Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

Relationship of nocturnal hypoglycemia to daytime glycemia in IDDM.

In view of the continuing debate about the clinical relevance of nocturnal hypoglycemia as an explanation for high blood glucose (BG) levels before breakfast, we prospectively analyzed 281 overnight BG profiles (blood samples obtained at 2100, 0200-0300, and 0700) in 66 consecutive patients with insulin-dependent diabetes mellitus. Nocturnal hypoglycemia (0200-0300 BG concentration less than or equal to 50 mg/dl) occurred in 27 patients (41%) and in 36 profiles (13%). All the patients with nocturnal hypoglycemia received two or more injections of insulin each day. When hypoglycemia occurred at 0200-0300, the preceding BG concentration at 2100 was significantly lower than when nocturnal BG was greater than 100 mg/dl (108 +/- 11 vs. 145 +/- 12 mg/dl; P less than .05; mean +/- SE). A BG less than or equal to 120 mg/dl at 2100 preceded nocturnal hypoglycemia in 24 (67%) of 36 profiles. The mean BG at 0700 was significantly lower in the profiles associated with nocturnal hypoglycemia than in those with nocturnal BG levels greater than 150 mg/dl (156 +/- 10 vs. 201 +/- 11 mg/dl; P less than .05). BG values greater than 180 mg/dl at 0700 were infrequently (11 of 143 or 8% of profiles) preceded by nocturnal hypoglycemia, and no instances of major hyperglycemia (BG greater than 300 mg/dl) at 0700 were preceded by nocturnal hypoglycemia. Furthermore, BG at 0700, 1100, and 1500 on the day before the occurrence of nocturnal hypoglycemia were similar to those on the day after.(ABSTRACT TRUNCATED AT 250 WORDS)

Likelihood linkage analysis (LLA) classification method: an example treated by hand.

This paper describes a very general method of data analysis using a hierarchical classification. The data can be provided by observation, experiment or knowledge; their nature can be numerical, qualitative or logical. First, the classical view of the context of data representation, in which the algorithm of hierarchical ascendant construction of the classification tree is set, is treated in a synthetic manner. The main notion in our method is one of 'similarity'. This must be elaborated in the best way, taking into account the mathematical nature of the objects to be compared. Here we adopt a set of theoretical and combinatorial representation of the descriptive attributes, which are interpreted in terms of relations. Then we introduce a probability scale for similarity measurement by using a likelihood concept. The largest part of the paper concerns an illustrating example, moderately sized, detailing very minutely the different steps and the different calculations assumed by the method. The data structure handled with this example is the simplest possible. Then, general aspects and methodological extensions are evoked. We end by indicating the interest of the described approach in future works, in which we are involved, concerning typological organization of genetic sequences. We emphasize the 'explanation' aspect of the obtained results, with respect to a given description. For this purpose, classifications (on the object set and on the attribute set) on the one hand and machine learning techniques on the other, intervene efficiently.

Immunologic response to a single dose of tetanus toxoid in older people.

OBJECTIVES: Several studies have demonstrated that a large percentage of older people are inadequately immunized against tetanus. The aim of this study was to assess the immunity against tetanus in a group of individuals aged 69 and older and to examine the immune response to a single dose of tetanus toxoid. DESIGN: A convenience sample of 115 residents of a large retirement home, aged 69 and older, was studied. After a blood sample for anti-tetanus antibody titer, a single dose of tetanus toxoid vaccine was administered. Repeat titers were obtained 6 weeks after the vaccination and analyzed by ELISA assay. Antibody levels equal to or greater than 0.1 IU/mL were considered protective. RESULTS: Sixty-seven of 115 (58.3%) individuals had adequate antibody titers. Those individuals who reported having been vaccinated with tetanus toxoid in the past were more likely to be immunized adequately compared with those who reported having never been vaccinated (66.7% vs 39.3%, P = .02). After vaccination, 34 of 46 (73.9%) individuals with inadequate antibody titers became seropositive. Those who remained seronegative had mean prevaccination antibody titers significantly lower than those who seroconverted. Sixteen of 17 (94.1%) persons who reported having been vaccinated in the past and were found to be seronegative developed adequate antibody titers following vaccination, compared with only nine of 16 (56.2%) who reported never having been vaccinated (P = .04). There was no association between seroconversion rate and age, sex, underlying diseases, and army service. CONCLUSIONS: Most individuals will develop an adequate anti-tetanus antibody titer following administration of a single dose of tetanus vaccine. A history of past immunization is a good predictor of becoming adequately immunized. It is important that physicians follow the current recommendations for adult immunization and initiate campaigns to ensure that the older population is protected against tetanus.

