Terminal ileal photography or biopsy to verify total colonoscopy: does the endoscope agree with the microscope?

BACKGROUND: Various modalities exist to document the extent of colonoscopy, including a terminal ileum (TI) biopsy, which is considered the criterion standard by some authorities. A TI biopsy adds to procedure costs, is potentially hazardous, and the detection of pathology in routinely acquired biopsy specimens of a macroscopically normal TI is limited. A safer, less costly alternative for documenting total colonoscopy is desirable. OBJECTIVE: To evaluate the effectiveness of TI photography as a means of documenting total colonoscopy. We also assessed the diagnostic yield of TI biopsies in patients with a macroscopically normal TI. DESIGN: Prospective, observational study. SETTING: District general hospital in the United Kingdom. PATIENTS: A total of 232 unselected patients undergoing colonoscopy, TI intubation, photography, and biopsy. MAIN OUTCOME MEASUREMENTS: Independent, experienced endoscopists were asked to state whether villi (and, therefore, TI entry) were "definitely," "probably," or "definitely not" depicted in TI photographs. This was compared with TI histology as a means of verifying total colonoscopy. The diagnostic yield of biopsy specimens from a macroscopically normal TI was determined. RESULTS: Reviewers agreed that villi were "definitely present" in 93.8%, "probably present" in 5.9%, and "definitely not" present in 0.3% of cases, with excellent interobserver agreement (kappa value = 0.778, P < .0001). TI photographs "definitely" depicting villi (93.8%) did not differ significantly from histology confirming TI mucosa (96.1%, P = .285). Microscopic evidence of pathology was only detectable in 2.3% of patients with an endoscopically normal TI. CONCLUSIONS: TI photography is an effective, safe, and cost-effective means of documenting total colonoscopy. Routine biopsy of a "normal" TI has a low diagnostic yield.     

Perception gap in quality-of-life ratings: an empirical investigation of nursing home residents and caregivers

PURPOSE: Several studies have previously documented the existence of a perception gap-the extent to which quality-of-life ratings provided by nursing home residents and caregivers diverge. In this study we use Helson's adaptation-level theory to investigate three types of antecedents: (a) focal factors, (b) background factors, and (c) residual factors. DESIGN AND METHODS: We calculated the perception gap for 11 quality-of-life domains. Caregivers rated both job satisfaction and their perception of quality of life of residents in the unit where they provided service. Concurrently, residents from these units completed quality-of-life interviews. We computed the perception gap by subtracting the residents' ratings from the caregivers' ratings for each quality-of-life domain. We conducted a hierarchical linear model using 3,850 observations to predict the perception gap. RESULTS: Caregivers perceive quality of life to be lower than residents do across all domains fairly consistently. Caregiver demographics do not directly predict the perception gap. However, satisfaction with work, pay, and promotion were significant predictors (p <.05), and satisfaction with supervisor was a marginally significant predictor (p <.10), of the perception gap. As satisfaction with these job dimensions increased, the perception gap decreased. Additional models show that several caregiver demographics directly influence job-satisfaction dimensions, though they did not influence the perception gap. IMPLICATIONS: Job-satisfaction dimensions, rather than caregiver characteristics, are the appropriate predictors of the perception gap. However, caregiver demographics exert their influence indirectly by means of job satisfaction. A key finding is that higher job satisfaction leads to a smaller perception gap. Helson's adaptation-level theory appears to be a useful approach for understanding the antecedents of the perception gap.     

