N-acetyl-cysteine in the prevention of vascular restenosis after percutaneous balloon angioplasty

BACKGROUND: Vascular inflammation generating oxidized metabolites at the site of balloon angioplasty is believed to play a major role in the process of vessel restenosis. Glutathione, the most potent endogenous antioxidant, may have protective effects after angioplasty by suppressing local inflammatory response. The aim of the study was to test the hypothesis that oral administration of N-acetyl-cysteine (NAC, a precursor of glutathione) reduces restenosis in an animal model of vascular injury. METHODS: In New Zealand white rabbits, an atherosclerotic lesion was introduced to both iliac arteries by air denudation of the endothelium while feeding the animals a high-cholesterol diet. After 4 weeks, all animals underwent balloon angioplasty of the endothelial injury site and half of the group was started on 150 mg/kg NAC per day. Quantitative angiography was performed prior to the angioplasty and at the final procedure 3 weeks later. Glutathione levels were determined in all animals at the beginning and the end of the study. RESULTS: Although not statistically significant, plasma glutathione level increased in the NAC group from 32.4+/-4.4 to 39.7+/-11.6 micromol/l, while it decreased from 30.6+/-13.4 to 28.3+/-11.5 micromol/l in the control group. During the study period, 6 vessels occluded leaving 14 vessels for analysis. Quantitative angiographic analyses prior to angioplasty and at follow-up showed no significant difference with respect to stenosis progression between the groups. Measurement of neointima formation by histology showed also no significant difference between the groups (0.175+/-0.040 mm(2) vs. 0.123+/-0.075 mm(2)), neither did intimal macrophage count as a marker for local inflammatory response. CONCLUSIONS: Despite an increase in plasma glutathione level in the NAC-treated group, there was no reduction in lesion progression after balloon angioplasty. Therefore, NAC does not seem to prevent restenosis after vascular intervention in this animal model.     

Cyclodextrin Reduces Intravenous Toxicity of a Model Compound

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration.GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ～20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.     

Correlation of symptoms with location and severity of pelvic organ prolapse

OBJECTIVE: The purpose of this study was to compare the symptoms that are related to pelvic floor dysfunction with the location and severity of the coexisting prolapse. STUDY DESIGN: Two hundred thirty-seven consecutive patients with symptomatic pelvic organ prolapse came to Johns Hopkins Medicine during a 24-month period beginning in July 1998 and completed a symptom-specific Likert scale questionnaire that included standardized questions that were compiled from commonly used validated instruments. All questionnaires were completed by the patients before they were seen by a physician. Further evaluation included a standardized physical examination that included the International Continence Society's system for grading uterovaginal prolapse. Symptoms were categorized according to both severity and associated anatomic compartment. Symptoms that were related to urinary and anal incontinence and voiding, defecatory, sexual, and pelvic floor dysfunction were analyzed with respect to location and severity of pelvic organ prolapse with the use of the nonparametric correlation coefficient, Kendall's tau-b. RESULTS: The mean age of the women was 57.2 years (range, 23-93 years); 109 of the women (46%) had undergone hysterectomy. Overall, stage II was the most common pelvic organ prolapse (51%) that was encountered. In 77 patients (33%), anterior compartment pelvic organ prolapse predominated; 46 patients (19%) demonstrated posterior compartment prolapse, whereas 26 patients (11%) had apical prolapse. In 88 patients (37%), no single location was more severe than another. Voiding dysfunction that was characterized by urinary hesitancy, prolonged or intermittent flow, and a need to change position was associated with the increasing severity of anterior and apical pelvic organ prolapse. Pelvic pressure and discomfort along with visualization of prolapse were strongly associated with worsening stages of pelvic organ prolapse in all compartments. Defecatory dysfunction characterized by incomplete evacuation and digital manipulation was associated with worsening posterior compartment pelvic organ prolapse. Impairment of sexual relations and duration of abstinence were strongly associated with worsening pelvic organ prolapse. An inverse correlation was observed between increasing severity of pelvic organ prolapse and urinary incontinence and enuresis. CONCLUSION: Women with pelvic organ prolapse experience symptoms that do not necessarily correlate with compartment-specific defects. Increasing severity of pelvic organ prolapse is weakly to moderately associated with several specific symptoms that are related to urinary incontinence and voiding, defecatory, and sexual dysfunction.     

