Splanchnic amino acid balance is affected by moderate variations of dietary protein in the developing Zucker rat.
This study attempted to determine the influence of moderate chronic variations in dietary protein intake, on splanchnic amino acid balances. Two series of 30-day-old male lean (Fa/?) Zucker rats were fed ad libitum for 30 days with either a standard diet (reference diet: RD), a high-protein diet (HP) (35%) or a low-protein diet (LP) (9%). After 30 days of dietary treatment, blood was withdrawn from hepatic vein, portal vein and arterial aorta in one set of rats. In another series the splanchnic organ blood flows were determined using fluorescent microspheres. From the individual amino acid concentration in each sample and the blood flows, we calculated the intestinal and hepatic balances. There were no significant differences in the hepatic arterial, portal or supra-hepatic flows induced by dietary protein content. The RD group showed a marked intestinal uptake of Gln and Cit and a net release of Pro, Ala and Gly. The LP group showed the same pattern, with increased release of Ala and Gly. In contrast to this limited amino acid release, the HP group showed a generalized net release of amino acids from the intestine. The RD group only show a net Gln release from the liver. Conversely, the HP group showed net uptake of Gln, Pro, Ala, Tyr and Lys, and the LP group took up Gly and Ala and released Asn, Gln and Cit. Our results indicate that growing Zucker rats respond to long-term moderate changes in the protein intake, diminishing the growth pattern only in the LP group, but not in the HP group. In spite of the limited amino acid supply, the LP group followed a similar pattern of intestinal balance for Ala, Gln, Pro, Gly and Cit, as showed by the RD group. On the other hand, excess of dietary amino acids in the HP group seems to promote a lower utilization of Gln by intestine probably due to an increased release of Ala instead of Gln from peripheral tissues.


Analyses of the PRF1 gene in individuals with hemophagocytic lymphohystiocytosis reveal the common haplotype R54C/A91V in Colombian unrelated families associated with late onset disease.
Familial hemophagocytic lymphohistiocytosis (FHL), is a rare autosomal recessive disorder characterized by an impairment of cytotoxic cells and uncontrolled activation of macrophages. This study presents the first description of four patients with FHL type 2 in Latin America. Patient 1 fulfilled the disease diagnostic criteria since 2 months of age, whereas patients 2, 3 and 4 exhibited the typical manifestations of the disease only later in their childhood. The PRF1 genetic analysis in these patients revealed two previously reported mutations: L17fsx50 and R54C. Interestingly, seven out of the 8 alleles evaluated here in patients carried the haplotype R54C/A91V, suggesting that this is a highly frequent FHL type 2 allele in Colombia. This haplotype confers residual cytotoxic function leading to late onset disease. Therefore, this report highlights the remarkable complexity of FHL diagnostic, emphasizing the importance of the genetic characterization of the disease.


A numerical taxonomic study of coryneform and related bacteria.
Two hundred and thirty-three strains of coryneform bacteria, including representatives of the genera Arthrobacter, Brevibacterium, Cellulomonas, Corynebacterium, Erysipelothrix, Jensenia, Kurthia, Listeria, Microbacterium, Mycobacterium, Nocardia and Propionibacterium and other related bacteria, were studied using 173 morphological, physiological and biochemical tests. The bacteria were grown on a soil extract medium which allowed growth of all the strains, and all were incubated at 30 degrees C. The results were subjected to computer analysis. The majority of the strains grouped into eight main clusters representing: (A) Lactobacillus, Listeria, Microbacterium thermosphactum and Streptococcus faecalis; (B) Erysipelothrix and Streptococcus pyogenes; (C) animal corynebacteria and Microbacterium flavum; (D) Cellulomonas and related bacteria; (E) Propionibacterium; (F) Arthrobacter, Brevibacterium, Kurthia and Mycobacterium rhodochrous; (G) plant pathogenic corynebacteria; (H) Nocardia. Based on these clusters, several recommendations are made regarding the classification of the coryneform area. (i) The members of clusters A and B at present placed in the Corynebacteriaceae would seem better moved to the Lactobacillaceae. (ii) The genus Corynebacterium would best be retained for the types species C. diphtheriae, closely related animal corynebacteria and Micro. flavum. (iii) Cellulomonas and Propionibacterium are distinct taxa more closely related to Corynebacterium than to either Arthrobacter or Lactobacillus. (iv) Clusters F and G are evidently heterogeneous. In particular the positions of Kurthia and the plant pathogenic corynebacteria are unclear. Arthrobacter is a large loose taxon and it is premature to decide on its taxonomic rank. The genus Brevibacterium should be retained for B. linens and closely related strains. (v) The cellulolytic forms of Nocardia should be removed from the genus; they are however quite distinct from Cellulomonas.


ASCORBATE PEROXIDASE6 protects Arabidopsis desiccating and germinating seeds from stress and mediates cross talk between reactive oxygen species, abscisic acid, and auxin.
A seed's ability to properly germinate largely depends on its oxidative poise. The level of reactive oxygen species (ROS) in Arabidopsis (Arabidopsis thaliana) is controlled by a large gene network, which includes the gene coding for the hydrogen peroxide-scavenging enzyme, cytosolic ASCORBATE PEROXIDASE6 (APX6), yet its specific function has remained unknown. In this study, we show that seeds lacking APX6 accumulate higher levels of ROS, exhibit increased oxidative damage, and display reduced germination on soil under control conditions and that these effects are further exacerbated under osmotic, salt, or heat stress. In addition, ripening APX6-deficient seeds exposed to heat stress displayed reduced germination vigor. This, together with the increased abundance of APX6 during late stages of maturation, indicates that APX6 activity is critical for the maturation-drying phase. Metabolic profiling revealed an altered activity of the tricarboxylic acid cycle, changes in amino acid levels, and elevated metabolism of abscisic acid (ABA) and auxin in drying apx6 mutant seeds. Further germination assays showed an impaired response of the apx6 mutants to ABA and to indole-3-acetic acid. Relative suppression of abscisic acid insensitive3 (ABI3) and ABI5 expression, two of the major ABA signaling downstream components controlling dormancy, suggested that an alternative signaling route inhibiting germination was activated. Thus, our study uncovered a new role for APX6, in protecting mature desiccating and germinating seeds from excessive oxidative damage, and suggested that APX6 modulate the ROS signal cross talk with hormone signals to properly execute the germination program in Arabidopsis.


Rising infant mortality in Delaware: an examination of racial differences in secular trends.
Recent increases in the Delaware Infant Mortality Rate (IMR) have been attributed to a rise in the mortality of very low birth weight (VLBW, <1500 g) infants born to mothers of higher socioeconomic status. This study examines whether the determinants of infant mortality trends in Delaware vary by race. Linked birth/infant death cohort files for the two periods 1993-1997 and 1998-2002 were used to evaluate the determinants of infant mortality trends separately for White and Black racial groups. Kitagawa analyses determined the components of race-specific infant mortality trends attributable to changes in both the birthweight distribution and birthweight-specific mortality rates. Maternal characteristics were examined to identify factors associated with IMR changes. Between the two time periods, infant mortality increased 23% among White infants and 17% among Black infants. For both races, the infant mortality increase was explained by increases in the incidence and mortality of VLBW infants, specifically below <500 grams for Blacks and <1,000 grams for Whites. The increased incidence of VLBW deliveries was statistically significant only among Whites, almost 40% of which was explained by an increase in multiple births. For both Whites and Blacks, the increase in VLBW mortality occurred mainly among births to more traditionally advantaged women who were twenty or older, at least high school educated, married, privately insured, had received first trimester prenatal care, and those who delivered multiple births. These findings suggest that conventional strategies of increasing access to prenatal care among disadvantaged women may be insufficient to reverse recent IMR increases in Delaware, irrespective of race. Future efforts should focus on understanding the causes of the increased infant mortality associated with higher socioeconomic status, including changes in assisted reproductive technology utilization, maternal health status, and obstetric practice.


Estimating COVID-19 R t in Real-time: An Indonesia health policy perspective.
COVID-19 (SARS COV2 n-corona virus) is the newfangled virus of the coronavirus family. COVID-19 can cause serious illness with symptoms of fever, cold, cough, and respiratory blockage. COVID-19 is a contagious virus, which originated in Wuhan, China. After one month, WHO declared it as a Pandemic due to its rapid spreading. Presently, Indonesia is also facing a hard time controlling the spread. Hence, it is essential to understand the spread rate in Indonesia and to analyze the strategies to minimize the virus spread. The proposed study can be used to assess variations in virus spread both nationally, and sub-nationally. This allows public health officials and policy-makers to track the progress of the outbreak in near real-time using an epidemiologically valid measure.


Changes in Left Ventricular Ejection Fraction Predict Survival and Hospitalization in Heart Failure With Reduced Ejection Fraction.
Left ventricular remodeling, as commonly measured by left ventricular ejection fraction (LVEF), is associated with clinical outcomes. Although change in LVEF over time should reflect response to therapy and clinical course, serial measurement of LVEF is inconsistently performed in observational settings, and the incremental prognostic value of change in LVEF has not been well characterized. The β-Blocker Evaluation of Survival Trial measured LVEF by radionuclide ventriculography at baseline and at 3 and 12 months after randomization. We built a series of multivariable models with 16 clinical parameters plus change in LVEF for predicting 4 major clinical end points, including the trial's primary end point of all-cause mortality. Among 2484 patients with at least 1 follow-up LVEF, change in LVEF was the second most significant predictor (behind baseline creatinine) of all-cause mortality (adjusted hazard ratio for improvement in LVEF by ≥5 U responder versus nonresponder [95% confidence intervals] for all-cause mortality=0.62 [0.52-0.73]). Other end points, including heart failure hospitalization or the composite of all-cause mortality and heart failure hospitalization, yielded similar results. LVEF change ≥5 U was associated with a modest increase in discrimination when added to traditional predictors and was predictive of outcomes in both the bucindolol and placebo treatment groups. LVEF change as a predictor of outcomes was affected by sex and race, with evidence that LVEF improvement is associated with less survival benefit in African Americans and women. Serial evaluation for LVEF change predicts both survival and heart failure hospitalization and provides a dynamic/real-time measure of prognosis in heart failure with reduced LVEF. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000560.


