Superior discriminating value of ACTH-stimulated serum 21-deoxycortisol in identifying heterozygote carriers for 21-hydroxylase deficiency

P>Background Congenital adrenal hyperplasia caused by classic 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder with a high prevalence of asymptomatic heterozygote carriers (HTZ) in the general population, making case detection desirable by routine methodology. HTZ for classic and nonclassic (NC) forms have basal and ACTH-stimulated values of 17-hydroxyprogesterone (17OHP) that fail to discriminate them from the general population. 21-Deoxycortisol (21DF), an 11-hydroxylated derivative of 17OHP, is an alternative approach to identify 21OHD HTZ. Objective To determine the discriminating value of basal and ACTH-stimulated serum levels of 21DF in comparison with 17OHP in a population of HTZ for 21OHD (n = 60), as well as in NC patients (n = 16) and in genotypically normal control subjects (CS, n = 30), using fourth generation tandem mass spectrometry after HPLC separation (LC-MS/MS). Results Basal 21DF levels were not different between HTZ and CS, but stimulated values were increased in the former and virtually nonresponsive in CS. Only 17 center dot 7% of the ACTH-stimulated 21DF levels overlapped with CS, when compared to 46 center dot 8% for 17OHP. For 100% specificity, the sensitivities achieved for ACTH-stimulated 21DF, 17OHP and the quotient [(21DF + 17OHP)/F] were 82 center dot 3%, 53 center dot 2% and 87%, using cut-offs of 40, 300 ng/dl and 46 (unitless), respectively. Similar to 17OHP, ACTH-stimulated 21DF levels did not overlap between HTZ and NC patients. A positive and highly significant correlation (r = 0 center dot 846; P < 0 center dot 001) was observed between 21DF and 17OHP pairs of values from NC and HTZ. Conclusion This study confirms the superiority of ACTH-stimulated 21DF, when compared to 17OHP, both measured by LC-MS/MS, in identifying carriers for 21OHD. Serum 21DF is a useful tool in genetic counselling to screen carriers among relatives in families with affected subjects, giving support to molecular results.

A quantitative coronary angiography-matched comparison between a prospective randomised multicentre cutting balloon angioplasty and bare metal stent trial (REDUCE III) and the Rapamycin-Eluting Stent Evaluation At Rotterdam Cardiology Hospital (RESEARCH) study

Aims: There remains significant concern about the long-term safety of drug-eluting stents (DES). However, bare metal stents (BMS) have been used safely for over two decades. There is therefore a pressing need to explore alternative strategies for reducing restenosis with BMS. This study was designed to examine whether IVUS-guided cutting balloon angioplasty (CBA) with BMS could convey similar restenosis rates to DES. Methods and results: In the randomised REstenosis reDUction by Cutting balloon angioplasty Evaluation (REDUCE III) study, 521 patients were divided into four groups based on device and IVUS use before BMS (IVUS-CBA-BMS: 137 patients; Angio-CBA-BMS: 123; IVUS-BA-BMS: 142; and Angio-BA-BMS: 119). At follow-up, the IVUS-CBA-BMS group had a significantly lower restenosis rate (6.6%) than the other groups (p=0.016). We performed a quantitative coronary angiography (QCA) based matched comparison between an IVUS-guided CBA-BMS strategy (REDUCE III) and a DES strategy (Rapamycin-Eluting-Stent Evaluation At Rotterdam Cardiology. Hospital, the RESEARCH study). We matched the presence of diabetes, vessel size, and lesion severity by QCA. Restenosis (>50% diameter stenosis at follow-up) and target vessel revascularisation (TVR) were examined. QCA-matched comparison resulted in 120-paired lesions. While acute gain was significantly greater in IVUS-CBA-BMS than DES (1.65 +/- 0.41 mm vs. 1.28 +/- 0.57 mm, p=0.001), late loss was significantly less with DES than with IVUS-CBA-BMS (0.03 +/- 0.42 mm vs. 0.80 +/- 0.47 mm, p=0.001). However, no difference was found in restenosis rates (IVUS-CBA-BMS: 6.6% vs. DES: 5.0%, p=0.582) and TVR (6.6% and 6.6%, respectively). Conclusions: An IVUS-guided CBA-BMS strategy yielded restenosis rates similar to those achieved by DES and provided an effective alternative to the use of DES.

