Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein

OBJECTIVE: A severely virilized 46, XX newborn girl was referred to our center for evaluation and treatment of congenital adrenal hyperplasia (CAH) because of highly elevated 17alpha-hydroxyprogesterone levels at newborn screening; biochemical tests confirmed the diagnosis of salt-wasting CAH. Genetic analysis revealed that the girl was compound heterozygote for a previously reported Q318X mutation in exon 8 and a novel insertion of an adenine between nucleotides 962 and 963 in exon 4 of the CYP21A2 gene. This 962_963insA mutation created a frameshift leading to a stop codon at amino acid 161 of the P450c21 protein. AIM AND METHODS: To better understand structure-function relationships of mutant P450c21 proteins, we performed multiple sequence alignments of P450c21 with three mammalian P450s (P450 2C8, 2C9 and 2B4) with known structures as well as with human P450c17. Comparative molecular modeling of human P450c21 was then performed by MODELLER using the X-ray crystal structure of rabbit P450 2B4 as a template. RESULTS: The new three dimensional model of human P450c21 and the sequence alignment were found to be helpful in predicting the role of various amino acids in P450c21, especially those involved in heme binding and interaction with P450 oxidoreductase, the obligate electron donor. CONCLUSION: Our model will help in analyzing the genotype-phenotype relationship of P450c21 mutations which have not been tested for their functional activity in an in vitro assay.     

Reproductive and lifestyle factors associated with early menopause in Mexican women

OBJECTIVE: The purpose of this study was to evaluate the relationship between certain reproductive and lifestyle factors and the occurrence of early natural menopause. MATERIAL AND METHODS: A case/control study was conducted on a basal population of 2510 women participating in the "Mexican Institute of Social Security health workers cohort study". Cases were defined as those women for whom natural menopause presented by age 47. Information was obtained through a self-administered questionnaire. RESULTS: The risk of early menopause is associated with short menstrual cycles [<26 days, OR = 3.79 (IC 95% 1.37-10.52)], a short period of oral contraceptives use [<1 year, OR = 2.63 (IC 95% 1.10-6.29)], a lower number of pregnancies [<2, OR = 1.63 (IC 95% 1.03-2.57)], low body mass index [< or =27 kg/m2, OR = 1.64 (IC 95% 1.10-2.43)], low schooling level [<6 years, OR = 3.02 (IC 95% 1.26-7.23)], smoking history [>15 cigarettes/day, OR = 2.7 (IC 95% 1.00-7.30)], and birth cohorts [> or =950, OR = 4.09 (IC 95% 2.62-6.39)]. CONCLUSIONS: The findings of this study suggest that both reproductive and lifestyle factors are significant elements in the occurrence of early menopause in Mexican women.     

Metabolic syndrome and coronary heart disease equivalent conditions in predicting cardiovascular events in young to middle-aged adults

There are questions concerning the validity of the metabolic syndrome as a diagnostic entity and whether the syndrome predicts coronary heart disease (CHD) better than global risk stratification. The use of the metabolic syndrome as a potential adjunct to improve global risk stratification has received less attention. The authors evaluated the relationship between the metabolic syndrome and cardiovascular disease compared with coronary heart disease equivalent. Two hundred thirty-six subjects undergoing elective coronary angiography had bilateral carotid ultrasound studies and global risk scores calculated. Mean total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglyceride values were normal. The metabolic syndrome was associated with carotid atherosclerosis (odds ratio, 2.3; confidence interval, 1.2-4.2), coronary disease (odds ratio, 2.9; confidence interval, 1.6-5.4), and future cardiovascular events. Rates for future events and coronary and carotid atherosclerosis were similar for subjects with the metabolic syndrome compared with coronary heart disease equivalent. Combined, the two conditions identified 70% of subjects who developed events. The metabolic syndrome is associated with cardiovascular disease and provides additive information to clinical risk stratification.     

