial infarction: case-control study in Japan.
While lowering the blood cholesterol level has been shown to decrease the risk of coronary heart disease (CHD) in Western countries, little is known about the relationship between lipid-lowering drugs and CHD risk in Japan. A case-control study of nonfatal acute myocardial infarction (AMI) was conducted in Japan. A total of 658 cases aged 40-79 years and 1,274 community controls matched to each case by sex, year of birth, and residence were compared for their use of lipid-lowering drugs and level of serum total cholesterol. The study used 2 definitions of hypercholesterolemia: (i) either serum total cholesterol > or =6.21 mmol/L (240 mg/dl) or current use of hypolipidemic drugs; and (ii) either serum total cholesterol of > or =5.69mmol/L (220mg/dl) or current use of hypolipidemic drugs. Unconditional logistic regression analysis was used to adjust for hypertension, angina pectoris, diabetes mellitus, smoking, alcohol use, and physical activity as well as for sex and age. As compared with nonhypercholesterolemic subjects, those with untreated hypercholesterolemia had a significantly increased risk of AMI whereas no increase in the risk was observed for treated hypercholesterolemia. In the group with hypercholesterolemia, regardless of the definition, the adjusted odds ratios decreased progressively when the achieved cholesterol levels were lower.


Electrochemical degradation of phenol using electrodes of Ti/RuO(2)-Pt and Ti/IrO(2)-Pt.
Electrochemical degradation of phenol was evaluated at two typical anodes, Ti/RuO(2)-Pt and Ti/IrO(2)-Pt, for being a treatment method in toxic aromatic compounds. The influences of current density, dosage of NaCl, initial phenol concentration on electrochemical phenol degradation were investigated. It was found that Ti/RuO(2)-Pt anode had a higher oxygen evolution potential than Ti/IrO(2)-Pt anode, which will increase the current efficiency for electrochemical degradation, and the instantaneous current efficiency (ICE) was relatively higher at the initial time during phenol electrolysis. HOCl formed during electrolysis would play an important role on the oxidation of phenol. For the Ti/RuO(2)-Pt anode, phenol concentration decreased from around 8mg/L to zero after 30min of electrolysis with 0.3g/L NaCl as supporting electrolyte at the current density of 10mA/cm(2). Although phenol could be completely electrochemical degraded at both Ti/RuO(2)-Pt and Ti/IrO(2)-Pt anodes, phenol degradation was slower at the Ti/IrO(2)-Pt anode than at the Ti/RuO(2)-Pt anode due to the fact that passivation was to be found at the Ti/IrO(2)-Pt anode.