Laparoscopic Roux-en-Y gastric bypass for the treatment of morbid obesity: experience with 50 patients.
Roux-en-Y gastric bypass is currently considered the gold standard surgical option for the treatment of morbid obesity. Open RYGB is associated with a high risk of complications. Laparoscopic RYGB has been shown to reduce perioperative morbidity and improve recovery. To review our experience with laparoscopic RYGB during a 19 month period. The data were collected prospectively. The study group comprised all patients who underwent laparoscopic RYGB for treatment of morbid obesity as their primary operation between February 2006 and July 2007. The reported outcome included surgical results, weight loss, and improved status of co-morbidities, with follow-up of up to 19 months. The mean age of the 50 patients was 36.7 years. Mean body mass index was 44.7 kg/m2 (range 35-76 kg/m2); mean duration of surgery was 171 minutes. There was no conversion to open surgery. The mean length of stay was 4 days (range 2-7 days). Five patients (10%) developed a complication, but none of them required early reoperation and there were no deaths. Mean follow-up was 7 months (range 40 days-19 months). The excess body weight loss was 55% and 61% at 6 and 12 months respectively. Diabetes resolved completely or significantly improved in all five patients with this condition, as did hypertension in eight patients out of nine. Laparoscopic RYGB is feasible and safe. The results in terms of weight loss and correction of co-morbidities are comparable to other previously published studies. However, only surgeons with experience in advanced laparoscopic as well as bariatric surgery should attempt this procedure.


Psychiatric presentation of an arachnoid cyst.
A 23 year old white male, successful until 18 months prior to presentation, began noticing a decrease in mental functions which began to speed up with time. This progressed to a point where he had changes in his personality which appeared schizophreniform in nature. The patient was admitted to a general hospital for evaluation and a large arachnoid cyst was found in his left temporal lobe. He was taken to surgery where the lesion was removed. Postoperatively the patient's personality and mental status reverted back to the premorbid state.


State regulation and the delivery of physical therapy services.
The study purpose was to examine the relationship between state regulations of physical therapists (PT) and three dependent variables: physical therapist assistant (PTA) utilization more than 50 percent of the time during the treatment episode (high PTA utilization), number of visits, and patient self-reported functional health status (FHS) at discharge. We evaluated regulations governing licensure of PTAs, PT/PTA ratio, frequency of PT re-evaluation, and PTA supervision. The analytic sample included 63,900 patients from 38 states drawn from 395 clinics who participated in the Focus on Therapeutic Outcomes Inc. (Knoxville, TN) database in 2000 and 2001. Using a Bayesian modeling approach with the Markov Chain Monte Carlo estimation method, we fitted separate multilevel multivariate regression models predicting high PTA utilization, number of visits, and discharge FHS. Patients completed FHS surveys at intake and discharge. Clinicians recorded the number of visits and percentage of time a patient spent with each provider. After controlling for patient, therapist, and clinic characteristics, the presence of state regulations regarding PTA supervision was not associated with the likelihood of high PTA utilization. High PTA utilization and regulations requiring full-time onsite supervision were associated with more visits, whereas regulation of PT/PTA ratio was associated with fewer visits. Supervisory regulations were associated with better discharge FHS. High PTA utilization and use of therapy aides were associated with more visits per episode and lower discharge FHS. The use of care extenders in place of PTs is likely to result in less efficient and lower quality care in outpatient rehabilitation.


Superiority of long-acting to short-acting loop diuretics in the treatment of congestive heart failure.
Diuretics are the most prescribed drug in heart failure (HF) patients. However, clinical evidence about their long-term effects is lacking. The purpose of this study was to compare the therapeutic effects of furosemide and azosemide, a short- and long-acting loop diuretic, respectively, in patients with chronic heart failure (CHF). In this multicenter, prospective, randomized, open, blinded endpoint trial, we compared the effects of azosemide and furosemide in patients with CHF and New York Heart Association class II or III symptoms. 320 patients (160 patients in each group, mean age 71 years) were followed up for a minimum of 2 years. The primary endpoint was a composite of cardiovascular death or unplanned admission to hospital for congestive HF. During a median follow-up of 35.2 months, the primary endpoint occurred in 23 patients in the azosemide group and in 34 patients in the furosemide group (hazard ratio [HR], 0.55, 95% confidence interval [CI] 0.32-0.95: P=0.03). Among the secondary endpoints, unplanned admission to hospital for congestive HF or a need for modification of the treatment for HF were also reduced in the azosemide group compared with the furosemide group (HR, 0.60, 95%CI 0.36-0.99: P=0.048). Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admission to hospital for congestive HF.


Aesthetic Outcome and Psychosexual Distress After Treatment for Vulvar High-Grade Squamous Intraepithelial Lesions.
This study compared aesthetic outcome, psychosexual distress, and treatment satisfaction between women receiving surgical treatment or medical treatment with imiquimod for vulvar high-grade squamous intraepithelial lesion. This is an extended analysis of the multicenter, randomized noninferiority trial "topical imiquimod versus surgery for vulvar intraepithelial neoplasia." Patients were randomized to primary topical treatment or surgery and stratified by unifocal or multifocal disease. Digital photos of vulvar appearance were subsequently assessed for aesthetic outcome by 3 investigators blinded to group allocation. Psychosexual distress and treatment satisfaction were assessed with the Cervical Dysplasia Distress Questionnaire, the Sexual Activity Questionnaire, and the Client Satisfaction Questionnaire at baseline and follow-up. One hundred ten patients aged between 19 and 82 years were enrolled. Per-protocol analysis showed complete clinical response in 80% (37/46) using imiquimod, compared with 79% (41/52) after one surgical intervention. Photodocumentation at baseline and 6-month follow-up was available for 84 of these patients (44 imiquimod, 40 surgery). Blinded reviewer assessments of lesion size and lesion severity showed improvement from baseline to follow-up, with no differences between treatment groups. Sexual pleasure, discomfort, and distress remained stable from baseline to follow-up in both groups. Good aesthetic outcome of vulvar high-grade squamous intraepithelial lesion treatment can be achieved with imiquimod and surgery, consisting of ablation or local excision. Treatment satisfaction and stable psychosexual health may not be dependent on chosen treatment modality, but rather on counseling in accordance with patients' preferences.


Cross-link formation of the cysteine 228-tyrosine 272 catalytic cofactor of galactose oxidase does not require dioxygen.
Galactose oxidase (GO) belongs to a class of proteins that self-catalyze assembly of their redox-active cofactors from active site amino acids. Generation of enzymatically active GO appears to require at least four sequential post-translational modifications: cleavage of a secretion signal sequence, copper-dependent cleavage of an N-terminal pro sequence, copper-dependent formation of a C228-Y272 thioether bond, and generation of the Y272 radical. The last two processes were investigated using a truncated protein (termed premat-GO) lacking the pro sequence and purified under copper-free conditions. Reactions of premat-GO with Cu(II) were investigated using optical, EPR, and resonance Raman spectroscopy, SDS-PAGE, and X-ray crystallography. Premat-GO reacted anaerobically with excess Cu(II) to efficiently form the thioether bond but not the Y272 radical. A potential C228-copper coordinated intermediate (lambda max = 406 nm) in the processing reaction, which had not yet formed the C228-Y272 cross-link, was identified from the absorption spectrum. A copper-thiolate protein complex, with copper coordinated to C228, H496, and H581, was also observed in a 3 min anaerobic soak by X-ray crystallography, whereas a 24 h soak revealed the C228-Y272 thioether bond. In solution, addition of oxygenated buffer to premat-GO preincubated with excess Cu(II) generated the Y272 radical state. On the basis of these data, a mechanism for the formation of the C228-Y272 bond and tyrosyl radical generation is proposed. The 406 nm complex is demonstrated to be a catalytically competent processing intermediate under anaerobic conditions. We propose a potential mechanism which is in common with aerobic processing by Cu(II) until the step at which the second electron acceptor is required.


Bench-to-bedside review: carbon dioxide.
Carbon dioxide is a waste product of aerobic cellular respiration in all aerobic life forms. PaCO2 represents the balance between the carbon dioxide produced and that eliminated. Hypocapnia remains a common - and generally underappreciated - component of many disease states, including early asthma, high-altitude pulmonary edema, and acute lung injury. Induction of hypocapnia remains a common, if controversial, practice in both adults and children with acute brain injury. In contrast, hypercapnia has traditionally been avoided in order to keep parameters normal. More recently, advances in our understanding of the role of excessive tidal volume has prompted clinicians to use ventilation strategies that result in hypercapnia. Consequently, hypercapnia has become increasingly prevalent in the critically ill patient. Hypercapnia may play a beneficial role in the pathogenesis of inflammation and tissue injury, but may hinder the host response to sepsis and reduce repair. In contrast, hypocapnia may be a pathogenic entity in the setting of critical illness. The present paper reviews the current clinical status of low and high PaCO2 in the critically ill patient, discusses the insights gained to date from studies of carbon dioxide, identifies key concerns regarding hypocapnia and hypercapnia, and considers the potential clinical implications for the management of patients with acute lung injury.


