Mutation analysis and haplotype correlation for 139 cystic fibrosis patients from the Nebraska Regional Cystic Fibrosis Center

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations with an approximate frequency of one in 2,500 live births and a carrier frequency of one in 25. We studied 400 individuals seen at The Nebraska Regional Cystic Fibrosis Center that included 139 CF patients, 206 parents, and 55 unaffected siblings to determine the frequency of the ΔF508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X mutations. In addition, we determined haplotypes on each of these individual's chromosomes using four markers that included XV-2c, KM-19, pMP6d.9, and G2. Results from this study showed that the ΔF508 mutation was present in 70% of CF chromosomes. Of the 139 CF patients 74 (53%) were homozygous for the ΔF508 deletion, 47 (34%) were heterozygous for the ΔF508 deletion and an unknown mutation, and 18 (13%) carried two unknown mutations. Four additional-mutations were also found in our population and included G542X (6%), G551D (5%), R553X (4%), and R560T (1%). One patient was documented to be a compound heterozygote for G542X/G551D. A polymorphism, F508C, that has previously been reported in several families was also present in our study. The most common haplotype associated with the ΔF508 deletion in our CF patients was the E haplotype (CF Consortium B) while other mutations were associated with a variety of haplotypes. © 1993 Wiley-Liss, Inc.     

Mechanical properties of experimental dental composites containing a combination of mesoporous and nonporous spherical silica as fillers

ObjectivesMesoporous fillers have been investigated for use in dental composites because of their potential for creating micromechanical filler/resin matrix interphase bonding. Such a micromechanical bonding could eliminate the need for the silane treatment of fillers for interfacial chemical bonding that is prone to hydrolysis in the oral environment. In the case of micromechanical bonding, dental polymer chains are threaded mechanically (like a “necklace”) through nanosized channels in the fillers.MethodsA combination of mesoporous silica, which was synthesized using the non-surfactant templating method, and nonporous spherical silica (500 nm) was used to prepare experimental dental composites. The porous silica used in this study contained interconnected pores and channels as opposed to porous fillers containing surface pores. The compressive strength, compressive modulus, flexural modulus, and flexural strength of these composites were evaluated.ResultsThe results showed that composites containing a combination of mesoporous and nonporous fillers have better mechanical properties than the composites having either of these fillers alone.SignificanceThe results showed that a combination of mesoporous and nonporous materials can be used to prepare stronger dental materials that may resist hydrolysis and wear.     

Prolonged treatment with oral and inhaled tulobuterol does not induce airways tachyphlaxis

β ₂-agonists have been shown to induceβ ₂-adrenoceptor down-regulation in vivo and in vitro. Whether this has any functional relevance remains unclear. Tulobuterol is a new syntheticβ ₂-agonist with potent and prolonged bronchodilator activity when given by oral and inhaled routes. The effect of tulobuterol aerosol (400μg q.i.d.) and tulobuterol tablets (2 mg b.i.d.) was studied in patients with chronic asthma and reversible airways obstruction in two separate trials. Tulobuterol produced significant bronchodilatation after the first and final dose over a 6-h period and the effects were comparable. The bronchodilator activity of tulobuterol given by inhalation and oral routes was not attenuated after 6 months of continuous treatment. There was significant improvement in symptom score and lung function measurements. Side effects, predominantly tremors, were observed at the start of treatment with tablet formulation but the incidence and severity of tremors decreased after 6 months. The changes in BP and pulse rate were not clinically significant. These results confirm the potent bronchodilator activity of tulobuterol and the lack of tachyphylaxis after prolonged treatment.     

Centrally Mediated Erectile Dysfunction in Rats with Type 1 Diabetes: Role of Angiotensin II and Superoxide

