Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption

BACKGROUND: Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. MATERIALS AND METHODS: The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. RESULTS: Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety-related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. CONCLUSIONS: The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits.

Long-term follow-up after complete resection of well-differentiated cancer confined to the thyroid gland

BACKGROUND: Papillary or follicular thyroid carcinomas exhibit a relatively benign course. Hence, long-term follow-up studies with well-defined disease stages and treatment details are needed to evaluate treatment strategies. METHODS: Patients who underwent complete resection of well-differentiated thyroid carcinoma (WDTC) confined to the thyroid gland between 1972 and 1990 identified from a prospective database were assessed. Follow-up was performed by interview, review of patient charts, and analysis of the Death Registry. Primary endpoints were overall survival (OS) and disease-specific survival (DSS). Review of histology was performed and extent of thyroid resection, postoperative therapy, and recognized prognostic factors but not lymphadenectomy were evaluated. RESULTS: Of 2,867 patients, 213 had complete resection of WDTC confined to the thyroid gland. Follow-up was completed in 166 patients with median age 54.2 (range, 20-85) years, and median follow-up of 27.2 (range, 15.6-34.5) years. The 10- and 20-year OS was 71 and 55%, respectively. DSS at 10 and 20 years was 81 and 69%, respectively, and correlated with age, histology, tumor size, radio-iodide ablation (RIA), and external beam irradiation (EBR) treatment. No patient died of WDTC more than 18 years after resection. Total or near-total thyroidectomy without lymphadenectomy was not superior to partial thyroidectomy. In multivariate analysis for DSS, age was the dominant factor, which correlated with histology. CONCLUSION: After a median follow-up of 27 years, about one-third of patients died of WDTC. Age, histology and postoperative therapy but not extent of thyroid resection determined DSS.

Growth potential of U-clip interrupted versus polypropylene running suture anastomosis in congenital cardiac surgery: intermediate term results

Although U-clip anastomoses were studied for hemodynamics and patency, their potential for unimpeded growth after congenital cardiovascular surgery has not been investigated yet. In 53 children aged 2.1+/-3.3 years operated on between March 1998 and August 2005 growth of U-clip (U) vs. polypropylene running sutured (P) anastomoses in coarctation repair (Coarc; n=26), bi-directional Glenn (BDG; n=13) and arterial switch operation (ASO; n=14) was retrospectively analysed. Coarc showed 2.39+/-4.33 vs. 3.09+/-2.24 mm of growth during the observation period (21+/-16 vs. 30+/-27 months); no growth (0 vs.16%), restenosis (14 vs. 37%) and reinterventions (14 vs. 11%) were similar (all in U vs. P, P=ns). BDG showed 3.68+/-3.43 vs. 2.50+/-2.55 mm (P=ns) of growth during 15+/-5 vs. 29+/-18 months (P=0.046); no growth (17 vs. 0%), stenosis (0 vs. 14%) and reinterventions (0%) were similar in U vs. P, respectively (P=ns). Main pulmonary artery (MPA) anastomosis in ASO showed 0.28+/-1.73 vs. 1.30+/-3.16 mm of growth during 8+/-14 vs. 28+/-28 months; no growth (60 vs. 14%), stenosis (50 vs. 63%) and reinterventions (0%) were similar (all in U vs. P, P=ns). Anastomotic growth, stenosis and reintervention rates show no difference between interrupted U-clip and polypropylene running sutured technique in Coarc repair, BDG and MPA anastomosis in ASO.