The prevalence of diabetes and associated coronary risk factors in urban and rural older Mexican populations.

OBJECTIVE: To determine the prevalence of diabetes and examine its association with food intake, anthropometric and metabolic variables, and other coronary risk factors in urban and rural older Mexican populations. DESIGN: A cross-sectional study. SETTING: Three Mexican communities (urban areas of medium and low income and a rural area). PARTICIPANTS: A total of 121 men and 223 women aged 60 years and older and 93 men and 180 women aged 35 to 59 years were selected randomly for inclusion in the survey, which was derived from the CRONOS study (Cross-Cultural Research on Nutrition in the Older Adult Study Group) promoted by the European Economic Community. MEASUREMENTS: A personal interview assessed demographic information, personal medical history, and functional status, and a 24-hour diet recall was obtained. A physical examination included anthropometric and blood pressure measurements. A fasting blood sample was obtained for measurements of lipids, insulin, and glucose. RESULTS: Diabetes prevalence was higher in men than in women for all age groups: 16.7% versus 9.5% in younger adults and 30.8% versus 22.8% in older adults. For all age groups, diabetes was more highly prevalent in urban communities. Using a multivariate stepwise logistic regression, variables associated independently with diabetes in older individuals were: gender (male sex: OR = 2.1; P < .009); diminished carbohydrate intake in the diet (OR = 0.77; P < .03); central distribution of adiposity (OR = 1.9; P < .03); and functional disability (OR = 2.3; P < .01). This relationship was not observed with living area, income, education, fiber and alcohol intake, body mass index, or age. Individuals 80 years and older had a diminished atherogenic risk profile. Diabetes in older people was associated significantly with hypertriglyceridemia, impaired functional status, and an increased prevalence of ischemic heart disease; in younger adults diabetes was associated with low density lipoprotein (LDL) hypercholesterolemia, hypertriglyceridemia, and a proportionally higher fat intake. CONCLUSION: This survey confirms the high prevalence of diabetes in the older Mexican population - particularly in men and in individuals living in urban areas - associated with an increased prevalence of other coronary risk factors. Diabetes was associated with higher fat, low carbohydrate, low fiber diets and increased prevalence of central distribution of adiposity. In the older subjects, diabetes was associated significantly with hypertriglyceridemia, impaired functional status, and increased prevalence of ischemic heart disease. A bias produced by early mortality and a survivorship effect must be considered in studies of older individuals. The health situation in the older Mexican population presents a complex problem that needs correct diagnosis and better strategies to benefit those segments of the population at increased risk.

Hypopituitarism in two brothers born by breech delivery.