IntroductionErectile dysfunction is a serious complication of diabetes mellitus. Apart from the peripheral actions, central mechanisms are also responsible for penile erection.AimThis study aims to determine the contribution of angiotensin (ANG) II in the dysfunction of central N-methyl-D-aspartic acid (NMDA)- and nitric oxide (NO)-induced erectile responses in streptozotocin-induced type 1 diabetic (T1D) rats.MethodsThree weeks after streptozotocin injections, rats were randomly treated with the angiotensin-converting enzyme inhibitor-enalapril, or the ANG II type 1 receptor blocker, losartan, or the superoxide dismutase mimetic, tempol, or vehicle via chronic intracerebroventricular infusion by osmotic mini-pump for 2 weeks.Main Outcome MeasureCentral NMDA receptor stimulation or the administration of the NO donor, sodium nitroprusside (SNP)-induced penile erectile responses and concurrent behavioral responses were monitored in conscious rats.ResultsTwo weeks of enalapril, losartan, or tempol treatment significantly improved the erectile responses to central microinjection of both NMDA and SNP in the paraventricular nucleus (PVN) of conscious T1D rats (NMDA responses—T1D+enalapril: 1.7 ± 0.6, T1D+losartan: 2.0 ± 0.3, T1D+tempol: 2.0 ± 0.6 vs. T1D+vehicle: 0.6 ± 0.3 penile erections/rat in the first 20 minutes, P < 0.05; SNP responses—T1D+enalapril: 0.9 ± 0.3, T1D+losartan: 1.3 ± 0.3, T1D+tempol: 1.4 ± 0.4 vs. T1D+vehicle: 0.4 ± 0.2 penile erections/rat in the first 20 minutes, P < 0.05). Concurrent behavioral responses including yawning and stretching, induced by central NMDA and SNP microinjections, were also significantly increased in T1D rats after enalapril, losartan, or tempol treatments. Neuronal NO synthase expression within the PVN was also significantly increased, and superoxide production was reduced in T1D rats after these treatments.ConclusionsThese data strongly support the contention that enhanced ANG II mechanism/s within the PVN of T1D rats contributes to the dysfunction of central NMDA-induced erectile responses in T1D rats via stimulation of superoxide. Zheng H, Liu X, and Patel KP. Centrally mediated erectile dysfunction in rats with type 1 diabetes: Role of angiotensin II and superoxide. J Sex Med 2013;10:2165–2176.     

Diabetes Severity,Metabolic Syndrome,and the Risk of Erectile Dysfunction

IntroductionErectile dysfunction (ED) is more common in men with type 2 diabetes mellitus (T2DM), obesity, and/or the metabolic syndrome (MetS).AimThe aim of this study is to investigate the associations among proxy measures of diabetic severity and the presence of MetS with ED in a nationally representative U.S. data sample.MethodsWe performed a cross‐sectional analysis of adult participants in the 2001–2004 National Health and Nutrition Examination Survey.Main Outcome MeasuresED was ascertained by self‐report. T2DM severity was defined by calculated measures of glycemic control and insulin resistance (IR). IR was estimated using fasting plasma insulin (FPI) levels and the homeostasis model assessment of IR (HOMA‐IR) definition. We classified glycemic control using hemoglobin‐A1c (HbA1c) and fasting plasma glucose (FPG) levels. MetS was defined by the American Heart Association and National Heart, Lung, and Blood Institute criteria. Logistic regression models, adjusted for sociodemographics, risk factors, and comorbidities, were fitted for each measure of T2DM severity, MetS, and the presence of ED.ResultsProxy measures of glycemic control and IR were associated with ED. Participants with FPG between 100–126 mg/dL (5.6–7 mmol/L) and ≥126 mg/dL (>7 mmol/L) had higher odds of ED, odds ratio (OR) 1.22 (confidence interval or CI, 0.83–1.80), and OR 2.68 (CI, 1.48–4.86), respectively. Participants with HbA1c 5.7–6.4% (38.8–46.4 mmol/mol) and ≥6.5% (47.5 mmol/mol) had higher odds of ED (OR 1.73 [CI, 1.08–2.76] and 3.70 [CI, 2.19–6.27], respectively). When FPI and HOMA‐IR were evaluated by tertiles, there was a graded relation among participants in the top tertile. In multivariable models, a strong association remained between HbA1c and ED (OR 3.19 [CI,1.13–9.01]). MetS was associated with >2.5‐fold increased odds of self reported ED (OR 2.55 [CI, 1.85–3.52]).ConclusionsPoor glycemic control, impaired insulin sensitivity, and the MetS are associated with a heightened risk of ED. Weinberg AE, Eisenberg M, Patel CJ, Chertow GM, and Leppert JT. Diabetes severity, metabolic syndrome, and the risk of erectile dysfunction. J Sex Med 2013;10:3102–3109.     

Perinatal outcomes in inflammatory bowel disease

Objective: To determine whether inflammatory bowel disease (IBD) is associated with increased risk for adverse perinatal outcome.

Methods: A case–control study of 116 singleton pregnancies with IBD compared to 56?398 singleton controls delivered between 1986 and 2001.

Results: Patients with IBD were slightly older (32.8 vs. 30.6 years, p <?0.001), more likely to be Caucasian or Asian than Black or Latino (92% vs. 57%, p <?0.001) and have private health insurance (33% vs. 3%, p <?0.001). IBD was associated with an increased risk for labor induction (32% vs. 24%, p?=?0.002), chorioamnionitis (7% vs. 3%, p?=?0.04) and Cesarean section (32% vs. 22%, p?=?0.007), but there were no differences in neonatal outcomes. Subgroup analysis demonstrated an increased risk for low birth weight (LBW) in the ulcerative colitis group vs. the Crohn's disease group (19% vs. 0%, p?=?0.002). Patients with prior surgery for IBD had a lower incidence of LBW (0% vs. 12%, p?=?0.03). Flares during pregnancy were associated with an increased risk for preterm delivery (27% vs. 8%, p?=?0.02) and LBW (32% vs. 3%, p?=?0.003).