Long-term follow-up after stroke in childhood

Over the last few years, the importance of paediatric stroke has become more and more evident; however, there is still little known about long-term neurological and especially neuropsychological outcome of these children. By retrospective chart review, questionnaire and clinical examination with structured interview, we analysed initial presentation, aetiology and long-term outcome of children suffering ischaemic childhood stroke between 1985 and 1999. A total of 20 children (13 boys) suffered acute arterial ischaemic events. Aetiology was detected in 14, and suspected in another five. Follow-up after 1-15 years (mean 7 years) was possible for 16 children; two had died and two were lost to follow-up. Only two were completely healthy, five suffered mild, six moderate, and three severe handicap. Eleven children presented with combined neurological and neuropsychological problems. Neurological problems were mild to moderate hemisyndrome in 11, dysphasia, epilepsy and other in six each. Mild to severe neuropsychological problems were detected in 13 children, school problems in eight, attention deficits in nine and behaviour problems in seven, increased fatigability and headache in six each. Recurrence was observed in three children, all due to progressive underlying disease. Outcome was most affected by the presence of combined cortical/subcortical and least affected by subcortical infarction. Epilepsy affected neuropsychological outcome. CONCLUSION: although prognosis of paediatric stroke is better than for adult stroke, neurological and especially neuropsychological long-term problems significantly influence the lives of these children. Careful long-term follow-up to support these children in their school career and integration into professional life is necessary. Future studies should evaluate whether specific treatments during the acute episode could improve outcome for these children.

Long-term follow up (37-69 years) of patients with bladder exstrophy treated with ureterosigmoidostomy: uro-nephrological outcome

OBJECTIVE: To describe the urological and nephrological long-term outcome of patients born with classical bladder exstrophy treated with bilateral ureterosigmoidostomies in early childhood. PATIENTS AND METHOD: Out of 42 patients born with bladder exstrophy in Switzerland between 1937 and 1968, 25 participated in this study; seven had died, seven were lost to follow up and three refused consent. Assessment included chart review, clinical examination, and assessment of renal function and morphology. RESULTS: After a follow-up period of 37-69 years ((mean 50 years), 13 of the 25 participants (52%) had their ureterosigmoidostomy still in place. All others had different forms of urinary diversions. Fifteen (60%) patients had normal renal function or mild chronic kidney disease as assessed by estimated glomerular filtration rate. Three patients were on renal replacement therapy. MRI (n=16) showed 10 morphologically normal kidneys. One patient suffered from adenocarcinoma of the colon, five had benign colonic polyps, one urethral papillary carcinoma and 18 no evidence of tumor. CONCLUSION: The majority of our patients have normal or mildly impaired renal function and a well functioning ureterosigmoidostomy. This is remarkable, given the fact that ureterosigmoidostomies are considered to be refluxing high-pressure reservoirs at risk of renal injury and malignancy.

Cortical and trabecular bone mineral density in transsexuals after long-term cross-sex hormonal treatment: a cross-sectional study

The aim of this study was to explore the effect of long-term cross-sex hormonal treatment on cortical and trabecular bone mineral density and main biochemical parameters of bone metabolism in transsexuals. Twenty-four male-to-female (M-F) transsexuals and 15 female-to-male (F-M) transsexuals treated with either an antiandrogen in combination with an estrogen or parenteral testosterone were included in this cross-sectional study. BMD was measured by DXA at distal tibial diaphysis (TDIA) and epiphysis (TEPI), lumbar spine (LS), total hip (HIP) and subregions, and whole body (WB) and Z-scores determined for both the genetic and the phenotypic gender. Biochemical parameters of bone turnover, insulin-like growth factor-1 (IGF-1) and sex hormone levels were measured in all patients. M-F transsexuals were significantly older, taller and heavier than F-M transsexuals. They were treated by cross-sex hormones during a median of 12.5 years before inclusion. As compared with female age-matched controls, they showed a significantly higher median Z-score at TDIA and WB (1.7+/-1.0 and 1.8+/-1.1, P < 0.01) only. Based on the WHO definition, five (who did not comply with cross-sex hormone therapy) had osteoporosis. F-M transsexuals were treated by cross-sex hormones during a median of 7.6 years. They had significantly higher median Z-scores at TEPI, TDIA and WB compared with female age-matched controls (+0.9+/-0.2 SD, +1.0+/-0.4 SD and +1.4+/-0.3 SD, respectively, P < 0.0001 for all) and reached normal male levels except at TEPI. They had significantly higher testosterone and IGF-1 levels (p < 0.001) than M-F transsexuals. We conclude that in M-F transsexuals, BMD is preserved over a median of 12.5 years under antiandrogen and estrogen combination therapy, while in F-M transsexuals BMD is preserved or, at sites rich in cortical bone, is increased to normal male levels under a median of 7.6 years of androgen treatment in this cross sectional study. IGF-1 could play a role in the mediation of the effect of androgens on bone in F-M transsexuals.