Combined glucosamine and chondroitin sulfate provides functional and structural benefit in the anterior cruciate ligament transection model

Evidence that combined glucosamine sulfate and chondroitin sulfate (Gluchon) or isolated glucosamine (Glu) modifies joint damage in osteoarthritis (OA) is still lacking. We studied joint pain and cartilage damage using the anterior cruciate ligament transection (ACLT) model. Wistar rats were subjected to ACLT of the right knee ( OA) or sham operation. Groups received either Glu (500 mg/kg), Gluchon (500 mg/kg glucosamine +400 mg/kg chondroitin) or vehicle (non-treated-NT) per os starting 7 days prior to ACLT until sacrifice at 70 days. Joint pain was evaluated daily using the rat-knee joint articular incapacitation test. Structural joint damage was assessed using histology and biochemistry as the chondroitin sulfate ( CS) content of cartilage by densitometry (microgram per milligram dried cartilage), comparing to standard CS. The molar weight (Mw) of the CS samples, used as a qualitative biochemical parameter, was obtained by comparing their relative mobility on a polyacrylamide gel electrophoresis to standard CS. Gluchon, but not Glu, significantly reduced joint pain (P<0.05) compared to NT. There was an increase in CS content in the OA group (77.7 +/- 8.3 mu g/mg) compared to sham (53.5 +/- 11.2 mu g/mg) (P<0.05). The CS from OA samples had higher Mw (4:62 +/- 0:24 x 10(4) g/mol) compared to sham (4:18 +/- 0:19 x 10(4) g/mol) (P<0.05). Gluchon administration significantly reversed both the increases in CS content (54.4 +/- 12.1 mu g/mg) and Mw (4:18 +/- 0:2 x 104 g/mol) as compared to NT. Isolated Glu decreased CS content though not reaching statistical significance. Cartilage histology alterations were also significantly prevented by Gluchon administration. Gluchon provides clinical (analgesia) and structural benefits in the ACLT model. This is the first demonstration that biochemical alterations occurring in parallel to histological damage in OA are prevented by Gluchon administration.

Electrophysiological characteristics of the Marshall bundle in humans

BACKGROUND Marshall bundles (MBs) are the muscle bundles within the ligament of Marshall. OBJECTIVE This trial sought to the electrophysiological characteristics of the MB and the anatomical connections between MB and left atrium (LA) in patients with persistent atrial fibrillation (AF). METHODS We enrolled 72 patients (male: female 59: 13, age 59.9 +/- 9.4 years) who underwent MB mapping and ablation for AF. MB mapping was done via an endocardial or epicardial approach during sinus rhythm and AF. RESULTS Recordings were successful in 64 of 72 patients (89%). A single connection was noted in 11 of 64 patients between the MB and the coronary sinus (CS) muscle sleeves. The MB recordings showed distinct MB potentials with a proximal-to-distal activation pattern during sinus rhythm. During AF, organized passive activations and dissociated slow MB ectopic activities were commonly observed in this type of connection. Double connections to both CS and LA around left pulmonary veins were noted in 23 of 64 patients (36%). After the ablation of the distal connection, MB recording showed typical double potentials as in single connection. Multiple connections were noted in 30 of 64 patients (47%). During sinus rhythm, the earliest activation was in the middle of the MB. The activation patterns were irregular and variable in each patient. During AF, rapid and fractionated complex activations were noted in all patients of this group. CONCLUSION We documented 3 different types of MB-LA connections. Rapid and fractionated activations were most commonly observed in the MB that had multiple LA connections.