Post-operative management of esophageal atresia-tracheoesophageal fistula and gastroesophageal reflux: a Canadian Association of Pediatric Surgeons annual meeting survey.
Esophageal atresia (EA), with or without tracheoesophageal fistula (TEF), is commonly associated with gastroesophageal reflux (GER) after surgical repair. One risk factor for anastomotic stricture is post-operative GER. This survey assessed practice patterns among attendees at the Canadian Association of Pediatric Surgeons (CAPS) annual meeting with respect to management of GER post EA-TEF repair. A pre-piloted survey was handed out and collected at the 2012 CAPS annual meeting. Data were entered and coded, and descriptive statistics were calculated. We distributed 70 surveys, and 57 (81.4%) surveys were returned. On average, the incidence of EA-TEF is 8-10 cases per institution, per year. Anti-reflux medication is started immediately post-operatively in 74% of patients at institution of feeds (11%), or if symptoms of reflux develop (14%). Proton pump inhibitors and H2-receptor antagonists are used in approximately equal proportion. Patients are typically kept on anti-reflux medication for 3-6 months (37%) or 6-12 months (35%). Most CAPS attendees treat postoperative GER prophylactically. However, there is no consistency in management strategy regarding which anti-reflux agent to use or for how long. A multi-centered study is required to establish a standardized protocol for the post-operative management of EA-TEF to prevent reflux and its effect on anastomotic strictures.


Proposal for genetic characterisation of wild-type mumps strains: preliminary standardisation of the nomenclature.
Though mumps virus (MuV) is a monotypic virus, genetic variation between strains has been described. Viruses have been placed into genotypes designated A-L based on the nucleotide sequence of the small hydrophobic (SH) gene, which is the most variable gene in the mumps genome. Molecular characterisation of MuV is an important component of mumps surveillance because it can help identify the transmission pathways of the virus as well as distinguish between wild-type and vaccine strains. Here, we propose a standardized nomenclature and an analysis protocol for the genetic characterisation of mumps strains to facilitate expansion of molecular epidemiological studies. In addition to assigning standard reference strains for the recognized genotypes of MuV, a convention is proposed for naming for strains and criteria to designate a new genotype.


Anger-sensitive networks: characterizing neural systems recruited during aggressive social interactions using data-driven analysis.
Social neuroscience uses increasingly complex paradigms to improve ecological validity, as investigating aggressive interactions with functional magnetic resonance imaging (fMRI). Standard analyses for fMRI data typically use general linear models (GLM), which require a priori models of task effects on neural processes. These may inadequately model non-stimulus-locked or temporally overlapping cognitive processes, as mentalizing about other agents. We used the data-driven approach of independent component analysis (ICA) to investigate neural processes involved in a competitive interaction. Participants were confronted with an angry-looking opponent while having to anticipate the trial outcome and the opponent's behaviour. We show that several spatially distinctive neural networks with associated temporal dynamics were modulated by the opponent's facial expression. These results dovetail and extend the main effects observed in the GLM analysis of the same data. Additionally, the ICA approach identified effects of the experimental condition on neural systems during inter-trial intervals. We demonstrate that cognitive processes during aggressive interactions are poorly modelled by simple stimulus onset/duration variables and instead have more complex temporal dynamics. This highlights the utility of using data-driven analyses to elucidate the distinct cognitive processes recruited during complex social paradigms.


Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming.
The biological and clinical heterogeneity of neuroblastoma (NB) demands novel biomarkers and therapeutic targets in order to drive the most appropriate treatment for each patient. Hypoxia is a condition of low-oxygen tension occurring in poorly vascularized tumor tissues. In this study, we aimed to assess the role of hypoxia in the pathogenesis of NB and at developing a new clinically relevant hypoxia-based predictor of outcome. We analyzed the gene expression profiles of 1882 untreated NB primary tumors collected at diagnosis and belonging to four existing data sets. Analyses took advantage of machine learning methods. We identified NB-hop, a seven-gene hypoxia biomarker, as a predictor of NB patient prognosis, which is able to discriminate between two populations of patients with unfavorable or favorable outcome on a molecular basis. NB-hop retained its prognostic value in a multivariate model adjusted for established risk factors and was able to additionally stratify clinically relevant groups of patients. Tumors with an unfavorable NB-hop expression showed a significant association with telomerase activation and a hypoxic, immunosuppressive, poorly differentiated, and apoptosis-resistant tumor microenvironment. NB-hop defines a new population of NB patients with hypoxic tumors and unfavorable prognosis and it represents a critical factor for the stratification and treatment of NB patients.


Inhaled salmeterol/fluticasone propionate: a review of its use in chronic obstructive pulmonary disease.
The salmeterol/fluticasone propionate dry powder inhaler (DPI) [Advair Diskus, Seretide Accuhaler] contains the long-acting beta2-adrenoceptor agonist salmeterol and the inhaled corticosteroid fluticasone propionate. In the US, twice-daily salmeterol/fluticasone propionate 50/250 microg is approved for use in adults with chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis, and in the EU, the twice-daily 50/500 microg dosage is approved for use in patients with severe COPD, repeat exacerbations and significant symptoms despite bronchodilator therapy. In patients with moderate-to-severe COPD, twice-daily inhaled salmeterol/fluticasone propionate 50/250 or 50/500 microg for 24-52 weeks improves predose forced expiratory volume in 1 second (FEV1) significantly more than salmeterol monotherapy, improves postdose or postbronchodilator FEV1 significantly more than fluticasone propionate monotherapy and results in clinically significant improvements in health-related quality of life. Salmeterol/fluticasone propionate 50/500 microg significantly reduced annual COPD exacerbations, especially in severe COPD. Some corticosteroid-related adverse events were increased in recipients of fluticasone propionate with or without salmeterol versus salmeterol monotherapy or placebo; withdrawal from fluticasone propionate, including combination therapy, needs careful management to minimise COPD exacerbations. The DPI combining a corticosteroid and long-acting beta2-agonist provides benefits over monotherapy and may encourage patient compliance in COPD.


Aceclidine effects on outflow facility after ciliary muscle disinsertion.
Aceclidine increases outflow facility with little accommodative effect. To determine whether this dissociation resides in the ciliary muscle (CM) or trabecular meshwork (TM), we measured aceclidine effects on perfusion outflow facility in both eyes of 8 rhesus monkeys after unilateral disinsertion of the CM from the TM. Facility in the control eyes increased by approximately 250% following intravenous pilocarpine and by an additional approximately 250% following intracameral pilocarpine, relative to baseline and uncorrected for washout. In CM-disinserted eyes, the facility response to intravenous and intracameral pilocarpine averaged approximately 25% of that in contralateral controls. Cytochalasin B, which acts directly on the TM to increase facility but is not additive to maximal pilocarpine doses in normal eyes, had no additional effect beyond that of pilocarpine in control eyes but induced an additional 100% facility increase relative to baseline in CM-disinserted eyes. The accommodative response to carbachol in CM-disinserted eyes was approximately 80% of that in contralateral controls, consistent with retention of CM contractility and the gonioscopic appearance of shallow CM disinsertion. Intracameral aceclidine HCl doses of 5 and 50 micrograms increased outflow facility by approximately 80 and 250%, respectively, in control eyes, and by approximately 0 and 80% in CM-disinserted eyes. Either the low aceclidine dose affected facility via the CM, while the high dose exerted an additional effect on the TM, or aceclidine acted only via the CM, with the low dose being ineffective and the high dose modestly effective in CM-disinserted eyes because only a few CM-TM attachments remained.


The relationship between diabetes and depressive symptoms in men with or at risk of HIV infection.
The aim of the study was to compare the prevalence of comorbid diabetes and depressive symptoms in men living with HIV (MLWH) with that in men without HIV infection and to determine associations between glycaemic control and depressive symptoms. Participants included 920 MLWH and 840 men without HIV infection from the Multicenter AIDS Cohort Study (MACS) with available data regarding glycaemic status [categorized as normal for fasting blood glucose (FBG) < 100 mg/dL, prediabetes for FBG 100-125 mg/dL, and diabetes, defined by self-report, diabetes medication use or FBG ≥ 126 mg/dL on at least two consecutive visits, with diabetes classified as controlled if Hemoglobin A1c (HbA1C) < 7.5% and uncontrolled if HbA1C ≥ 7.5%]. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) score, with CES-D ≥ 16 scores classified as elevated depressive symptoms. A modified Poisson regression model with robust variance was used and adjusted for covariates including HIV serostatus. Compared to men without HIV infection, MLWH had a higher mean CES-D score, but a similar prevalence of diabetes (11.3% versus 12.8%, respectively; P = 0.33). The concomitant prevalence of diabetes and elevated depressive symptoms did not differ by HIV serostatus (P = 0.215). In an adjusted analysis, men with uncontrolled diabetes had a greater prevalence of depressive symptoms compared to men with normoglycaemia (prevalence ratio = 1.43; 95% confidence interval 1.11, 1.84). The association between glycaemic status and depressive symptoms did not differ by HIV serostatus (P = 0.22 for interaction). Both controlled and uncontrolled diabetes were independently associated with a greater prevalence of depressive symptoms, regardless of HIV serostatus. These results highlight the importance of identifying depression in people with diabetes.


Pseudopodial actin dynamics control epithelial-mesenchymal transition in metastatic cancer cells.
A key cellular process associated with the invasive or metastatic program in many cancers is the transformation of epithelial cells toward a mesenchymal state, a process called epithelial to mesenchymal transition or EMT. Actin-dependent protrusion of cell pseudopodia is a critical element of mesenchymal cell migration and therefore of cancer metastasis. However, whether EMT occurs in human cancers and, in particular, whether it is a prerequisite for tumor cell invasion and metastasis, remains a subject of debate. Microarray and proteomic analysis of actin-rich pseudopodia from six metastatic human tumor cell lines identified 384 mRNAs and 64 proteins common to the pseudopodia of six metastatic human tumor cell lines of various cancer origins leading to the characterization of 19 common pseudopod-specific proteins. Four of these (AHNAK, septin-9, eIF4E, and S100A11) are shown to be essential for pseudopod protrusion and tumor cell migration and invasion. Knockdown of each of these proteins in metastatic cells resulted in reduced actin cytoskeleton dynamics and induction of mesenchymal-epithelial transition (MET) that could be prevented by the stabilization of the actin cytoskeleton. Actin-dependent pseudopodial protrusion and tumor cell migration are therefore determinants of EMT. Protein regulators of pseudopodial actin dynamics may represent unique molecular targets to induce MET and thereby inhibit the metastatic potential of tumor cells.