Tobacco,alcohol intake,and diet in relation to adenocarcinoma of the esophagus and gastric cardia

Little is known about the etiology of adenocarcinoma of the distal esophagus/cardia, a cancer which has increased in incidence in the United States over the last two decades. We analyzed data on smoking, alcohol use, dietary intake, and other factors obtained from 173 hospitalized males with adenocarcinoma of the distal esophagus/cardia (cases) and 4,544 hospitalized males with diseases not related to smoking and of other organ systems than the gastrointestinal tract (controls). Cases of squamous cell carcinoma of the esophagus (n=136) and adenocarcinoma of the distal stomach (n=122) were included as separate case groups. All subjects were interviewed in 28 hospitals in eight cities in the US between 1981 and 1990. After adjustment for covariates, the odds ratio (OR) for adenocarcinoma of the distal esophagus/cardia for current smokers was 2.3 (95 percent confidence interval [CI]=1.4–3.9) and that for ex-smokers was 1.9 (CI=1.2–3.0) relative to never-smokers. The OR for drinkers of four or more ounces of whiskey-equivalents of alcohol per day (relative to those consuming less than one drink per week) was 2.3 (CI=1.3–4.3). Intakes of total fat and vitamin A from animal sources were significant risk factors and fiber intake was associated inversely with adenocarcinoma of the distal esophagus/cardia. Although the number of female cases of adenocarcinoma of the distal esophagus/cardia was small (n=21), significant associations were observed for smoking and alcohol.Dr Kabat is in the Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. At the time of this work be was with the Division of Epidemiology, American Health Foundation, New York, NY. Drs Ng and Wynder are with the Division of Epidemiology, American Health Foundation. Address correspondence to Dr Kabat, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Belfer Bldg, Rm 1302, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Supported by National Cancer Institute Program Project grant CA32617 and Center grant CA17613.     

A team approach to improving colorectal cancer services using administrative health data

Background  

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Canada and accounts for 11.9% of all cancer-related mortality. Fortunately, previous studies have provided evidence of improved outcomes from access to timely and appropriate health services along the disease trajectory in CRC. As a result, the CIHR/CCNS Team in Access to Colorectal Cancer Services in Nova Scotia (Team ACCESS) was created to build colorectal cancer (CRC) research capacity in Nova Scotia (NS) and to study access to and quality of CRC services along the entire continuum of cancer care.     

The clinical application of surface pH measurements to longitudinally assess white spot enamel lesions

Objectives

Means of objectively assessing white spot enamel lesions (WSEL) are critical for determining their potential activity and monitoring the success of preventive treatments. The aim of this study was to determine whether surface pH measurements of WSEL changed during a preventive course of care designed to remineralize the lesions.

Methods

Eight healthy subjects (1 male and 7 females) with at least one WSEL were recruited (19–64 years). Each subject was placed on a preventive treatment program including the daily application of a CPP-ACP paste (MI paste, GC Corp., Japan) with custom fitted trays for more than 6 months. The surface pH values of sound enamel and WSEL were monitored for up to 2 years using a micro-pH sensor. The visual appearance of the WSEL was monitored via digital photography, and images were analyzed qualitatively on a 5-point scale to assess the success of the remineralization preventive program. The relationship between the qualitative assessment of WSEL appearance and the WSEL pH was investigated using a Spearman's rho non-parametric correlation.

Results

The surface pH of the WSEL was different to that of the sound enamel surrounding it in all patients at all times. All lesions showed visual improvement as the treatment period progressed. The pH of the WSEL increased towards that of sound enamel over the course of treatment significantly correlating with the visual improvement of the lesion (rho = 0.63, p < 0.0001).

Conclusions

The clinical assessment of WSEL surface pH changes with time may have utility as an additional objective measure for the assessment of WSEL activity.     

Metastasectomy of neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

Background

Neuroendocrine (NE) tumors commonly afflict patients with multiple endocrine neoplasia type 1 (MEN1). It is thought that patients with MEN1 have improved survival compared with individuals with analogous lesions. The role of metastasectomy of NE tumors in MEN1 patients is not clearly defined.