Combined CA125 and mesothelin levels for the diagnosis of malignant mesothelioma

BACKGROUND: Malignant mesothelioma is an aggressive, uniformly fatal tumor. Serum markers would be useful for the diagnosis of this disease. One potential marker is mesothelin. The purpose of this study was to study the mesothelin biomarker in a large patient cohort and to determine if another biomarker, CA125, improves on the sensitivity of mesothelin in the diagnosis of mesothelioma. METHODS: Serum levels of mesothelin and CA125 were determined by commercially available assays in 117 samples obtained at diagnosis from patients with pleural malignant mesothelioma, 33 healthy, asbestos-exposed individuals, 53 patients with asbestos-related lung or pleural disease, and 30 patients presenting with benign pleural effusions. Cross-validated sensitivities were determined, and receiver operator characteristic curves were generated to compare the diagnostic accuracy of the biomarkers. RESULTS: CA125 had a cross-validated sensitivity of 27% for mesothelioma patients at a specificity of 95% relative to asbestos-exposed individuals, or 50% relative to individuals with benign pleural effusions. Mesothelin had a cross-validated sensitivity of 52% for mesothelioma patients, at a sensitivity of 95% relative to individuals with benign lung or pleural disease. CA125 and mesothelin levels were discordant in > 50% of mesothelioma patients. Combining the data from the two biomarkers using a logistic regression model did not improve sensitivity for detecting mesothelioma above that of the mesothelin marker alone. CONCLUSION: Combining mesothelin and CA125 data does not improve the sensitivity of mesothelioma diagnosis over mesothelin alone. The use of both markers potentially increases the number of patients who can be monitored.     

The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine

BACKGROUND & AIMS: It has been generally assumed that interstitial cells of Cajal (ICC) in the human gastrointestinal tract have similar functions to those in rodents, but no direct experimental evidence exists to date for this assumption. This is an important question because pathologists have noted decreased numbers of ICC in patients with a variety of motility disorders, and some have speculated that loss of ICC could be responsible for motor dysfunction. Our aims were to determine whether myenteric ICC (ICC-MY) in human jejunum are pacemaker cells and whether these cells actively propagate pacemaker activity. METHODS: The mucosa and submucosa were removed, and strips of longitudinal muscle were peeled away to reveal the ICC-MY network. ICC networks were loaded with the Ca(2+) indicator fluo-4, and pacemaker activity was recorded via high-speed video imaging at 36.5 degrees C +/- 0.5 degrees C. RESULTS: Rhythmic, biphasic Ca(2+) transients (6.03 +/- 0.33 cycles/min) occurred in Kit-positive ICC-MY. These consisted of a rapidly propagating upstroke phase that initiated a sustained plateau phase, which was associated with Ca(2+) spikes in neighboring smooth muscle. Pacemaker activity was dependent on inositol 1,4,5-triphosphate receptor-operated stores and mitochondrial function. The upstroke phase of Ca(2+) transients in ICC-MY appeared to result from Ca(2+) influx through dihydropyridine-resistant Ca(2+) channels, whereas the plateau phase was attributed to Ca(2+) release from inositol 1,4,5-triphosphate receptor-operated Ca(2+) stores. CONCLUSIONS: Each ICC-MY in human jejunum generates spontaneous pacemaker activity that actively propagates through the ICC network. Loss of these cells could severely disrupt the normal function of the human small intestine.     

Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone

CONTEXT: The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes. OBJECTIVE: We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo). PATIENTS: This study included 3548 Diabetes Prevention Program participants. DESIGN: We performed Cox regression analysis using genotype at PPARG P12A, intervention, and their interactions as predictors of diabetes incidence. We also genotyped five other PPARG variants implicated in the response to troglitazone and assessed their effect on insulin sensitivity at 1 yr. RESULTS: Consistent with prior cross-sectional studies, P/P homozygotes at PPARG P12A appeared more likely to develop diabetes than alanine carriers (hazard ratio, 1.24; 95% confidence interval, 0.99-1.57; P=0.07) with no interaction of genotype with intervention. There was a significant interaction of genotype with body mass index and waist circumference (P=0.03 and 0.002, respectively) with the alanine allele conferring less protection in more obese individuals. Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr. CONCLUSIONS: The proline allele at PPARG P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.     

