Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study

OBJECTIVE: To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women. DESIGN: In 1780 unrelated members of the community-based Framingham Heart Study offspring cohort, systolic blood pressure and diastolic blood pressure were measured over a total of six examination cycles encompassing 24 years of follow-up. Multivariate regression analyses were used to assess the relation between untreated cross-sectional and longitudinal blood pressure and polymorphisms at the estrogen receptor-alpha (ESR1), estrogen receptor-beta (ESR2), aromatase (CYP19A1), and nuclear receptor coactivator 1 (NCOA1) genes after adjustment for common risk factors. RESULTS: In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1. Polymorphisms in ESR1, CYP19A1, and NCOA1 were associated with diastolic blood pressure in women. CONCLUSIONS: Although the underlying relations between genes involved in estrogen action and hypertension remain to be completely understood, our findings provide suggestive evidence of gender-specific contributions of estrogen-related genes to blood pressure variation. As no correction for multiple testing was performed in the analyses, we view these results as suggestive and not definitive. Further studies are warranted to confirm these results using a comprehensive set of polymorphisms in order to shed more light on the involvement of estrogen in blood pressure regulation.     

Enhanced production of oxygen radicals in nocturnal asthma.

Although the mechanisms of nocturnal worsening of pulmonary function in asthmatics have not been entirely established, airway inflammation is felt to be a major factor in disease severity. Consequently, to determine whether changes in bronchoalveolar lavage (BAL) fluid cellular components and their functions are related to nocturnal airway obstruction, we performed BAL at 4:00 A.M. and at 4:00 P.M. in asthma subjects with (n = 5) and without (n = 10) nocturnal asthma. No significant changes were observed from 4:00 P.M. to 4:00 A.M. in the concentration of total cells or the percentage or concentration of eosinophils or neutrophils in BAL fluid from subjects with or without nocturnal asthma. However, superoxide anion generation by air-space cells from subjects with nocturnal asthma was significantly greater at 4:00 A.M. than at 4:00 P.M. (6.9 +/- 1.7 versus 1.8 +/- 0.5 nmol/500K cells/h, p less than 0.05). Moreover, superoxide production at 4:00 A.M. was greater in subjects with than in those without nocturnal asthma (6.9 +/- 1.7 versus 2.2 +/- 0.6, p less than 0.02). Furthermore, in our group of asthmatics, the change in generation of superoxide anion from 4:00 P.M. to 4:00 A.M. was significantly correlated with the change in FEV1 (r = -0.71, p less than 0.01). We conclude that the development of nocturnal airway obstruction in asthma is associated with enhanced production of oxygen radicals by air-space cells. Because oxygen radicals can cause airway injury and thus enhance bronchial obstruction, it is possible that the release of these reactive compounds is causally associated with nocturnal asthma.     

Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease: results from a German national survey

OBJECTIVES: Previous studies have suggested that inflammatory bowel disease (IBD) patients rank high among users of complementary and alternative medicine (CAM). To further elucidate this phenomenon, we sent questionnaires to a large sample of IBD patients in Germany to determine the patterns and predictors of their CAM use. METHODS: Pretested 73-item questionnaires were mailed to a randomly selected representative sample of 1000 IBD patients from the approximately 16,000 members and associates of the German Crohn's and Colitis Association. Predictors of CAM use were evaluated by logistic regression models. RESULTS: Completed questionnaires were returned by 684 patients (female patients, 61.4%; Crohn's disease patients, 58.3%; ulcerative colitis patients, 38.2%). Of the 671 adult respondents, 344 (51.3%) had experience with CAM, and significantly more of the ulcerative colitis patients (59.8%) than the Crohn's disease patients (48.3%) had experience with CAM. There was no difference by gender. Homeopathy (52.9%) and herbal medicine (43.6%) were the most commonly used types of CAM. The most frequent personal reasons for CAM use were the search for an "optimum treatment" (78.9%) and the wish to stop taking steroids (63.8%). Using logistic regression, we found that total cortisone intake (P = 0.0077), but not duration of disease, was a strong predictor of CAM use. Other predictors were experience with psychosomatic and psychotherapeutic support (P = 0.0029), relaxation techniques (P = 0.0284), an academic education (P = 0.0173), a diet utilizing whole grains (P = 0.0123), and a normal body weight (P = 0.0215). Although 80% of patients indicated that they were interested in using CAM in the future, only 24.7% felt sufficiently informed about it. CONCLUSIONS: More than 50% of a large group of German IBD patients had used CAM. Prolonged or intensive steroid treatment, an academic education, active ways of coping, and a health-conscious life-style are associated with CAM use. Given the potential side effects and interactions, the treating physician should focus on thorough information about the benefits and limitations of conventional and complementary treatment options, especially for IBD patients who have received prolonged or intensive steroid treatment.     

Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection

To test the hypothesis that rhinovirus (RV)-induced immune responses influence the outcome of RV infections, we inoculated 22 subjects with allergic rhinitis or asthma with RV16. Nasal secretions and induced sputum were repeatedly sampled over the next 14 d. RV16 infection increased nasal granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-8, which was accompanied by neutrophilia in blood and nasal secretions. Nasal G-CSF correlated closely with increased blood neutrophils (r(s) = 0.69, p < 0.005), whereas nasal neutrophils correlated with both G-CSF (r(s) = 0.87, p < 0.001) and IL-8 (r(s) = 0.75, p < 0.001). Although similar relationships were present in sputum, changes in sputum neutrophils and G-CSF with RV16 infection were relatively modest. In addition, virus-induced changes in the sputum interferon-gamma-to-IL-5 messenger RNA ratio were inversely related to both peak cold symptoms (r(s) = -0.60, p < 0.005) and the time to viral clearance (undetectable picornavirus RNA). These results indicate that airway IL-8 and G-CSF are closely associated with virus-induced neutrophilic inflammation during an experimental RV infection in atopic volunteers. In addition, the balance of airway T-helper cell type 1 (Th1)- and Th2-like cytokines induced by RV infection may help determine the clinical outcome of common cold infections, raising the possibility that the individual subject's immune response, rather than atopic status per se, is important in this regard.     

The effect of procaterol treatment on beta-adrenergic bronchodilation and polymorphonuclear leukocyte responsiveness

Procaterol is a new and effective beta-adrenergic bronchodilator. To determine if procaterol administration could cause tachyphylaxis, airway and leukocyte beta-adrenergic function were monitored in 10 patients with asthma during two 4-wk, double-blind treatment periods, each preceded by a 2-wk beta-agonist washout. Treatment periods were randomized to placebo or procaterol (2 wk, 0.1 mg/day; 2 wk, 0.2 mg/day). At each 7 biweekly evaluations, the patient's cumulative bronchodilator dose-response to inhaled isoproterenol (0.1 to 0.64%) was measured, and venous blood was collected to quantitate, in vitro, the polymorphonuclear leukocyte (PMN) beta-adrenergic receptor's 125Iodo-cyanopindolol (125I-CYP) ligand binding and the PMN cyclic AMP response to isoproterenol and procaterol. Neither the airway nor leukocyte beta-adrenergic characteristics were changed during placebo treatment. Procaterol treatment reduced (p less than 0.05) the maximal 125I-CYP binding to PMN membranes but only during the initial 2 wk at low dosage. The percent PMN cyclic AMP increase to procaterol (10(-5) M) was also significantly (p less than 0.05) less during active treatment (141 +/- 40%) than during washout (256 +/- 24%) or placebo (257 +/- 32%). In contrast, procaterol treatment did not alter the acute isoproterenol bronchodilation response as measured by either the percent improvement in FEV1 or the dose required to produce 50% maximal bronchodilation. The duration of bronchodilation was not measured. Therefore, although procaterol therapy of asthma is associated with decreased PMN beta-adrenergic function, airway smooth muscle function appears not to be altered.     

Objectively characterizing Huntington’s disease using a novel upper limb dexterity test

Journal of Neurology - The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent...     

EEC‐ and ADULT‐Associated TP63 Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences

TP63 germ‐line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm‐derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA‐binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild‐type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN‐P63α‐specific REs derived from genes closely related to the clinical manifestations of the TP63‐associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.     

Long-term bowel disorders following radial cystectomy: an underestimated issue?

Purpose

Patients after radical cystectomy (RC) frequently complain about bowel disorders (BDs). Reports addressing related long-term complications are sparse. This cross-sectional study assessed changes in bowel habits (BH) after RC.

Methods

A total of 89 patients with a minimum follow-up ≥1 year after surgery were evaluated with a questionnaire. Patients with BD prior to surgery were excluded. Symptoms such as diarrhea, constipation, bloating/flatulence, incomplete defecation, uncontrolled stool loss, and impact on quality of life (QoL) were assessed.

Results

A total of 46.1 % of patients reported changes in BH; however, only 25.8 % reported experiencing related dissatisfaction. Primary causes of dissatisfaction were diarrhea and uncontrolled stool loss. The most common complaints were bloating/flatulence and the feeling of incomplete defecation, but these symptoms did not necessarily lead to dissatisfaction or impairment in quality of life. No difference was identified between an orthotopic neobladder and ileal conduit, and even patients without bowel surgery were affected. QoL, health status, and energy level were significantly decreased in unsatisfied patients.

Conclusions

About 25 % of patients complain about BDs after RC. More prospective studies assessing symptoms, comorbidities, and dietary habits are necessary to address this issue and to identify strategies for follow-up recommendations.