Methods

A review of MEN1 patients undergoing surgery for NE tumors from 1994 to 2010 at a single tertiary care center was performed. Tumor function, the extent of metastasis, R0 resection, and survival were analyzed.

Results

We identified 30 patients who underwent resection including synchronous and metachronous metastasectomy. Synchronous metastases were identified in 19 patients (63%), whereas 11 (37%) had metachronous disease. R0 resection was achieved in 93% of patients. Estimated 10-year survival is 86.4% (95% confidence interval, 60% to 100%) with no factors predictive of overall survival. The disease-free interval at 1, 5, and 10 years was 89%, 50%, and 19%, respectively, with recurrence occurring at a median of 5.4 years (95% confidence interval, 77.7% to 100%). Synchronous metastasis (P = .0072; hazard ratio [HR], 3.4) and nonfunctioning tumors (P = .014; HR, 3.3) were more likely to recur, whereas age (P = .09; HR, 1.5), gender (P = .49; HR, 1.3), and the site of metastasis (P = .81; HR, 1.1) did not influence recurrence.

Discussion

Patients with MEN1 benefit from resection of metastatic NE disease. Despite a high recurrence rate, survival and disease-free interval is favorable vs patients without MEN1.     

Combined functional MRI and tractography to demonstrate the connectivity of the human primary motor cortex in vivo

In this study, we combined advanced MR techniques to explore primary motor cortex (M1) connectivity in the human brain. We matched functional and anatomical information using motor functional MRI (fMRI) and white matter tractography inferred from diffusion tensor imaging (DTI). We performed coregistered DTI and motor task fMRI in 8 right-handed healthy subjects and in 1 right-handed patient presenting with a left precentral tumour. We used the fast-marching tractography (FMT) algorithm to define 3D connectivity maps within the whole brain, from seed points selected in the white matter adjacent to the location of the maximum of fMRI activation. Connectivity maps were then anatomically normalised and analysed using statistical parametric mapping software (SPM99) allowing group comparisons (left versus right hemisphere in control subjects and patient versus control subjects). The results demonstrated, in all control subjects, strong connections from M1 to the pyramidal tracts, premotor areas, parietal cortices, thalamus, and cerebellum. M1 connectivity was asymmetric, being more extensive in the dominant hemisphere. The patient had differences in M1 connectivity from the control group. Thus, fMRI-correlated DTI-FMT is a promising tool to study the structural basis of functional networks in the human brain in vivo.     

13Carbon mixed triglyceride breath test and pancreatic enzyme supplementation in cystic fibrosis

Children with cystic fibrosis have variable degrees of exocrine pancreatic insufficiency which, if untreated, is the main cause of fat malabsorption. The impact of pancreatic enzyme supplementation on fat digestion was measured in 41 children with cystic fibrosis, 11 healthy controls, and five children with mucosal diseases by a non-invasive test of intraluminal lipolysis using 13carbon (13C) labelled mixed triglyceride (1,3-distearyl, 2[13C] octanoyl glycerol). The children with cystic fibrosis without pancreatic supplements had a median (range) 13C cumulative percentage dose recovered over six hours (cPDR) of 3.1% (0-31.7), the controls 31.0% (21.8-41.1), and the subjects with mucosal disease 27.8% (19.7-32.5). In 23 subjects with cystic fibrosis the usual dose of pancreatic enzyme supplements increased the cPDR to a median of 23.9% (0-45.6), and twice the usual dose of enteric coated microspheres increased the cPDR to 31.1% (11.1-47.8). There was no significant difference between the median cPDR of normal controls and children with mucosal disease, but there was a highly significant difference between these groups and children with untreated cystic fibrosis. Thirteen children with cystic fibrosis had no 13C recovery in their breath without enzymes and 10 showed marked increases with regular enzymes. In eight children doubling the dose of enzymes caused no or minimal improvement. The mixed triglyceride breath test offers a simple, non-invasive way of assessing the need for pancreatic enzyme supplementation in children with cystic fibrosis and could be used to optimise treatment.