Large variations in absolute wall shear stress levels within one species and between species

Wall shear stress (WSS), the frictional force between blood and endothelium, is an important determinant of vascular function. It is generally assumed that WSS remains constant at a reference value of 15 dyn/cm(2). In a study of small rodents, we realized that this assumption could not be valid. This review presents an overview of recent studies in large and small animals where shear stress was measured, derived from velocity measurements or otherwise, in large vessels. The data show that large variations exist within a single species (human: variation of 2-16 N/m(2)). Moreover, when we compared different species at the same location within the arterial tree, an inverse relationship between animal size and wall shear stress was noted. When we related WSS to diameter, a unique relationship was derived for all species studied. This relationship could not be described by the well-known r(3) law of Murray, but by the r(2) law introduced by Zamir et al. in 1972. In summary, by comparing data from the literature, we have shown that: (i) the assumption of a physiological WSS level of approximately 15 dyn/cm(2) for all straight vessels in the arterial tree is incorrect; (ii) WSS is not constant throughout the vascular tree; (iii) WSS varies between species; (iv) WSS is inversely related to the vessel diameter. These data support an "r(2) law" rather than Murray's r(3) law for the larger vessels in the arterial tree.     

Circulating sex hormones and gene expression of subcutaneous adipose tissue oestrogen and alpha-adrenergic receptors in HIV-lipodystrophy: implications for fat distribution

OBJECTIVE: Circulating oestradiol and testosterone, which have been shown to increase in human immunodeficiency virus (HIV)-infected patients following highly active antiretroviral therapy (HAART), may influence fat distribution and insulin sensitivity. Oestradiol increases subcutaneous adipose tissue in humans possibly through binding to oestrogen-receptor-alpha, which in turn activates anti-lipolytic alpha2A-adrenergic-receptor. DESIGN AND METHODS: To address these issues circulating pituitary-gonadal-axis hormones and gene expression of receptors in subcutaneous adipose tissue were determined in 31 nondiabetic HIV-infected male patients receiving HAART (16 with lipodystrophy), in whom measures of fat distribution (CT and DEXA-scans) and insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were available. RESULTS: Total and free oestradiol and testosterone were decreased in lipodystrophic patients compared to nonlipodystrophic patients, whereas luteinizing hormone, follicle-stimulating hormone and prolactin were similar and normal in both study groups. Ratio of subcutaneous to total abdominal fat mass, limb fat, and insulin sensitivity, which were all decreased in lipodystrophic patients, correlated positively with both plasma oestradiol and testosterone (n = 31). Glycerol concentration during clamp (a marker of lipolysis) correlated inversely with expression of alpha2A-adrenergic-receptor, ratio of subcutaneous to total abdominal fat mass, and limb fat, respectively. Expression of alpha2A-adrenergic-receptor correlated positively with expression of oestrogen-receptor-alpha. CONCLUSIONS: The results fit the hypothesis that sex hormones play a role in altered fat distribution and insulin sensitivity of male patients with HIV-lipodystrophy. The effect of oestradiol on the subcutaneous fat depot and lipolysis may be mediated in part through binding to the oestrogen-receptor-alpha, in turn activating anti-lipolytic alpha2A-adrenergic-receptor.     

Small-molecule agonists for the glucagon-like peptide 1 receptor

The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.     

Rheumatic mitral valve stenosis mimicking advanced lung cancer

This report describes a patient with a perihilar mass and mediastinal lymphadenopathy mimicking advanced lung cancer. The patient, a 45-year old regular smoker, was admitted to hospital for dyspnea and tachyarrhythmia, and during hospitalization he was diagnosed with severe rheumatic mitral valve stenosis (MVS) and aortic regurgitation as well as pulmonary venous hypertension. Surgical valve replacement and removal of an atrial thrombus was delayed considerably by diagnostic work-up for suspected malignancy. After cardiac surgery had been performed, recovery was uneventful. On follow-up 1 year later, echocardiography showed well-functioning prosthetic mitral and aortic valves, and normal findings on chest X-ray. Perihilar masses and mediastinal lymphadenopathy presented in this case constitute infrequent yet established findings in MVS, resulting from pulmonary venous congestion and hypertension, and focal lymphedema.