Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder of childhood associated with inappropriate hypersecretion of insulin by the pancreas. The pathogenesis of the condition has hitherto remained controversial. We show here that insulin-secreting cells from a homogeneous group of five infants with PHHI lack ATP-sensitive K+ channel (KATP) activity. As a consequence, PHHI beta-cells are spontaneously electrically active with high basal cytosolic Ca2+ concentrations due to Ca2+ influx. Our findings define the pathogenesis of this disease as a novel K+ channel disorder.     

The prognostic significance of sialyl-Tn antigen in women treated with breast carcinoma treated with adjuvant chemotherapy

BACKGROUND: Sialyl-Tn (STn) represents an aberrantly glycosylated mucin epitope that is expressed in breast carcinoma and other adenocarcinomas and is an important factor in the development of novel immunotherapeutic approaches. The primary aim of the current study was to investigate the influence of STn expression on the prognoses of patients with breast carcinoma. METHODS: A cohort of 207 women diagnosed with invasive breast carcinoma who were treated with anthracycline-containing adjuvant chemotherapy and were enrolled in a randomized clinical trial were studied. Expression of STn was determined by an immunohistochemical procedure in which the B72.3 monoclonal antibody was used. Kaplan-Meier and Cox proportional regression survival analyses were used to compare low STn and high STn patients. RESULTS: Forty-eight (23%) of the 207 specimens demonstrated high STn staining (>25% cells were immunoreactive). During a median follow-up of 5 years, high STn patients had worse disease free survival than low STn patients (55% vs. 74%, respectively; P = 0.03). High STn expression was significantly associated with age (P = 0.04) but not with other conventional prognostic markers. In multivariate analysis using the Cox regression model, high STn emerged as an independent prognostic indicator for disease free survival (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.09-3.73) and for overall survival (HR, 2.16; 95% CI, 0.95-4.92). CONCLUSIONS: The results of this study suggest that STn may be a valuable marker for identifying women at high risk of developing recurrent breast carcinoma who may be candidates for trials investigating new therapies in combination with standard adjuvant therapy.     

Transport of GM1 and GM1 inner ester across an in vitro model of the blood-brain barrier

Gangliosides, especially GM1, attenuate the in vivo damage caused by various neurotoxins. The chemically neutral inner ester of GM1 may be a better cytoprotective agent against some neurotoxins than the parent GM1 compound, because it may cross the blood-brain barrier (BBB) more easily than the anionic GM1. Using an in vitro bovine brain endothelial cell model of the BBB, we show the inner ester more readily transverse the tight junction barrier of this model than does GM1. Further, it is demonstrated that the GM1 inner ester is stable for several hours at pH values between 7.0 and 8.2 at 37 degrees C. Finally, the results illustrate that the BBB model may be useful for testing other gangliosides and their various derivatives for increased ability to cross the BBB.     

Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds

CDKN2 has been implicated as a melanoma susceptibility gene in some kindreds with a family history of this disease. Mutation analysis of CDKN2 in 17 familial melanoma Australian kindreds revealed a paucity of exon mutations and none of the previously described disease-related mutations. One novel germline mutation was found in exon one, Arg24Pro, which segregates with melanoma in 1/17 kindreds. Two previously described polymorphisms, Ala148Thr and a base change at nucleotide 540 were detected and one novel polymorphism in the untranslated region of exon 3 (nucleotide 580) was also found. Together with other recent reports, these findings provide support for CDKN2 as a susceptibility locus for familial melanoma but suggest that other loci are involved in some hereditary melanoma kindreds.     

A strategic supportive model for health prevention in the elderly: profile of a Puerto Rican geriatric population in a public health sector