Residential mobility during pregnancy and the potential for ambient air pollution exposure misclassification.
Studies of environmental exposures and adverse birth outcomes often rely on maternal address at birth obtained from the birth certificate to classify exposure. Although the gestational age of interest is often early pregnancy, maternal addresses are not available for women who move during pregnancy when using maternal addresses abstracted from birth certificates. The aim of this study was to explore the extent of ambient air pollutant exposure misclassification due to maternal residential mobility during pregnancy among the subgroup of a New York birth cohort. The authors obtained the maternal addresses at birth from the New York Birth Certificate, and the maternal addresses by gestational age from the National Birth Defect Prevention Study for New York participants for the study period 1997-2002. Among the 1324 mothers, 172 (13.0%) moved once during pregnancy and 46 (3.5%) moved at least twice. When accounting for multiple addresses among some individuals, of the 218 mothers who moved, 38 (2.9%) moved in the 3rd to 8th weeks after conception (critical period, not exclusive from the 1st trimester), 80 (6.0%) moved in the 1st trimester, 112 (8.5%) in the 2nd trimester, and 51 (3.9%) in the 3rd trimester. Air monitoring data from the New York Department of Environmental Conservation were used as surrogates to compute the ambient ozone and PM(10) exposures for mothers with complete residential data. This study estimates exposure using maternal address at birth obtained from birth certificates, compared to exposure estimates when using maternal addresses by gestational age obtained from maternal interview, the gold standard. Average exposures during pregnancy were similar when using interview based versus birth certificate addresses (0.035 vs. 0.035 ppm for ozone, and 20.11 vs. 20.09 microg/m(3) for PM(10), respectively). Kappa statistics and percent agreement were calculated to measure the degree of agreement for dichotomous exposure measurements (<median vs.>=median) and weighted kappa for quartile exposure measurements by gestational age. All the statistics indicated a high agreement between the two measurements. For mothers who moved, the majority maintained their address in the same exposure region. Given the low mobility during pregnancy and the short distance moved, the exposure assignment did not change substantially when using the more accurate interview based addresses in this study. However, the level of observed agreement may decrease for studies that require smaller geographic zones for exposure assignments or with more mobile study populations.


Cluster of two cases of botulism due to Clostridium baratii type F in France, November 2014.
The first two cases in France of botulism due to Clostridium baratii type F were identified in November 2014, in the same family. Both cases required prolonged respiratory assistance. One of the cases had extremely high toxin serum levels and remained paralysed for two weeks. Investigations strongly supported the hypothesis of a common exposure during a family meal with high level contamination of the source. However, all analyses of leftover food remained negative.


Oxygenation targets in ICU patients with COVID-19: A post hoc subgroup analysis of the HOT-ICU trial.
Supplemental oxygen is the key intervention for severe and critical COVID-19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage. In spring 2020, 110 COVID-19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT-ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO2 ) of 8 kPa (lower oxygenation group) or a PaO2 of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID-19 patients. At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58-1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end-expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant. Targeting a PaO2 of 8 kPa may be beneficial in ICU patients with COVID-19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial. ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.


Relation of Longitudinal Changes in Quality of Life Assessments to Changes in Functional Capacity in Patients With Heart Failure With and Without Anemia.
Clinical status in heart failure is conventionally assessed by the physician's evaluation, patients' own perception of their symptoms, quality of life (QoL) tools, and a measure of functional capacity. These aspects can be measured with tools such as the New York Heart Association functional class, QoL tools such as the EuropeanQoL-5 dimension, the Kansas City Cardiomyopathy Questionnaire, patient global assessment (PGA), and by 6-minute walk test (6MWT), respectively. The ferric carboxymaltose in patients with heart failure and iron deficiency (FAIR-HF) trial demonstrated that treatment with intravenous ferric carboxymaltose in iron-deficient patients with symptomatic heart failure with reduced left ventricular function, significantly improved all 5 outcome measures. This analysis assessed the correlations between the longitudinal changes in the measures of clinical status, as measured by QoL tools and the changes in the measures of functional capacity as measured by the 6MWT. This analysis used the database from the FAIR-HF trial, which randomized 459 patients with chronic heart failure (reduced left ventricular ejection fraction) and iron deficiency, with or without anemia to ferrous carboxymaltose or placebo. The degree of correlation between QoL tools and the 6MWT was assessed at 4, 12, and 24 weeks. The data demonstrate highly significant correlations between QoL and functional capacity, as measured by the 6MWT, at all time points (p <0.001). Changes in PGA, Kansas City Cardiomyopathy Questionnaire, and EuroQoL-5D correlated increasingly over time with changes in 6MWT performance. Interestingly, the strongest correlation at 24 weeks is for the PGA, which is a simple numerical scale (r = -0.57, p <0.001). This analysis provides evidence that QoL assessment show a significant correlation with functional capacity, as measured by the 6MWT. The strength of these correlations increased over time.


Radiotherapy in Wilms' tumour.
Radiotherapy in the treatment of Wilms' tumour has had a long and distinguished history. In the pre-chemotherapy era, it was shown that radiotherapy given postoperatively increased the survival of patients with this disease. As Wilms' tumour is highly chemosensitive, the use of radiotherapy has been modified and it is now clear that it is not necessary for patients with stage I and II favourable histology (approximately 60% of all patients with Wilms' tumour). No dose response has been demonstrated for radiotherapy in Wilms' tumour; therefore, the National Wilms' Tumor Study protocols use 10 Gy. Results from the International Society of Pediatric Oncology and United Kingdom Children's Cancer Study Group have shown that radiotherapy must continue to be used in certain circumstances.


In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response.
Harnessing regulatory T (Treg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific Treg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific Treg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8(+) T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-β, under which the autoantigenic peptides directed naïve CD4(+) T cells to differentiate into Foxp3(+) Treg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific Treg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific Treg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.


Tickling expectations: neural processing in anticipation of a sensory stimulus.
Predictions of the near future can optimize the accuracy and speed of sensory processing as well as of behavioral responses. Previous experience and contextual cues are essential elements in the generation of a subjective prediction. Using a blocked fMRI paradigm, we investigated the pattern of neural activation in anticipation of a sensory stimulus and during the processing of the somatosensory stimulus itself. Tickling was chosen as the somatosensory stimulus rather than simple touch in order to increase the probability to get a high degree of anticipation. The location and nature of the stimulus were well defined to the subject. The state of anticipation was initiated by attributing an uncertainty regarding the time of stimulus onset. The network of activation and deactivation during anticipation of the expected stimulus was similar to that engaged during the actual sensory stimulation. The areas that were activated during both states included the contralateral primary sensory cortex, bilateral areas in the inferior parietal lobules, the putative area SII, the right anterior cingulate cortex and areas in the right prefrontal cortex. Similarly, common decreases were observed in areas of sensorimotor cortex located outside the area representing the target of stimulus, i.e., areas that process information which is irrelevant to the attended process. The overlapping pattern of change, during the somatosensory stimulation and the anticipation, furthers the idea that predictions are subserved by a neuronal network similar to that which subserves the processing of actual sensory input. Moreover, this study indicates that activation of primary somatosensory cortex can be obtained without intra-modal sensory input. These findings suggest that anticipation may invoke a tonic top-down regulation of neural activity.


An overview of the design and methods for retrieving high-quality studies for clinical care.
With the information explosion, the retrieval of the best clinical evidence from large, general purpose, bibliographic databases such as MEDLINE can be difficult. Both researchers conducting systematic reviews and clinicians faced with a patient care question are confronted with the daunting task of searching for the best medical literature in electronic databases. Many have advocated the use of search filters or "hedges" to assist with the searching process. The purpose of this report is to describe the design and methods of a study that set out to develop optimal search strategies for retrieving sound clinical studies of health disorders in large electronics databases. To describe the design and methods of a study that set out to develop optimal search strategies for retrieving sound clinical studies of health disorders in large electronic databases. An analytic survey comparing hand searches of 170 journals in the year 2000 with retrievals from MEDLINE, EMBASE, CINAHL, and PsycINFO for candidate search terms and combinations. The sensitivity, specificity, precision, and accuracy of unique search terms and combinations of search terms were calculated. A study design modeled after a diagnostic testing procedure with a gold standard (the hand search of the literature) and a test (the search terms) is an effective way of developing, testing, and validating search strategies for use in large electronic databases.