Conclusion: IBD was an independent risk factor for Cesarean section but there was no increase in adverse perinatal outcome. Crohn's disease, prior IBD surgery and quiescent disease were associated with a lower risk for LBW.     

Risk factors for pancreatic fistula after stapled gland transection

The objective of this study was to identify risk factors for pancreatic fistula (PF) after stapled transection in distal pancreatectomy (DP). Patients undergoing DP using a stapler for transection between 2005 and 2009 were identified from a pancreatic resection database. Variables examined included patient and tumor characteristics, staple size, and the use of mesh reinforcement. Univariate and multivariate regression analyses were performed to identify risk factors for postoperative PF. One hundred forty-nine had stapled transection, and of these, 25 (17%) had mesh reinforcement. The overall morbidity and mortality rates were 28 per cent and less than 1 per cent; 34 (23%) were diabetic. The rate of clinically significant PF was 14 per cent. On univariate analysis, diabetes (P = 0.04), a firm pancreas (P = 0.03), use of mesh staple line reinforcement (P = 0.02), use of a 4.1-mm staple cartridge (P = 0.01), and blood loss greater than 100 mL (P = 0.01) were associated with higher pancreatic fistula rates. On multivariate analysis, only the presence of diabetes (OR, 4.17; 95% CI, 1.1-15.3; P = 0.03) and the use of a 4.1-mm cartridge (OR, 8.57; 95% CI, 1.2-60.2; P = 0.03) were independently associated with pancreatic fistula formation. Stapled pancreatic transection provides an acceptable PF rate after DP. Diabetes and staple size influence PF rates. In our experience, use of mesh staple line reinforcement did not reduce the incidence of PF after stapled transection.     

Assessment of physical functioning in the clinical care of the patient with advanced kidney disease

Maintenance of independent living is the top health priority among patients with advanced chronic kidney disease (CKD). Mobility limitation is often the first sign of functional limitation leading to loss of independence. Regular assessments of physical capacity can help provide kidney health providers identify patients at risk of frailty and other adverse health‐related outcomes that contribute to the loss of functional independence. These physical capacities can be measured with commonly used self‐reported measures of physical function or by objective physical performance testing. The current review describes commonly used assessments of self‐reported physical function and physical performance. First, we describe the disablement process and how these assessments can be performed with commonly used quality of life instruments measuring self‐reported physical function or objective physical performance tests. Second, we identify the determinants and correlates of self‐reported physical function and physical performance and their contribution to the frailty phenotype. Third, we describe the association of physical capacities with clinical outcomes. We conclude with on possible approach to identifying and intervening on persons with CKD at high risk of functional decline.     

Concomitant contraceptive implant and efavirenz use in women living with HIV: perspectives on current evidence and policy implications for family planning and HIV treatment guidelines

Introduction : Preventing unintended pregnancies is important among all women, including those living with HIV. Increasing numbers of women, including HIV‐positive women, choose progestin‐containing subdermal implants, which are one of the most effective forms of contraception. However, drug–drug interactions between contraceptive hormones and efavirenz‐based antiretroviral therapy (ART) may reduce implant effectiveness. We present four inter‐related perspectives on this issue. Discussion : First, as a case study, we discuss how limited data prompted country‐level guidance against the use of implants among women concomitantly using efavirenz in South Africa and its subsequent negative effects on the use of implants in general. Second, we discuss the existing clinical data on this topic, including the observational study from Kenya showing women using implants plus efavirenz‐based ART had three‐fold higher rates of pregnancy than women using implants plus nevirapine‐based ART. However, the higher rates of pregnancy in the implant plus efavirenz group were still lower than the pregnancy rates among women using common alternative contraceptive methods, such as injectables. Third, we discuss the four pharmacokinetic studies that show 50–70% reductions in plasma progestin concentrations in women concurrently using efavirenz‐based ART as compared to women not on any ART. These pharmacokinetic studies provide the biologic basis for the clinical findings. Fourth, we discuss how data on this topic have marked implications for both family planning and HIV programmes and policies globally. Conclusion : This controversy underlines the importance of integrating family planning services into routine HIV care, counselling women appropriately on increased risk of pregnancy with concomitant implant and efavirenz use, and expanding contraceptive method mix for all women. As global access to ART expands, greater research is needed to explore implant effectiveness when used concomitantly with newer ART regimens. Data on how HIV‐positive women and their partners choose contraceptives, as well as information from providers on how they present and counsel patients on contraceptive options are needed to help guide policy and service delivery. Lastly, greater collaboration between HIV and reproductive health experts at all levels are needed to develop successful strategies to ensure the best HIV and reproductive health outcomes for women living with HIV.