Periodontal and general health in long-term periodontal maintenance patients treated in a Norwegian private practice: a descriptive report from a compliant and partially compliant survivor population

BACKGROUND There is weak evidence to support the benefit of periodontal maintenance therapy in preventing tooth loss. In addition, the effects of long-term periodontal treatment on general health are unclear. METHODS Patients who were compliant and partially compliant (15 to 25 years' follow-up) in private practice were observed for oral and systemic health changes. RESULTS A total of 219 patients who were compliant (91 males and 128 females) were observed for 19.1 (range 15 to 25; SD ± 2.8) years. Age at reassessment was 64.6 (range: 39 to 84; SD ± 9.0) years. A total of 145 patients were stable (0 to 3 teeth lost), 54 were downhill (4 to 6 teeth lost), and 21 patients extreme downhill (>6 teeth lost); 16 patients developed hypertension, 13 developed type 2 diabetes, and 15 suffered myocardial infarcts (MIs). A minority developed other systemic diseases. Risk factors for MI included overweight (odds ratio [OR]: 9.04; 95% confidence interval [CI]: 2.9 to 27.8; P = 0.000), family history with cardiovascular disease (OR: 3.10; 95% CI: 1.07 to 8.94; P = 0.029), type 1 diabetes at baseline (P = 0.02), and developing type 2 diabetes (OR: 7.9; 95% CI: 2.09 to 29.65; P = 0.000). A total of 25 patients who were partially compliant (17 males and eight females) were observed for 19 years. This group had a higher proportion of downhill and extreme downhill cases and MI. CONCLUSIONS Patients who left the maintenance program in a periodontal specialist practice in Norway had a higher rate of tooth loss than patients who were compliant. Patients who were compliant with maintenance in a specialist practice in Norway have a similar risk of developing type 2 diabetes as the general population. A rate of 0.0037 MIs per patient per year was recorded for this group. Due to the lack of external data, it is difficult to assess how this compares with patients who have periodontal disease and are untreated.

Long-term clinical, microbiological, and radiographic outcomes of Brånemark™ implants installed in augmented maxillary bone for fixed full-arch rehabilitation

PURPOSE The purpose of this study was to document the long-term outcome of Brånemark implants installed in augmented maxillary bone and to identify parameters that are associated with peri-implant bone level. MATERIAL AND METHODS Patients of a periodontal practice who had been referred to a maxillofacial surgeon for iliac crest bone grafting in the atrophic maxilla were retrospectively recruited. Five months following grafting, they received 7-8 turned Brånemark implants. Following submerged healing of another 5 months, implants were uncovered and restorative procedures for fixed rehabilitation were initiated 2-3 months thereafter. The primary outcome variable was bone level defined as the distance from the implant-abutment interface to the first visible bone-to-implant contact. Secondary outcome variables included plaque index, bleeding index, probing depth, and levels of 40 species in subgingival plaque samples as identified by means of checkerboard DNA-DNA hybridization. RESULTS Nine out of 16 patients (eight females, one male; mean age 59) with 71 implants agreed to come in for evaluation after on average 9 years (SD 4; range 3-13) of function. One implant was deemed mobile at the time of inspection. Clinical conditions were acceptable with 11% of the implants showing pockets ≥ 5 mm. Periodontopathogens were encountered frequently and in high numbers. Clinical parameters and bacterial levels were highly patient dependent. The mean bone level was 2.30 mm (SD 1.53; range 0.00-6.95), with 23% of the implants demonstrating advanced resorption (bone level > 3 mm). Regression analysis showed a significant association of the patient (p < .001) and plaque index (p = .007) with bone level. CONCLUSIONS The long-term outcome of Brånemark implants installed in iliac crest-augmented maxillary bone is acceptable; however, advanced peri-implant bone loss is rather common and indicative of graft resorption. This phenomenon is patient dependent and seems also associated with oral hygiene.