Muscle sympathetic nerve activity in patients with Chagas` disease

Background: The progression of heart failure in Chagas` disease has been explained by remodeling, leading to neurohumoral activation, or by the direct parasite damage to parasympathetic neurons during acute phase, leading to early sympathetic activation and progressive heart failure. To help distinguish between these hypotheses we studied muscle sympathetic nerve activity (MSNA) at rest and during handgrip exercise (30% of maximal voluntary contraction) in patients with Chagas` disease and normal ejection fraction vs. patients with heart failure. Methods: A consecutive study of 72 eligible out-patients/subjects was conducted between July 1998 and November 2004. The participants were classified in three advanced heart failure groups (New York Heart Association Functional Classes II-III): Chagas` disease (n-15), ischemic (n=15) and idiopathic cardiomyopathy (n-15). Twelve Chagas` disease patients without heart failure and normal ejection fraction, and 15 normal controls were also studied. MSNA was recorded directly from the peroneal nerve by microneurography technique. Results: MSNA was greater in heart failure patients when compared with Chagas` disease patients without heart failure (51 +/- 3 vs. 20 +/- 2 bursts/min P=0.0001). MSNA in Chagas` patients with normal ejection fraction and normal controls was not different. During exercise, MSNA was similar in all 3 heart failure groups. And, was lower in the Chagas` patients with normal ejection fraction than in patients with Chagas` disease and heart failure (28 +/- 1 vs. 63 +/- 5 bursts/min, respectively). Conclusion: MSNA is not elevated in patients with Chagas` disease with normal ejection fraction. These findings support the concept of remodeling and neurohumoral activation as a common pathway following significant cardiac injury. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Conditioned inhibition of autonomic Pavlovian conditioning in humans

The present study aimed to demonstrate conditioned inhibition of Pavlovian conditioning of autonomic responses in humans. Subjects (N = 21) were presented initially with four geometric shapes (A, B, C and D). An electric shock served as the unconditioned stimulus (US) during acquisition. Conditional stimuli lasted for 8 s and US onset coincided with CS offset. Subjects were trained with A-US, C-US, and AC-US pairings and AB alone and B alone presentations. The subsequent summation test consisted of C-US pairings and CB alone and CD alone presentations. Conditioning was evident in self-reported US expectancy and first and second interval electrodermal responses. Evidence for conditioned inhibition during the summation test was found in US expectancy and second interval electrodermal responses. (C) 1997 Elsevier Science B.V.

Validity of self-reported hysterectomy and tubal sterilisation

Both hysterectomy and tubal sterilisation offer significant protection from ovarian cancer, and the risk of cardiovascular disease in women is lowered after hysterectomy. Since little is known about the accuracy of women's self-reports of these procedures, we assessed their reliability and validity using data obtained in a case-control study of ovarian cancer. There was 100 per cent repeatability for both positive and negative histories of hysterectomy and tubal sterilisation among a small sample of women on reinterview. Verification of surgery was sought against surgeons' or medical records, or if these were unavailable, from randomly selected current general practitioners for 51 cases and 155 controls reporting a hysterectomy and 73 cases and 137 controls reporting a tubal sterilisation. Validation rate for self-reported hysterectomy against medical reports (32 cases, 96 controls) was 96 per cent (95 per cent confidence interval (CI) 91 to 99) and for tubal sterilisation (32 cases, 77 controls) it was 88 per cent (CI 81 to 93), which is likely to be an underestimate. Although findings are based on small numbers of women for whom medical reports could be ascertained, they are consistent with other findings that suggest women have good recall of past histories of hysterectomy and tubal sterilisation; this allows long-term effects of these procedures to be studied with reasonable accuracy from self-reports.

Vitamin D intoxication: a cause of hypocalcaemia and acute renal failure in a HIV patient

Hypercalcaemia in patients with HIV infection is usually associated with specific conditions such as lymphoma and granulomatous diseases. We described a case of severe hypercalcaemia consequent to vitamin D intoxication and secondary renal failure in a HIV patient under tenofovir using. Serum creatinine and calcium returned to near normal levels after vitamin D discontinuation, saline and furosemide administration. Some aspects of the drug-induced nephropathy are discussed.