Detection of Barrett's esophagus after endoscopic healing of erosive esophagitis

BACKGROUND: The presence of erosive esophagitis (EE) in patients presenting for upper endoscopy may prevent the detection of underlying Barrett's esophagus (BE) in the distal esophagus. AIM: To prospectively determine the proportion of patients detected with BE upon repeat endoscopy after healing of EE. METHODS: Patients with endoscopically confirmed EE without BE were treated with standard doses of acid suppression therapy and a repeat endoscopy was performed to assess the presence of BE. If columnar mucosa was visualized in the distal esophagus, targeted biopsies were obtained and all biopsies were evaluated for the presence of intestinal metaplasia. BE was defined as columnar mucosa in the distal esophagus with intestinal metaplasia on biopsy. RESULTS: A total of 172 patients with reflux symptoms were diagnosed with EE without BE on initial endoscopy. They were treated with standard doses of proton pump inhibitor therapy, and after a mean duration of 11 wk (range 8-16 wk), a repeat endoscopy was performed to confirm healing of EE and to document the presence of BE. On repeat endoscopy, EE was completely healed in 116 patients (67%), and of those, BE was suspected in 32 patients (i.e., columnar-lined distal esophagus) and was confirmed in 16 patients (13.8%). In the 56 patients with persistent EE on repeat endoscopy, columnar mucosa in areas of previously healed esophagitis was visualized in 8 and confirmed in 5 patients (8.9% of nonhealed cases). Overall, 21 (12%) patients were confirmed with BE on repeat endoscopy; all men, mean age 61 yr with a median BE length of 0.5 cm (range 0.5-5 cm, interquartile range 0.5 cm). The majority of these patients (N = 19) had short segment Barrett's esophagus (SSBE) (i.e., length <3 cm). CONCLUSIONS: In patients with EE undergoing treatment with acid suppressive therapy, BE (mainly SSBE) is detected in approximately 12% of patients on repeat endoscopy. Patients with reflux symptoms undergoing endoscopy for the detection of BE (i.e., screening) should be treated with acid suppressive therapy prior to endoscopy to enhance the yield of BE. Alternatively, if the goal is to document BE and if EE is found at the initial endoscopy, then repeat endoscopy may be considered after acid suppressive therapy.     

Symptom and function heterogenicity among patients with distal esophageal spasm: studies using combined impedance-manometry

BACKGROUND: Combined multichannel intraluminal impedance and esophageal manometry (MII-EM) is a clinically available tool that assesses the functional defect of various manometric abnormalities. The aim of our study was to evaluate esophageal bolus transit in patients with manometrically defined distal esophageal spasm (DES). METHODS: Patients referred for esophageal function testing underwent combined MII-EM studies including 10 liquid and 10 viscous swallows. Individual swallows were classified using previously published manometric and impedance criteria. DES is traditionally defined as > or =20% simultaneous contractions in the distal esophagus. Diagnosis of esophageal transit abnormalities was defined by the presence of > or =30% incomplete liquid or > or =40% incomplete viscous swallows. RESULTS: Data from 71 patients (43 female, mean age 57 yr, range 16-85) with a manometric diagnosis of DES were analyzed. During liquid swallows, patients with chest pain had higher (p < 0.05) distal esophageal amplitudes (202.3 +/- 34.5 mmHg) and a higher (p < 0.05) percentage of swallows with complete bolus transit (89%+/- 3%) compared to patients presenting with dysphagia (amplitude 117.8 +/- 8.7 mmHg; percentage of complete transit 69%+/- 5%) and patients with reflux symptoms (amplitude 116.4 +/- 12.7 mmHg; percentage of complete transit 74%+/- 5%). Fifty-one percent of the DES patients had a normal bolus transit for liquid and viscous, 24% abnormal bolus transit for one substance, and 25% abnormal bolus transit for liquid and viscous. CONCLUSION: Pressure and bolus transit information in patients with manometrically defined DES points toward heterogenicity of this group of patients. Outcomes data are warranted to evaluate whether stratifying DES patients based on pressure and bolus transit information may improve the clinical approach.     