Usefulness of inducible ventricular tachycardia to predict long-term adverse outcomes in arrhythmogenic right ventricular cardiomyopathy

The role of the electrophysiologic (EP) study for risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy is controversial. We investigated the role of inducible sustained monomorphic ventricular tachycardia (SMVT) for the prediction of an adverse outcome (AO), defined as the occurrence of cardiac death, heart transplantation, sudden cardiac death, ventricular fibrillation, ventricular tachycardia with hemodynamic compromise or syncope. Of 62 patients who fulfilled the 2010 Arrhythmogenic Right Ventricular Cardiomyopathy Task Force criteria and underwent an EP study, 30 (48%) experienced an adverse outcome during a median follow-up of 9.8 years. SMVT was inducible in 34 patients (55%), 22 (65%) of whom had an adverse outcome. In contrast, in 28 patients without inducible SMVT, 8 (29%) had an adverse outcome. Kaplan-Meier analysis showed an event-free survival benefit for patients without inducible SMVT (log-rank p = 0.008) with a cumulative survival free of an adverse outcome of 72% (95% confidence interval [CI] 56% to 92%) in the group without inducible SMVT compared to 26% (95% CI 14% to 50%) in the other group after 10 years. The inducibility of SMVT during the EP study (hazard ratio [HR] 2.99, 95% CI 1.23 to 7.27), nonadherence (HR 2.74, 95% CI 1.3 to 5.77), and heart failure New York Heart Association functional class II and III (HR 2.25, 95% CI 1.04 to 4.87) were associated with an adverse outcome on univariate Cox regression analysis. The inducibility of SMVT (HR 2.52, 95% CI 1.03 to 6.16, p = 0.043) and nonadherence (HR 2.34, 95% CI 1.1 to 4.99, p = 0.028) remained as significant predictors on multivariate analysis. This long-term observational data suggest that SMVT inducibility during EP study might predict an adverse outcome in patients with arrhythmogenic right ventricular cardiomyopathy, advocating a role for EP study in risk stratification.

Mid-term results in relation to age and analysis of predictive factors after fixation of acetabular fractures using the modified Stoppa approach.

INTRODUCTION Data concerning outcome after management of acetabular fractures by anterior approaches with focus on age and fractures associated with roof impaction, central dislocation and/or quadrilateral plate displacement are rare. METHODS Between October 2005 and April 2009 a series of 59 patients (mean age 57 years, range 13-91) with fractures involving the anterior column was treated using the modified Stoppa approach alone or for reduction of displaced iliac wing or low anterior column fractures in combination with the 1st window of the ilioinguinal approach or the modified Smith-Petersen approach, respectively. Surgical data, accuracy of reduction, clinical and radiographic outcome at mid-term and the need for endoprosthetic replacement in the postoperative course (defined as failure) were assessed; uni- and multivariate regression analysis were performed to identify independent predictive factors (e.g. age, nonanatomical reduction, acetabular roof impaction, central dislocation, quadrilateral plate displacement) for a failure. Outcome was assessed for all patients in general and in accordance to age in particular; patients were subdivided into two groups according to their age (group "<60yrs", group "≥60yrs"). RESULTS Forty-three of 59 patients (mean age 54yrs, 13-89) were available for evaluation. Of these, anatomic reduction was achieved in 72% of cases. Nonanatomical reduction was identified as being the only multivariate predictor for subsequent total hip replacement (Adjusted Hazard Ratio 23.5; p<0.01). A statistically significant higher rate of nonanatomical reduction was observed in the presence of acetabular roof impaction (p=0.01). In 16% of all patients, total hip replacement was performed and in 69% of patients with preserved hips the clinical results were excellent or good at a mean follow up of 35±10 months (range: 24-55). No statistical significant differences were observed between both groups. CONCLUSION Nonanatomical reconstruction of the articular surfaces is at risk for failure of joint-preserving management of acetabular fractures through an isolated or combined modified Stoppa approach resulting in total joint replacement at mid-term. In the elderly, joint-preserving surgery is worth considering as promising clinical and radiographic results might be obtained at mid-term.