Clinical correlates of eating disorder comorbidity in women with bipolar disorder type I

Objective: To report on the presence of current and lifetime eating disorders (ED) in a well-defined sample of 137 female individuals with bipolar disorder type I. Methods: Trained psychiatrists interviewed the patients, and the diagnoses of BD and comorbidities were confirmed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Axis I Disorders. Clinical and demographic characteristics of both groups (group with ED vs. group without ED) were compared. Results: Female patients with ED had an earlier onset of BD and an increased number of mood episodes, predominantly depressive. Women in the ED group also had higher rates of comorbidity with substance use disorders and anxiety disorders and reported a history of suicide attempts more frequently than women without ED. Conclusion: The presence of ED is a correlate of severity of BD type 1, and interventions should be developed to minimize distress and suicide risk and to improve treatment outcome. (C) 2010 Elsevier B.V. All rights reserved.

Cost-effectiveness analysis of a hypothetical hepatitis C vaccine compared to antiviral therapy

We propose a mathematical model to simulate the dynamics of hepatitis C virus (HCV) infection in the state of Sao Paulo, Brazil. We assumed that a hypothetical vaccine, which cost was taken to be the initial cost of the vaccine against hepatitis B exists and it is introduced in the model. We computed its cost-effectiveness compared with the anti-HCV therapy. The calculated basic reproduction number was 1.20. The model predicts that without intervention a steady state exists with an HCV prevalence of 3%, in agreement with the Current epidemiological data. Starting from this steady state three interventions were simulated: indiscriminate vaccination, selective vaccination and anti-HCV therapy. Selective vaccination proved to be the strategy with the best cost-effectiveness ratio, followed by indiscriminate vaccination and anti-HCV therapy.

Collagen Type I, Collagen Type III, and Versican in Vocal Fold Lamina Propria

Objective: To analyze the distributions of collagen type I, collagen type III, and versican in the lamina propria of the human vocal fold. Design: Cross-sectional analysis of cadaveric vocal folds of adult human larynges. Setting: Academic tertiary referral center. Subjects: Larynges harvested at autopsy from 10 adult men and 10 adult women. Main Outcome Measures: Immunohistochemical reactions were performed using antihuman monoclonal antibodies to analyze the expression of collagen type I, collagen type III, and versican. Results: Collagen type I density was lower in the intermediate layer compared with the superficial and deep layers of vocal folds. Collagen type III density was lower in the intermediate layer compared with the deep layer. Versican density was lower in the superficial layer compared with the intermediate and deep layers. Versican density was lower in the lamina propria of women compared with men; this difference was noted in the superficial layer only. There was a positive correlation between collagen type III and versican densities within the lamina propria. Conclusion: Collagen type I, collagen type III, and versican are distributed differently within the lamina propria layers of the adult vocal folds.

Children with Cushing`s syndrome: primary pigmented nodular adrenocortical disease should always be suspected

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare form of bilateral adrenocortical hyperplasia that is inherited in an autosomal dominant manner and leads to ACTH-independent Cushing`s syndrome (CS). PPNAD may be isolated or associated with Carney Complex (CNC). For the diagnosis of PPNAD and CNC, in addition to the hormonal and imaging tests, searching for PRKAR1A mutations may be recommended. The aims of the present study are to discuss the clinical and molecular findings of two Brazilian patients with ACTH-independent CS due to PPNAD and to show the diagnostic challenge CS represents in childhood. Description of two patients with CS and the many sequential steps for the diagnosis of PPNAD is provided. Sequencing analysis of all coding exons of PRKAR1A in the blood, frozen adrenal nodules (patients 1 and 2) and testicular tumor (patient 1) is performed. After several clinical and laboratory drawbacks that misled the diagnostic investigation in both patients, the diagnosis of PPNAD was finally established and confirmed through pathology and molecular studies. In patient 1, sequencing of PRKAR1A gene revealed a novel heterozygous 10-bp deletion in exon 3, present in his blood, adrenal gland and testicular tumor. The etiologic diagnosis of endogenous CS in children is a challenge that requires expertise and a multidisciplinary collaboration for its prompt and correct management. Although rare, PPNAD should always be considered among the possible etiologies of CS, due to the high prevalence of this disease in this age group.