Relation of coronary atherosclerosis determined by electron beam computed tomography and plasma levels of n-terminal pro-brain natriuretic peptide in a multiethnic population-based sample (the Dallas Heart Study)

Elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are seen in the setting of cardiac ischemia and are associated with adverse outcomes in patients with coronary artery disease. The mechanisms leading to natriuretic peptide elevation in patients with coronary artery disease, including the contribution of coronary atherosclerosis itself, have not been fully elucidated. Measurement of NT-pro-BNP, electron beam computed tomography, and cardiac magnetic resonance imaging were performed in 2,445 subjects from the Dallas Heart Study who were free of heart failure and renal insufficiency. Electron beam computed tomography-determined coronary artery calcium scores were categorized as none (<10), mild (> or =10 to <100), moderate (> or =100 to <400), and severe (> or =400). NT-pro-BNP levels increased significantly across increasing coronary artery calcium score categories (p <0.0001 for trend). In multivariate models adjusted for age, gender, race, body mass index, hypertension, history of myocardial infarction, angina, angiotensin-converting enzyme inhibitor use, beta-blocker use, left ventricular (LV) ejection fraction, and LV mass, higher coronary artery calcium scores remained independently associated with higher log NT-pro-BNP levels (p = 0.03). This association persisted in similar models excluding patients with low LV ejection fractions, LV hypertrophy, angina pectoris, and a history of myocardial infarction. In conclusion, these findings support the hypothesis that coronary atherosclerosis may directly influence the activation of the cardiac neurohormonal system.     

Fluvastatin reduces the 4-year cardiac risk in patients with multivessel disease

BACKGROUND: To evaluate the impact of the extent of coronary disease (single- or multivessel) and of fluvastatin treatment on the incidence of long-term cardiac atherosclerotic complications in the Lescol Intervention Prevention Study (LIPS). METHODS: A total of 1063 patients with single-vessel disease and 614 patients with multivessel disease were randomized to receive fluvastatin (40 mg bid) or placebo for at least 3 years following a first successful percutaneous coronary intervention. The incidence of cardiac atherosclerotic events (cardiac death, non-fatal myocardial infarction, and coronary re-interventions not related to restenosis) was evaluated. RESULTS: Patients with multivessel disease tended to be older and presented a higher prevalence of associated risk factors and cardiovascular antecedents. The presence of multivessel disease markedly increased the risk of cardiac atherosclerotic events compared with single-vessel disease among patients allocated to placebo (RR 1.67 [95% CI: 1.24-2.25]; p<0.001). In patients treated with fluvastatin, however, no significant differences in long-term outcomes were observed between patients with multivessel disease and patients single-vessel disease (RR 1.28 [95% CI: 0.90-1.81]; p=0.2). CONCLUSIONS: Multivessel coronary disease impaired the 4-year outcomes after percutaneous intervention. However, the hazardous effect of multivessel disease was significantly reduced by long-term fluvastatin treatment.     

Improvement in health status following cough-suppression physiotherapy for patients with chronic cough

Cough-suppression physiotherapy is a novel self-help therapy for chronic cough. We evaluated the effectiveness of cough physiotherapy in a pilot prospective observational study. We assessed cough-specific health-related quality of life (HRQOL) with the Leicester Cough Questionnaire (LCQ) and subjectively reported cough frequency and sleep disturbance in 23 patients with chronic cough refractory to medical therapy, before and after outpatient-based cough-suppression physiotherapy. Cough-suppression physiotherapy consisted of education, counselling, cough control, breathing retraining, and vocal hygiene. There was a significant improvement in cough-specific HRQOL after cough physiotherapy; mean (standard error of mean [SEM]) LCQ total score before 12.4 (0.9) versus after 15.1 (0.9); 95% confidence interval of difference -4.1 to -1.3; p < 0.001. The improvement in cough-specific HRQOL was greater than the LCQ minimal clinically important difference of 1.3. A significant improvement was seen in all LCQ domains: physical (p = 0.001), psychological (p < 0.001) and social (p < 0.04). There was a significant reduction in cough frequency scores (p = 0.002) and sleep disturbance scores (p = 0.02). Our findings suggest cough-suppression physiotherapy may lead to a clinically significant improvement in cough-specific HRQOL in patients with chronic cough.