Intracellular alkalinization potentiates slow inward current and prolonged bursting in a molluscan neuron.
1. The bilaterally paired ventral white cells (VWCs) of the buccal ganglion of Pleurobranchaea drive the cyclic motor output of ingestive feeding behavior during prolonged and endogenously sustained burst episodes (7). The capacity to support burst episodes is specifically induced by appetitive (food) stimulation of chemosensory pathways (5). Cyclic 3',5'-adenosine monophosphate (cAMP) and its agonists also induce prolonged burst episodes (8) through potentiation of a slow inward current (6). 2. Intracellular alkalinization of the VWC by externally applied ammonium ion and methylamine (5-20 mM) induces bursting and enhances slow inward current measured under voltage-clamp conditions. The enhancement of slow inward current is seen in the induction or augmentation of a negative slope resistance region in the current-voltage relation and in the enhancement of slowly decaying inward current tails recorded near the K+ equilibrium potential following depolarizing voltage commands. 3. Intracellular injection of alkalinizing agents, bicarbonate ion and a strong buffer solution at pH 8.1, also enhance the inward current. In ammonium saline, enhancement of inward current is dependent on NH3 content, not NH4+; NH3 is the intracellular alkalinizing agent of ammonium saline. Therefore, the change in slow inward current is an effect specific to intracellular pH. 4. The time courses of inward current enhancement and intracellular pH change in NH4+ saline are similar. The results of this study suggest that normal fluctuations in intracellular pH may be significant determinants of the excitability and consequent activity of these and perhaps other neurons. The potential interaction of intracellular pH and cyclic AMP metabolism is discussed.


An observational study of the pattern of HIV infection in a specified rural area of India with special reference to migratory laborers.
Determination of the pattern of HIV/AIDS in patients attending voluntary confidential counseling and testing center (VCCTC) and prevention of parent-to-child transmission (PPTCT) center of a low-prevalence district of Eastern India. To find out high-risk group and interventional strategy for prevention. Cross-sectional exploratory secondary data analysis from the VCCTC and PPTCT register. Of the 1348 participants, 160 (11.86%) adults were HIV seropositive. Prevalence in males and females was 9.8% and 20.7%, respectively. Among 22 (1.63%) seropositive children, transmission was vertical in 18 (81.8%). Seventy-one (88.75%) positive adult males were migratory goldsmiths working in Mumbai and other big cities. They were clustered in a particular locality (Daspur). Goldsmiths migrated from Daspur to big cities are the bridge populations who are responsible for higher prevalence of HIV in their families and locality. Interventional strategies targeted at this high-risk group are suggested.


Cerebellar dysfunction in progressive supranuclear palsy: a transcranial magnetic stimulation study.
Progressive supranuclear palsy (PSP) rarely shows cerebellar signs and symptoms even though the cerebellar dentate nuclei are involved pathologically. This study evaluates cerebellar function using transcranial magnetic stimulation (TMS) to determine whether subclinical cerebellar involvement is present in PSP patients. We studied 11 patients with PSP, 11 patients with Parkinson's disease (PD), and 10 age-matched controls. Patients were examined with their usual medications and in their relative on state. Motor evoked potentials (MEPs) were recorded from the hand muscle. Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEPs elicited by TMS over the contralateral motor cortex, which we call cerebellar inhibition (CBI). Interstimulus intervals (ISIs) of 4 to 8 ms were used, and the time course of CBI was analyzed. The CBI was reduced in PSP patients. By contrast, the CBI was normal in PD patients in their on state. Although the CBI in their off state should be examined in future studies, the results described herein suggest that Purkinje cells or the dentato-thalamo-cortical pathway assessed by CBI is involved in PSP. Our results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients.


Stimulation of pig growth performance by porcine growth hormone: determination of the dose-response relationship.
The present study was undertaken to determine the relationship between dose of porcine growth hormone (pGH) and growth performance of pigs. Porcine GH was administered daily for 35 d [buffer-injected control = (C); 10 micrograms/kg body weight (BW) = (L); 30 micrograms/kg BW = (M); 70 micrograms/kg BW = (H)] to barrows (initial wt = 50 kg). Growth rate was significantly increased by pGH (14% for H dose vs C). Feed efficiency was increased in a dose-related manner (L = 7%, M = 10%, H = 17%) by pGH. There was a concurrent change in carcass composition of pGH-treated pigs. The H dose of pGH decreased the percentage of carcass lipid by 25% (P less than .05). Muscle mass was significantly increased in H vs C pigs (31 vs 26 kg). Serum insulin-like growth factor 1 (IGF-1) concentration increased in a manner that was linearly related to the pGH dose (r = .87). No antibodies to pGH were detected in any of the pigs. In summary, these results extend our earlier findings that pGH increases growth performance markedly. Based on the present findings it appears that the maximally effective dose of pGH is greater than 70 micrograms.kg BW-1.d-1 since several indices of the growth-promoting and metabolic effects of pGH (% carcass protein, % carcass lipid and feed efficiency) had not plateaued.


Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity.
DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig's increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.


Cohesin gene defects may impair sister chromatid alignment and genome stability in Arabidopsis thaliana.
In contrast to yeast, plant interphase nuclei often display incomplete alignment (cohesion) along sister chromatid arms. Sister chromatid cohesion mediated by the multi-subunit cohesin complex is essential for correct chromosome segregation during nuclear divisions and for DNA recombination repair. The cohesin complex consists of the conserved proteins SMC1, SMC3, SCC3, and an alpha-kleisin subunit. Viable homozygous mutants could be selected for the Arabidopsis thaliana alpha-kleisins SYN1, SYN2, and SYN4, which can partially compensate each other. For the kleisin SYN3 and for the single-copy genes SMC1, SMC3, and SCC3, only heterozygous mutants were obtained that displayed between 77% and 97% of the wild-type transcript level. Compared to wild-type nuclei, sister chromatid alignment was significantly decreased along arms in 4C nuclei of the homozygous syn1 and syn4 and even of the heterozygous smc1, smc3, scc3, and syn3 mutants. Knocking out SYN1 and SYN4 additionally impaired sister centromere cohesion. Homozygous mutants of SWITCH1 (required for meiotic sister chromatid alignment) displayed sterility and decreased sister arm alignment. For the cohesin loading complex subunit SCC2, only heterozygous mutants affecting sister centromere alignment were obtained. Defects of the alpha-kleisin SYN4, which impair sister chromatid alignment in 4C differentiated nuclei, do apparently not disturb alignment during prometaphase nor cause aneuploidy in meristematic cells. The syn2, 3, 4 scc3 and swi1 mutants display a high frequency of anaphases with bridges (~10% to >20% compared to 2.6% in wild type). Our results suggest that (a) already a slight reduction of the average transcript level in heterozygous cohesin mutants may cause perturbation of cohesion, at least in some leaf cells at distinct loci; (b) the decreased sister chromatid alignment in cohesin mutants can obviously not fully be compensated by other cohesion mechanisms such as DNA concatenation; (c) some cohesin genes, in addition to cohesion, might have further essential functions (e.g., for genome stability, apparently by facilitating correct recombination repair of double-strand breaks).


15N NMR relaxation studies of backbone dynamics in free and steroid-bound Delta 5-3-ketosteroid isomerase from Pseudomonas testosteroni.
The backbone dynamics of Delta(5)-3-ketosteroid isomerase (KSI) from Pseudomonas testosteroni has been studied in free enzyme and its complex with a steroid ligand, 19-nortestosterone hemisuccinate (19-NTHS), by (15)N relaxation measurements. The relaxation data were analyzed using the model-free formalism to extract the model-free parameters (S(2), tau(e), and R(ex)) and the overall rotational correlation time (tau(m)). The rotational correlation times were 19.23 +/- 0.08 and 17.08 +/- 0.07 ns with the diffusion anisotropies (D( parallel)/D( perpendicular)) of 1.26 +/- 0.03 and 1.25 +/- 0.03 for the free and steroid-bound KSI, respectively. The binding of 19-NTHS to free KSI causes a slight increase in the order parameters (S(2)) for a number of residues, which are located mainly in helix A1 and strand B4. However, the majority of the residues exhibit reduced order parameters upon ligand binding. In particular, strands B3, B5, and B6, which have most of the residues involved in the dimer interaction, have the reduced order parameters in the steroid-bound KSI, indicating the increased high-frequency (pico- to nanosecond) motions in the intersubunit region of this homodimeric enzyme. Our results differ from those of previous studies on the backbone dynamics of monomeric proteins, in which high-frequency internal motions are typically restricted upon ligand binding.


Vaginal Yolk Sac Tumor in an Infant: A Case Report and Literature Review of the Last 30 Years.
Vaginal yolk sac tumor is a rare malignant germ-cell tumor occurring most commonly in young girls. The treatment has evolved over the last 3 decades from radical surgery to conservative surgery with chemotherapy to chemotherapy alone. Here we present a case of a 6-month-old girl successfully treated with upfront surgery followed by chemotherapy. We include a literature review of studies on vaginal yolk sac tumor published in the last 30 years. We discuss the role of upfront surgery where possible followed by chemotherapy as a safe alternative to chemotherapy alone for the treatment of this rare malignancy.


IL-6 and TNF-α induced obesity-related inflammatory response through transcriptional regulation of miR-146b.
Obesity is associated with a low-grade inflammation of white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance, and even diabetes. MicroRNAs (miRNAs) have been implicated as negative regulators controlling diverse biological processes at the level of post-transcriptional repression. miR-146b is an intergenic miRNA that can regulate the inflammatory process by attenuating cytokine signaling via the nuclear factor-κB pathway. In this study, we focused on investigating the expression of miR-146b in mature human adipocytes and their response to proinflammatory cytokines. Our results showed that miR-146b was highly expressed in the mature adipocytes. The mature human adipocytes responded to proinflammatory cytokines (TNF-α and IL-6) by highly increasing the expression of miR-146b. We cloned and identified a potential promoter of the transcriptional regulation of miR-146b. Interestingly, a fragment about 950-bp length upstream sequences of miR-146b had apparent transcription activity. In addition, the increase in miR-146b promoter activity by TNF-α and IL-6 was also effectively elevated. Our results indicated that a novel role for miR-146b in adipose tissue inflammation and miR-146b may be an important mediator in the process of obesity complications via its own transcription mechanism.