OBJECTIVE: To introduce the ASSUME study with the presentation of a clinical, socio-demographic, preventive and psychological profile of a geriatric population of patients who receive their health care in the General Internal Medicine Ambulatory Sector of our institution. METHODS: The Assume study is a prospective, randomized trial which is directed at increasing the participation of patients in preventive health care strategies at a primary, secondary and tertiary level. In this paper we focus on the initial stage of the process which aims to define and synthesize predisposing risk factors in the geriatric patient which would be amenable to primary, secondary and tertiary preventive strategies. Through a process of patient interview profiles of a physical, social and psychological nature are have been constructed. With the availability of this profile a clearer definition of the potential benefit of preventive strategies could be established. In this paper we present the initial profile of patients of all patients randomized to the study as of Sept. 01, 1997. RESULTS: A total of 123 patients have been enrolled with 48(39%) males and 75(61%) females. The mean age of patients is 70 years with a median of 68 years. Cardiovascular disorders establish the leading disease events in our population of patients with Hypertension in 85%, Ischemic heart disease in 50%, Myocardial Infarction in 19% and 40% with a history of Congestive Heart failure. Diabetes and Heart Failure were seen in 40%. An average of 4.4 prescribed drugs per patient was documented. A minority of patients took more than 7 drugs and none took more than 9 medications. Most patients (67 or 55%) had not required hospitalizations in the preceding 12 months and none of the patients required more than 4 hospitalizations. The average LOS was 8.60 days. The Preventive Medicine profile reveals a large number of un-vaccinated adults. Regular cigarette smoking was seen in 12%. We have used the body mass index as a measure of adequacy of weight. We highlight the number of patients who have a BMI equivalent to an obese, severely obese or morbidly obese category (41%). The number of patients who follow a prescribed diet was found to be 54 patients for 44% of the study group. With regards to the interventions primarily designed for early cancer detecting, approximately half of the patients undergo the recommended annual screening interventions. The screening of visual accuracy was reported in 54%, dental screen (24%) and auditory screening (15%). Nearly a quarter of patients have severe depression. The CAPE testing reveal that in the information and orientation section most patients presented none or light dysfunction(87%). In the conductual phase marked or severe impairment was detected in 12% of patients. In the mental ability section 22% of patients presented marked or severe impairment. CONCLUSION: The geriatric population studied would benefit from modalities which would increment the modern modalities for primary and secondary prevention of disease. Follow-up studies will allow the evaluation of the effectiveness of the conceptual model proposed, which would increment the patient participation in these preventive modalities.     

Xenobiotic-enhanced expression of cytochromes P450 2E1 and 2B in primary cultured rat hepatocytes

The purpose of this investigation was to determine whether long-term, heavy resistance training would cause adaptations in rat skeletal muscle structure and function. Ten male Wistar rats (3 weeks old) were trained to climb a 40-cm vertical ladder (4 days/week) while carrying progressively heavier loads secured to their tails. After 26 weeks of training the rats were capable of lifting up to 800 g or 140% of their individual body mass for four sets of 12-15 repetitions per session. No difference in body mass was observed between the trained rats and age-matched sedentary control rats. Absolute and relative heart mass were greater in trained rats than control rats. When expressed relative to body mass, the mass of the extensor digitorum longus (EDL) and soleus muscles was greater in trained rats than control rats. No difference in absolute muscle mass or maximum force-producing capacity was evident in either the EDL or soleus muscles after training, although both muscles exhibited an increased resistance to fatigue. Individual fibre hypertrophy was evident in all four skeletal muscles investigated, i.e. EDL, soleus, plantaris and rectus femoris muscles of trained rats, but muscle fibre type proportions within each of the muscles tested remained unchanged. Despite an increased ability of the rats to lift progressively heavier loads, this heavy resistance training model did not induce gross muscle hypertrophy nor did it increase the force-producing capacity of the EDL or soleus muscles.     

Endoscopic repair of traumatic CSF rhinorrhea in a pediatric patient

In performing cancer chemotherapy, it is essential to know the expression of multidrug resistant (MDR) P glycoprotein (p-gp) on cancer cells. In the present study, in order to clarify the relationship between MDR of leukemic cells and cytologic, immunological and clinical features of acute nonlymphocytic leukemia (ANLL), leukemic cells in peripheral blood and/or bone marrows obtained from 28 ANLL patients were examined. Each smear was stained with C219 monoclonal antibody against P-gp by the APAAP method, and then 1,000 ANLL cells in each smear were observed. Among the FAB subtypes, M4 showed the highest proportion of leukemic cells expressing P-gp. Concerning the response to chemotherapy, five of seven patients (71%) having 1.0% or more of P-gp positive leukemic cells and 11 of 19 patients (58%) having less than 1.0% of those cells achieved complete remission. However, there was no significant correlation between P-gp expression and clinical outcome. There was also no significant correlation between P-gp expression and CD7 or CD34. Furthermore, no significant correlation between chromosome 7 abnormality and P-gp expression was observed. From these results, if we can clarify the mechanism of MDR and the relationship between MDR and cytogenetic or clinical features of ANLL with further study, P-gp expression may become a useful marker for predicting the outcome of ANLL.