Cholesteatoma surgery in children: long-term results of the inside-out technique

OBJECTIVE To present the anatomical and functional results of the inside-out technique applied in pediatric cholestetaoma surgery and to evaluate functionality with good hearing results against radicality with lower recurrence rate. METHODS Retrospective analysis and evaluation of the postoperative outcome in a consecutive series of 126 children or 130 ears operated between 1992 and 2008. With the inside-out technique, cholesteatoma is eradicated from the epitympanum toward the mastoid and, as a single stage procedure, functional reconstruction of the middle ear is achieved by tympanoossiculoplasty. RESULTS In 89.2% of all cases, the ear was dry postoperatively. 80.9% of the ears reached a postoperative air-bone gap of 30 dB or less and the median air conduction hearing threshold was 29 dB; in 60.9% of all cases, hearing was postoperatively improved. The recurrence rate was 16.2% in a mean postoperative follow-up 8.5 years. Altogether, 48 ears (36.9%) underwent revision surgery. The complication rate was 3.1% and involved only minor complications. CONCLUSION The inside-out technique allows a safe removal of cholesteatoma from the epitympanum toward the mastoid with a single-stage reconstruction of the ossicular chain. For this reason we support our individual approach, which allows creation of the smallest possible cavity for the size of the cholesteatoma. Our results confirm that the inside-out technique is effective in the treatment of pediatric cholesteatoma.

Coffee consumption attenuates short-term fructose-induced liver insulin resistance in healthy men.

BACKGROUND Epidemiologic and experimental data have suggested that chlorogenic acid, which is a polyphenol contained in green coffee beans, prevents diet-induced hepatic steatosis and insulin resistance. OBJECTIVE We assessed whether the consumption of chlorogenic acid-rich coffee attenuates the effects of short-term fructose overfeeding, dietary conditions known to increase intrahepatocellular lipids (IHCLs), and blood triglyceride concentrations and to decrease hepatic insulin sensitivity in healthy humans. DESIGN Effects of 3 different coffees were assessed in 10 healthy volunteers in a randomized, controlled, crossover trial. IHCLs, hepatic glucose production (HGP) (by 6,6-d2 glucose dilution), and fasting lipid oxidation were measured after 14 d of consumption of caffeinated coffee high in chlorogenic acid (C-HCA), decaffeinated coffee high in chlorogenic acid, or decaffeinated coffee with regular amounts of chlorogenic acid (D-RCA); during the last 6 d of the study, the weight-maintenance diet of subjects was supplemented with 4 g fructose · kg(-1) · d(-1) (total energy intake ± SD: 143 ± 1% of weight-maintenance requirements). All participants were also studied without coffee supplementation, either with 4 g fructose · kg(-1) · d(-1) (high fructose only) or without high fructose (control). RESULTS Compared with the control diet, the high-fructose diet significantly increased IHCLs by 102 ± 36% and HGP by 16 ± 3% and decreased fasting lipid oxidation by 100 ± 29% (all P < 0.05). All 3 coffees significantly decreased HGP. Fasting lipid oxidation increased with C-HCA and D-RCA (P < 0.05). None of the 3 coffees significantly altered IHCLs. CONCLUSIONS Coffee consumption attenuates hepatic insulin resistance but not the increase of IHCLs induced by fructose overfeeding. This effect does not appear to be mediated by differences in the caffeine or chlorogenic acid content. This trial was registered at clinicaltrials.gov as NCT00827450.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial

IMPORTANCE International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN19646069.