Examining the Public's Most Frequently Asked Questions About Carpal Tunnel Syndrome and Appraising Online Information About Treatment.
Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy. Patients often search online for health information regarding common musculoskeletal complaints. Thus, the purpose of this study was to use language processing information from Google to assess the content of CTS frequently asked questions (FAQs) searched online and the transparency and quality of online CTS information. On March 11, 2021, we searched Google for 3 terms "carpal tunnel syndrome treatment," "carpal tunnel syndrome surgical treatment," and "carpal tunnel syndrome non-surgical treatment" until a minimum of 100 FAQs and their answer links were extracted from each search. We used Rothwell classification to categorize the FAQs. The Journal of the American Medical Association's benchmark criteria were used to assess information transparency. Information quality was assessed using the Brief DISCERN tool. Our Google search returned 124 unique FAQs. Fifty-six (45.2%) were value based and most were related to the evaluation of treatment options (45/56, 80.4%). The most common source type was medical practices (26.6%). Nearly half of the answer sources (45.9%) were found to be lacking in transparency. One-way analysis of variance revealed a significant difference in mean Brief DISCERN scores among the 5 source types, F(4, 119) = 5.93, P = .0002, with medical practices averaging the worst score (13.73/30). Patients are most commonly searching Google to gain information regarding CTS treatment options. Online sources such as medical practices should use widely accepted rubrics for ensuring transparency and quality prior to publishing CTS information.


Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD).
Theories of grounded cognition propose that action verb knowledge relies in part on motor processing regions, including premotor cortex. Accordingly, impaired action verb knowledge in patients with amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD) is thought to be due to motor system degeneration. Upper motor neuron disease in ALS degrades the motor cortex and related pyramidal motor system, while disease in PD is centered in the basal ganglia and can spread to frontostriatal areas that are important to language functioning. These anatomical distinctions in disease may yield subtle differences in the action verb impairment between patient groups. Here we compare verbs where the body is the agent of the action to verbs where the body is the theme. To examine the role of motor functioning in body verb production, we split patient groups into patients with high motor impairment (HMI) and those with low motor impairment (LMI), using disease-specific measures of motor impairment. Regression analyses assessed how verb production in ALS and PD was related to motor system atrophy. We find a dissociation between agent- and theme-body verbs in ALS: ALS HMI were impaired for agent body verbs but not theme verbs, compared to ALS LMI. This dissociation was not present in PD patients, who instead show depressed production for all body verbs. Although patients with cognitive impairment were excluded from this study, cognitive performance significantly correlated with the production of theme verbs in ALS and cognitive/stative verbs in PD. Finally, regression analyses related the agent-theme dissociation in ALS to grey matter atrophy of premotor cortex. These findings support the view that motor dysfunction and disease in premotor cortex contributes to the agent body verb deficit in ALS, and begin to identify some distinct characteristics of impairment for verbs in ALS and PD.


Genomic Admixture Between Locally Adapted Populations of Arabidopsis thaliana (mouse ear cress): Evidence of Optimal Genetic Outcrossing Distance.
Admixture can break up divergent genetic architectures between populations, resulting in phenotypic novelty and generating raw material for environmental selection. The contribution of admixture to progeny trait variation and fitness varies based on the degree of genetic isolation between the parental populations, for which most studies have used geographic distance as a proxy. A novel approach is to estimate optimal crossing distance using the adaptive genetic distance between mates estimated from loci that contribute directly to local adaptation. Here, we aim to understand the effect of admixture on disrupting local adaptation of ecotypes of Arabidopsis thaliana separated along gradients of geographic, background, and locally adaptive genetic distances. We created experimental F1 hybrids between ecotypes that vary in geographic distance and used SNP data to estimate background (putatively neutral) and adaptive genetic distance. Hybrids were grown under controlled conditions, and fitness, growth, and phenology traits were measured. The different traits measured showed a clear effect of adaptive genetic distance, but not geographic distance. The earliest bolting hybrids were intermediate in the adaptive genetic distance between their parents, and also had higher biomass and fitness in terms of fruit and seed production. Our results suggest that disruption of locally adaptive genomic loci decreases the performance of offspring between distantly related parents, but that crosses between very closely related parents also reduce performance, likely through the expression of deleterious recessive alleles. We conclude that during admixture, selection may have to balance the consequences of disrupting local adaption while also avoiding inbreeding depression.


Multifaceted academic detailing program to increase pharmacotherapy for alcohol use disorder: interrupted time series evaluation of effectiveness.
Active consideration of effective medications to treat alcohol use disorder (AUD) is a consensus standard of care, yet knowledge and use of these medications are very low across diverse settings. This study evaluated the overall effectiveness a multifaceted academic detailing program to address this persistent quality problem in the US Veterans Health Administration (VHA), as well as the context and process factors that explained variation in effectiveness across sites. An interrupted time series design, analyzed with mixed-effects segmented logistic regression, was used to evaluate changes in level and rate of change in the monthly percent of patients with a clinically documented AUD who received naltrexone, acamprosate, disulfiram, or topiramate. Using data from a 20 month post-implementation period, intervention sites (n = 37) were compared to their own 16 month pre-implementation performance and separately to the rest of VHA. From immediately pre-intervention to the end of the observation period, the percent of patients in the intervention sites with AUD who received medication increased over 3.4 % in absolute terms and 68 % in relative terms (i.e., 4.9-8.3 %). This change was significant compared to the pre-implementation period in the intervention sites and secular trends in control sites. Sites with lower pre-implementation adoption, more person hours of detailing, but fewer people detailed, had larger immediate increases in medication receipt after implementation. The average number of detailing encounters per person was associated with steeper increases in slope over time. This study found empirical support for a multifaceted quality improvement strategy aimed at increasing access to and utilization of pharmacotherapy for AUD. Future studies should focus on determining how to enhance the programs effects, especially in non-responsive locations.


Immobilization of horseradish peroxidase on NH2-modified magnetic Fe3O4/SiO2 particles and its application in removal of 2,4-dichlorophenol.
Fe3O4 nanoparticles were prepared by a co-precipitation method with the assistance of ultrasound irradiation, and then coated with silica generated by hydrolysis and condensation of tetraethoxysilane. The silica-coated Fe3O4 nanoparticles were further modified with 3-aminopropyltriethoxysilane, resulting in anchoring of primary amine groups on the surface of the particles. Horseradish peroxidase (HRP) was then immobilized on the magnetic core-shell particles by using glutaraldehyde as a crosslinking agent. Immobilization conditions were optimized to obtain the highest relative activity of the immobilized enzyme. It was found the durability of the immobilized enzyme to heating and pH variation were improved in comparison with free HRP. The apparent Michaelis constants of the immobilized HRP and free HRP with substrate were compared, showing that the enzyme activity of the immobilized HRP was close to that of free HRP. The HRP immobilized particles, as an enzyme catalyst, were used to activate H2O2 for degrading 2,4-dichlorophenol. The rapid degradation of 2,4-dichlorophenol indicated that the immobilized enzyme has potential applications for removing organic pollutants.


Pancreatic carcinoma: < or = 2 cm versus > 2 cm in size.
Despite recent progress in diagnosis and therapy, the clinical course of patients with pancreatic carcinoma remains dismal. There have been several approaches to improve the clinical course of patients with pancreatic carcinoma, namely: (i) detection of small pancreatic carcinoma; (ii) radical resection with retroperitoneal clearance and portal vein resection; (iii) multidisciplinary therapy including chemoradiation; and so forth. In this series, eight Japanese patients with small pancreatic carcinoma measuring less than 2 cm in diameter (including two with non-invasive carcinoma and one with minimally invasive carcinoma) and 53 with larger pancreatic carcinoma were reviewed to find the diagnostic and therapeutic clues to improve the clinical course of patients with pancreatic carcinoma. Lymphatic (ly) and perineural (pn) permeation was significantly more frequent and extensive in the 53 patients with large pancreatic carcinoma than in the eight with small pancreatic carcinoma (ly 0/1/2/3:3/24/18/8 versus 5/2/1/0, P = 0.0284; pn 011/2/3:4/29/14/6 versus 3/2/3/0, P = 0.0491). The surgical margin was affected by malignant cells in 18 (34%) of the 53 patients with large carcinoma but none (0%) of the eight with small carcinoma (P = 0.0004). The comprehensive stage was significantly earlier in the eight with small carcinoma than in the 53 with large carcinoma (comprehensive stage I/II/II/IV:4/0/3/1 versus 0/3/26/24, P < 0.0001). Comprehensive curability of the eight small carcinoma cases was significantly higher than that of the 53 large carcinoma cases (comprehensive curability A/B/C:5/3/0 versus 9/5/39; P = 0.0003). 1-year and 3-year cumulative survival rates of the eight patients with small carcinoma were 100% and 82%, whereas those of the 53 with large carcinoma were 51% and 17%, respectively (P = 0.0207). However, the eight small carcinoma cases already showed frequent invasion to the vascular (v), lymphatic (ly) and perineural (pn) structure [v(+): 3/8, ly(+): 5/8, pn(+):5 /8] and lymph node metastasis (n) [n(+): 3/8]. Out of the eight small pancreatic carcinomas, one minimally invasive carcinoma and two non-invasive carcinomas showed no vascular, lymphatic or perineural invasion or lymph node metastasis. All the three patients have been doing well 19, 32 and 44 months after the operation. The diagnostic clues in the three patients were dilatation of the main pancreatic duct in one and of the branch duct in the other two. These findings suggest that surgical resection frequently cures patients with small pancreatic carcinoma but more effective adjuvant therapy should be developed to control lymphatic permeation, venous invasion or perineural infiltration in surgical resection of large pancreatic carcinoma. The supreme goal is to detect non-invasive or minimally invasive pancreatic carcinoma with a dilatation of the main or branch pancreatic duct as a diagnostic aid.