A description of adaptive and maladaptive behaviour in children and adolescents with Cri-du-chat syndrome

Background Psychological tests can be useful to record adaptive and maladaptive behaviours of children with intellectual disability. The objective of this study was to describe the adaptive and maladaptive behaviour of children and adolescents with Cri-du-chat syndrome. Methods The sample consisted of 10 children and adolescents with Cri-du-chat syndrome (mean chronological age = 11.3 years, mean mental age = 18 months). The developmental quotient was calculated through the Psychoeducational Profile - Revised. An observational protocol was used to record adaptive and maladaptive behaviours. Results The number of maladaptive behaviours observed was different among participants. However, all of them had high rates of adaptive behaviours, such as rule-following. Conclusions These results, though preliminary, justify that we continue to think about the need for psychoeducational interventions aimed at stimulating the repertoire of adaptive behaviours, in people with Cri-du-chat syndrome.

Estrogen receptor-positive breast carcinomas in younger women are different from those of older women: A pathological and immunohistochemical study

The higher frequency of triple-negative and HER-2-positive tumors detected in younger patients has been suggested as an explanation for the more aggressive tumor types observed in this age group. However, estrogen receptor (ER)-positive tumors are the most frequent subtype of breast carcinomas identified, even in younger patients. In this retrospective study, the morphological and immunohistochemical profiles of ER-positive breast carcinomas from women 35 yrs and younger that were diagnosed between 1997 and 2007 were evaluated. From these cases, 213 were selected based on the availability of pathology reports and paraffin blocks. For comparison, 117 consecutive cases of breast carcinomas diagnosed in patients >60 yrs from 2006 were included. Paraffin-embedded tumors were stained for expression of ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2). Ki-67 antigen, epidermal growth factor receptor (EGFR), cytokeratin 5/6, p53, vimentin, CD117, and p63 using tissue microarrays. ER-positive carcinomas were diagnosed in 120 (56.1%) samples of the younger patient group and in 92 (78.6%) samples of the older patient group. Of these ER-positive carcinomas, 48 (40%) from the younger patient group presented the subtype luminal A, compared with 53 (57.6%) from the older patient group (p=0.01). Tumors from the younger patient group were also associated with increased vascular involvement, co-expression of HER-2, and decreased expression of CD117. These results highlight differences in expression markers and the pathology of ER-positive tumors detected in younger women, with a notable characteristic being co-expression of HER-2. (C) 2010 Elsevier Ltd. All rights reserved.

Assessment of disease-free survival in patients with laryngeal squamous cell carcinoma treated with radiotherapy associated or not with chemotherapy

In early stage (I and II) laryngeal squamous cell carcinoma, both surgery and radiotherapy results in significant local and regional control. In advanced tumors (III and IV), radiotherapy alone has local-regional control rates of 32-43%. Aim: To assess disease-free survival in SCC laryngeal carcinoma patients submitted to radiotherapy alone and/or associated with chemotherapy. Materials and Methods: Retrospective study involving 84 cases of laryngeal SCC treated with radiotherapy or chemotherapy together with radiotherapy. Fifty-three cases were treated with intension to cure and 31 because of impossibility to resect the disease. As to clinical stage (CS), 12 were CS I, 15 II, 21 III and 5 IV. In the second group, 11 cases were EC III and 20 IV. Results: Mean age was 60 years, 84.5% were men. Fifty-eight (69.1%) cases had complete response and 26 (30.9%) had persistent or residual disease. Five-year disease-free survival was of 42.5%; 62.5% of the patients with organ preservation indication and 9.75 in the group of irressecable disease. Conclusion: disease-free survival of those patients submitted to radiotherapy because of laryngeal SCC was of 62.5%