The role of local design in membranes.
The IMP arrays are integral membrane multiprotein complexes that may be site-specific control centers regulating the local concentration of specific ions by functioning as pumps, gates, or channels. In the case of the fusion rosette, an increase in Ca2+ may trigger local membrane fusion; in other cases, Ca2+ or H+ may be important physiological regulators. Ca2+ dependent regulatory proteins, such as calmodulin, and other parameters prevent widespread dispersion of the ions and permit fine local regulation.


Hypergraphia in epilepsy: is there a specificity to temporal lobe epilepsy?
The purpose of this investigation was to determine the specificity of hypergraphia to temporal lobe epilepsy using the paradigm developed by Sachdev and Waxman (1981). One hundred and thirty-eight patients were sent a standard stimulus letter and the response rates were examined for the patient groups with temporal lobe epilepsy (N = 80), and without (N = 31), and mixed seizure types (N = 13). For those patients who responded, additional analyses involved the number of words per response and the presence/absence of any qualitative indices of the postulated interictal behavioural syndrome of temporal lobe epilepsy. The results were interpreted in the light of the contemporary definitions of hypergraphia and were related to the larger literature concerned with personality and behavioural change in temporal lobe epilepsy.


Function of micF as an antisense RNA in osmoregulatory expression of the ompF gene in Escherichia coli.
To analyze the function of micF as an antisera RNA in the osmoregulatory expression of the ompF gene in Escherichia coli, we performed two experiments. In the first experiment, two strains were constructed in which the transcription initiation site of the ompF gene and the transcription termination site of the micF gene were separated by 186 and 4,100 base pairs, respectively, on the chromosome. These two strains showed almost the same profile of ompF expression as the wild-type strain in which the two genes are separated by 10(6) base pairs. When a high-copy-number plasmid carrying the micF gene was introduced into these strains, ompF expression was completely repressed, whereas no repression was observed with a low-copy-number plasmid carrying the micF gene. These results indicate that the distance between the two genes on the chromosome is not critical for the function of micF. In the second experiment, expression of the ompF gene was examined by pulse-labeling in both the micF+ and the micF deletion strains. Upon a shift from a low- to a high-osmolarity medium, suppression of OmpF protein synthesis occurred more quickly and more extensively in the micF+ strain than in the micF deletion strain. The steady-state synthesis of the OmpF protein was also completely suppressed in the micF+ strain in the high-osmolarity medium, whereas the suppression was incomplete in the micF deletion strain. From these results we conclude that (i) the micF gene contributes to the fast and complete response of the OmpF synthesis to the medium osmolarity, and that (ii) the distance between the micF and ompF genes on the chromosomes is not critical for the function of the micF gene. The results suggest, rather, that the ratio of the copy numbers of the two genes is critical for the function of the micF gene.


Chemoenzymatic synthesis of branched oligo- and polysaccharides as potential substrates for starch active enzymes.
Oligo- and polysaccharides embodying the alpha-maltotriosyl-6(II)-maltotetraosyl structure were readily synthesized by transglycosylation of maltosyl fluoride onto panose and pullulan catalysed by the bacterial transglycosylase cyclodextrin glycosyltransferase (CGTase). The two products obtained proved useful for increasing the knowledge of substrate binding and processing at the active site of barley limit dextrinase that is involved in the metabolism of amylopectin by acting upon its branch points.


Ex vivo culture of adult CD34+ stem cells using functional highly porous polymer scaffolds to establish biomimicry of the bone marrow niche.
Haematopoiesis, the process of blood production, occurs from a tiny contingent of haematopoietic stem cells (HSC) in highly specialised three-dimensional niches located within the bone marrow. When haematopoiesis is replicated using in vitro two-dimensional culture, HSCs rapidly differentiate, limiting self-renewal. Emulsion-templated highly porous polyHIPE foam scaffolds were chosen to mimic the honeycomb architecture of human bone. The unmodified polyHIPE material supports haematopoietic stem and progenitor cell (HSPC) culture, with successful culture of erythroid progenitors and neutrophils within the scaffolds. Using erythroid culture methodology, the CD34+ population was maintained for 28 days with continual release of erythroid progenitors. These cells are shown to spontaneously repopulate the scaffolds, and the accumulated egress can be expanded and grown at large scale to reticulocytes. We next show that the polyHIPE scaffolds can be successfully functionalised using activated BM(PEG)2 (1,8-bismaleimido-diethyleneglycol) and then a Jagged-1 peptide attached in an attempt to facilitate notch signalling. Although Jagged-1 peptide had no detectable effect, the BM(PEG)2 alone significantly increased cell egress when compared to controls, without depleting the scaffold population. This work highlights polyHIPE as a novel functionalisable material for mimicking the bone marrow, and also that PEG can influence HSPC behaviour within scaffolds.


Patterns of cognitive impairment in Alzheimer's disease: assessment and differential diagnosis.
In routine clinical practice, the diagnosis of Alzheimer's disease (AD) is commonly made according to NINCDS-ADRDA criteria. As pathological verification is typically not available, such a diagnosis remains probable rather than definite. A diagnosis of probable AD is nevertheless fairly accurate (0.75-0.96), and may serve as a surrogate gold standard in clinical studies. Probable AD is often considered a diagnosis of exclusion, but AD neuropathology characteristically evolves in an ordered topographic sequence, which is mirrored in the pattern of evolution of neuropsychological deficits. Recognition of the resulting temporal profile of cognitive domain involvement allows positive rather than merely exclusionary diagnosis. Certain other dementias may be difficult to distinguish from AD clinically: notably frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and various subtypes of vascular cognitive impairment. The distinction is made more difficult by the existence of variants of AD, presenting with predominant impairment of executive, visuoperceptual, or language domains, as well as by the common occurrence of mixed pathologies. Against this background, the neuropsychological features of AD and its variant presentations, and its distinction from other dementias are reviewed. The properties of commonly-used cognitive assessment tools (MMSE, Mattis DRS, ADAS-Cog, CERAD and CAMDEX-R) are discussed, and the issue of diagnosing incipient AD on clinical grounds before the NINCDS-ADRDA criteria are fulfilled is addressed.


Psychosocial mechanisms of psychological health disparity in Japanese workers.
Recent epidemiologic research has shown that people with higher socioeconomic status (SES) (e.g., educational attainment) have better psychological health than those with lower SES. However, the psychosocial mechanisms of underlying this relationship remain unclear. To fill this gap, the current study examines the mediating effects of job demands and job resources in the relationship between educational attainment and psychological distress. The hypothesized model was tested using large data sets from two different studies: a cross-sectional study of 9,652 Japanese employees from 12 workplaces (Study 1), and a longitudinal study of 1,957 Japanese employees (Study 2). Structural equation modeling revealed that (1) educational attainment was positively related to psychological distress through job demands, (2) educational attainment was negatively related to psychological distress through job resources, and (3) educational attainment was not directly related to psychological distress. These results suggest that educational attainment has an indirect effect, rather than a direct one, on psychological distress among workers; educational attainment had both a positive and a negative relationship to psychological distress through job demands and job resources, respectively.


In vitro decondensation of the sperm chromatin in Holothuria tubulosa (sea cucumber) not affecting proteolysis of basic nuclear proteins.
Sea urchin and sea star oocyte extracts contain proteolytic activities that are active against sperm basic nuclear proteins (SNBP). This SNBP degradation has been related to the decondensation of sperm chromatin as a possible model to male pronuclei formation. We have studied the presence of this proteolytic activity in Holothuria tubulosa (sea cucumber) and its possible relationship with sperm nuclei decondensation. The mature oocyte extracts from H. tubulosa contain a proteolytic activity to SNBP located in the macromolecular fraction of the egg-jelly layer. SNBP degradation occurred both on sperm nuclei and on purified SNBP, histones being more easily degraded than protein Ø(o) (sperm-specific protein). SNBP degradation was found to be dependent on concentration, incubation time, presence of Ca(2+), pH, and this activity could be a serine-proteinase. Thermal denaturalization of the oocyte extracts (80 degrees C, 10-15 min) inactivates its proteolytic activity on SNBP but does not affect sperm nuclei decondensation. These results would suggest that sperm nuclei decondensation occurs by a mechanism different from SNBP degradation. Thus, the sperm nuclei decondensation occurs by a thermostable factor(s) and the removal of linker SNBP (H1 and protein Ø(o)) will be a first condition in the process of sperm chromatin remodeling.


Use of a cancer register for monitoring and evaluating a breast cancer screening programme.
To monitor the effectiveness of a breast cancer screening service accurate information is necessary on the incidence of breast cancer before and after screening is introduced. The Wessex Cancer Register has been used to provide data on the incidence prior to screening and arrangements are being made for the exchange of information between the Register and each screening service in Wessex in order that future registrations can be divided into screen-detected and symptomatically-detected cases. Since changes in mortality will not be apparent for some years and are not detectable in small populations, other indicators of effectiveness are required. Stage at presentation predicts mortality; a change in stage distribution as a result of screening would indicate future changes in mortality. The Cancer Register has been used to analyse stage distribution before the advent of screening. Procedures have been adopted for collecting staging data on all breast cancers diagnosed in the future, both within and without the screening service. In this way stage distribution will be compared before and after the implementation of the service and predictions made on the effect on mortality in the future. In addition, information on the incidence of interval cancers will be analysed using the Cancer Register so that, in the long term, an assessment can be made of the appropriate length of the interval between screens. These cancers will be notified to the screening office for review. A Cancer Register can provide the population base from which to measure the true effectiveness of a breast screening service on the community it serves.


Health-economic comparison of three recommended drugs for the treatment of osteoporosis.
Osteoporosis is a large and growing disease with significant health consequences. Based on an evaluation of clinical evidence, the German osteology umbrella organization DVO (Dachverband Osteologie deutschsprachiger wissenschaftlicher Fachgesellschaften) published guidelines in March 2003 for the diagnosis and treatment of osteoporosis. For prevention of fractures in women with postmenopausal and senile osteoporosis, these guidelines recommend three treatment options as first-line therapy: risedronate, alendronate and raloxifene. No evidence is currently available for the reduction of hip fractures by raloxifene. Only risedronate and alendronate, therefore, are recommended for prevention of hip fractures. Information on the cost-effectiveness of preventing and treating osteoporosis may support decision makers in more efficient allocation of resources. Accordingly, the objective of this study is the comparative assessment of the cost-effectiveness of risedronate, alendronate and raloxifene for patient populations in Germany at high risk of osteoporotic fracture due to low bone mineral density (BMD) (i.e., T-score < -2.5) and resulting from a history of at least one previous vertebral fracture, as compared to osteoporotic patients with no treatment. Target variables for the economic comparison are costs per hip fracture avoided and costs per quality-adjusted life year (QALY) gained. Hip fractures are the most costly and best-documented complication of osteoporosis. A cost-effectiveness analysis was therefore conducted, using as criteria for evaluating intervention the incremental cost per hip fracture avoided and the cost per QALY gained. We used a fracture-incidence-based Markov model of osteoporosis, with analysis of patients' transition across outcome states over time (e.g., fracture, healthy, dead). Base-case analysis was conducted on a cohort of 1,000 women aged 70 with low spine BMD and prevalent vertebral fracture, over 3 years of treatment with risedronate, alendronate or raloxifene, and with application of a 10-year analytic time horizon. Model inputs included hip and vertebral fracture incidence rates; relative risk of fracture given low BMD and prevalent vertebral fracture, fracture cost, treatment prices/day (risedronate: 35 mg, 1.76 euro; alendronate: 70 mg, 1.82 euro; raloxifene: 60 mg, 1.82 euro); health utility; and efficacy in terms of relative-risk reduction of fracture of the hip (60% risedronate; 51% alendronate; not significant raloxifene) and vertebrae (49% risedronate; 47% alendronate; 30% raloxifene). A 5% discount rate was applied to cost and outcomes. In the base case, treatment with risedronate reduces costs from the social insurance perspective with respect to both endpoints: i.e., costs per averted hip fracture and QALY. Over the 3-year treatment period and 10-year observation, furthermore, risedronate proved superior to alendronate and raloxifene (i.e., risedronate was less expensive and more effective). From the perspective of statutory health insurance, the cost per averted hip fracture is 37,348 euro for risedronate and 48,349 euro for alendronate (costs for raloxifene were not calculated due to a nonsignificant effect on prevention of hip fractures); and cost per QALY gained is 32,092 euro for risedronate, in comparison to patients in Germany with no therapy (alendronate 41,302 euro; raloxifene 1,247,119 euro). This cost-effectiveness analysis gives evidence that bisphosphonates are cost effective. Under consideration of current prices and the published clinical evidence, risedronate dominates the comparison of DVO-recommended drugs.


Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism.
Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.


Still air resistance during walking and running.
In everyday life during terrestrial locomotion our body interacts with two media opposing the forward movement of the body: the ground and the air. Whereas the work done to overcome the ground reaction force has been extensively studied, the work done to overcome still air resistance has been only indirectly estimated by means of theoretical studies and by measurements of the force exerted on puppets simulating the geometry of the human body. In this study, we directly measured the force exerted by still air resistance on eight male subjects during walking and running on an instrumented treadmill with a belt moving at the same speed of a flow of laminar air facing the subject. Overall, the coefficient of proportionality between drag and velocity squared (Aeff) was smaller during running than walking. During running Aeff decreased progressively with increasing average velocity up to an apparently constant, velocity independent value, similar to that predicted in the literature using indirect methods. A predictive equation to estimate drag as a function of the speed and the height of the running subject is provided.


Use of inhaled anti-inflammatory medication in children with asthma in managed care settings.
Many factors affect use of inhaled therapy in asthma. Relatively little is known about current patterns of use of anti-inflammatory medication in children with asthma and whether variations occur with age and use of bronchodilator medication. To study the factors associated with dispensing of anti-inflammatory (controller) asthma medication to children in 3 managed care organizations (MCOs). Using automated databases, a 1-year cross-sectional study of children with asthma aged 3 to 15 years cared for in 3 MCOs was used to evaluate the association of age and other factors with controller medication use. A total of 13 352 children were studied. Significantly fewer children aged 3 to 5 years were dispensed any (> or =1) controller medication than older children (P<.001). Among children dispensed 6 or more beta-agonists, only 39% also received 5 or more controller dispensings, with adolescents significantly less likely than younger children to receive 5 or more controllers (33%; P<.001). Significant differences were seen among MCOs in proportions of patients dispensed controller medication. In a multiple logistic regression model, controlling for frequency of beta-agonist dispensing and MCO, significantly lower dispensing of any controller medication was seen for those aged 3 to 5 years (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.7-0.9) and for girls (OR, 0.9; 95% CI, 0.8-0.96). In contrast, for repeated (> or =5) controller dispensing there were significantly fewer dispensings to adolescents (OR, 0.7; 95% CI, 0.6-0.9) and girls (OR, 0.8; 95% CI, 0.7-0.9). There may be differences in the use of preventive asthma medication in children that are affected by age, sex, and health care organization. Few children with frequent symptoms are using controllers regularly, as is recommended by national guidelines.


Population structure and its effect on haplotype diversity and linkage disequilibrium surrounding the xa5 locus of rice (Oryza sativa L.).
To assess the usefulness of linkage disequilibrium mapping in an autogamous, domesticated species, we have characterized linkage disequilibrium in the candidate region for xa5, a recessive gene conferring race-specific resistance to bacterial blight in rice. This trait and locus have good mapping information, a tractable phenotype, and available sequence data, but no cloned gene. We sampled 13 short segments from the 70-kb candidate region in 114 accessions of Oryza sativa. Five additional segments were sequenced from the adjacent 45-kb region in resistant accessions to estimate the distance at which linkage disequilibrium decays. The data show significant linkage disequilibrium between sites 100 kb apart. The presence of the xa5 resistant reaction in two ecotypes and in accessions with different haplotypes in the candidate region may indicate multiple origins or genetic heterogeneity for resistance. In addition, genetic differentiation between ecotypes emphasizes the need for controlling for population structure in the design of linkage disequilibrium studies in rice.


[Anastomotic fistula after gastrectomy. Diagnostic value of radiologic monitoring. Retrospective study of 123 gastrectomies].
In order to determine the usefulness of systematic radiological exploration after gastrectomy, 123 gastrectomies (39 total, 84 subtotal) performed over a 10-year period were reviewed. Control radiology had been carried out in 51% of the cases. Retrospectively, except for the lower percentage of total gastrectomies the two groups (with and without control radiology) were comparable. The overall incidence of fistula (9%) was similar to that found in the literature, bearing in mind that 90% of gastrectomies in this series were performed for cancer. The only two factors predictive of fistula were the presence of fever or of post-operative focal infection (P less than 0.001). It would appear that control radiology after gastrectomy is indicated only when post-operative fever is present. If this were done the number of useless examinations would be reduced and the cost-effectiveness ratio of radiology would be improved.


Locked versus standard unlocked plating of the pubic symphysis: a cadaver biomechanical study.
Although locked plating has been shown to have advantages for diaphyseal and metaphyseal fracture fixation, its benefits for pubic symphyseal disruption have not been established. With traditional plate fixation of the disrupted pubic symphysis, normal physiological symphyseal pelvic motion eventually results in plate breakage, screw breakage, and loosening of screws. A concern exists that common modes of locked plate construct failure could result in abrupt and complete loss of symphyseal fixation. The purposes of this study were to determine, using an open-book pelvic injury model, whether locked plating of the pubic symphysis 1) offers any advantage over standard unlocked plating; and 2) results in a potential increased risk of abrupt fixation failure. Twelve osteopenic cadaver pelvic specimens were acquired and dual-energy x-ray absorptiometry scans were obtained to ensure uniformity of the specimens' bone density. Sacrospinous, sacrotuberous, and anterior sacroiliac ligaments were released and the symphysis pubis was transected to simulate a partially stable open book (AO/Orthopaedic Trauma Association 61-B3.1) injury. Using a six-hole 3.5-mm plate specifically designed for the symphysis pubis with the capability of fixation in locked or unlocked mode, six pelvises were fixed with locked screws and six pelvises were fixed standard unlocked bicortical screws. There was no significant difference between these 2 groups with regard to bone density (P = 0.47). Two equally osteopenic pelvic specimens from each fixation group were selected for the purpose of obtaining failure data and determining an acceptable load for trialing. Both specimens failed at 1985 N. The remaining 10 pelvises were then mounted on a materials testing apparatus using the bilateral stance model as described by Tile. In accordance with the failure data, each pelvis was stressed at 440 N for a total of one million cycles (equivalent to 6.5 months of daily walking) or until fixation failure. All pelvic specimens in both fixation groups completed one million cycles without plate or screw failure. However, diastasis of the initial pubic symphysis reduction was found in all pelvises (mean, 2.45 mm; range, 1.5-4.0 mm) regardless of fixation method. This loss of reduction was not significantly different between the 2 fixation groups (P = 0.914). No abrupt failures occurred in either plating group. Consequently, any fear of catastrophic (ie, abrupt and complete) failure of locked symphyseal plates appears to be unfounded for open-book injuries treated in patients with low bone density. However, minor loss of the symphyseal reduction was evident in all pelvises regardless of the fixation method. Therefore, locked plating of the pubic symphysis does not appear to offer any advantage over the standard unlocked technique for an AO/Orthopaedic Trauma Association 61-B3.1 partially stable open-book pelvic injury pattern in osteopenic bone.