OBJECTIVE: To describe two brothers with hypopituitarism who had been born by breech delivery and to discuss whether this condition corresponds to a familial form or to a pituitary stalk section as a result of the breech delivery. METHODS: We present the clinical, biochemical, and magnetic resonance imaging (MRI) characteristics of two Mexican brothers, 19 and 21 years old, with hypopituitarism and a history of breech delivery. RESULTS: Physical examination of both patients showed short stature with normal body proportions, an obviously younger appearance than that expected for their chronologic age, high-pitched voice, irregularly positioned teeth, no axillary or pubic hair, and prepubertal genitalia. Biochemical testing showed low thyroxine and free thyroxine values with inadequate or normal thyrotropin, low basal testosterone, and mildly increased serum prolactin levels. Stimulation tests showed a normal and a delayed thyrotropin response to thyrotropin-releasing hormone, subnormal serum cortisol, considerably blunted growth hormone (GH) response to insulin-induced hypoglycemia, and absence of GH response to GH-releasing hormone in both cases. MRI showed an ectopic neuropituitary gland. In case 1, a caudal portion of a very thin pituitary stalk was observed, suggesting the preservation of a vascular component of the stalk. Because both parents of these brothers shared the major histocompatibility complex haplotype HLA-A*2301, B*3501, DRB1*0407, DQA1*03, DQB1*0201, consanguinity was suggested. CONCLUSION: The phenotype of these patients differs from that described in families with POU1F1 (Pit-1) and PROP1 mutations. These cases are most likely related to an autosomal recessive gene mutation that warrants further research. To our knowledge, this is the first report of hypopituitarism in two brothers born by breech delivery.

Effect of major improvement in glycemic control on results of cardiovascular function tests in patients with insulin-dependent diabetes mellitus.

OBJECTIVE: To evaluate the effect of major improvement in glycemic control on cardiovascular function tests in patients with insulin-dependent diabetes mellitus (IDDM). METHODS: Eight men with chronic, poorly controlled IDDM (serum fructosamine >300 mmol/L and mean fasting blood glucose >200 mg/dL), who were 24 +/- 6 years of age and had a mean duration of diabetes of 8 +/- 1 years, were studied. No patient had microalbuminuria, was taking medication other than insulin, or had evidence of heart disease. Patients underwent baseline continuous ambulatory blood pressure monitoring, echocardiographic studies, and cardiovascular autonomic function tests, which were repeated after 4 weeks of an intensified insulin treatment program (IITP), during which they reached and maintained blood glucose concentrations and serum fructosamine levels in near-normal, nondiabetic ranges. RESULTS: Substantial changes in glycemic control had no significant influence on results of ambulatory blood pressure monitoring, cardiovascular autonomic function tests, and echocardiographic studies. CONCLUSION: Major improvement in glycemic control during a 1-month period in patients with IDDM had no significant influence on cardiovascular function tests. We cannot exclude the possibility that, after a longer duration of an IITP or in patients with clinically evident heart disease or evidence of major complications of diabetes, different responses might be observed.

Diabetes knowledge and its determinants in a Mexican population.

PURPOSE: The purpose of this study was to measure the level of diabetes knowledge in a representative group of Mexican individuals with diabetes and to identify the factors that influence it. METHODS: A validated questionnaire was administered to 570 outpatients; 11.2% had Type 1 diabetes, 36.4% had Type 2 diabetes treated with insulin, and 52.2% had Type 2 diabetes treated with oral agents. Samples for HbA1c determination also were obtained. RESULTS: The percentage of correct answers in each section of the questionnaire was low. Type 1 patients had the highest scores, followed by the insulin-treated Type 2 patients; those with chronic complications also had high scores. Educational background, attendance at diabetes courses, age, and HbA1c concentration were the main predictors of knowledge. Attendance at courses was influenced by the severity of the disease. CONCLUSIONS: The amount of patient knowledge about diabetes-related issues was low in this representative Mexican population. The educational efforts were focused on those with the worst metabolic control and/or with diabetes complications.

Cells of human aminopeptidase N (CD13) transgenic mice are infected by human coronavirus-229E in vitro, but not in vivo.

Aminopeptidase N, or CD13, is a receptor for serologically related coronaviruses of humans, pigs, and cats. A mouse line transgenic for the receptor of human coronavirus-229E (HCoV-229E) was created using human APN (hAPN) cDNA driven by a hAPN promoter. hAPN-transgenic mice expressed hAPN mRNA in the kidney, small intestine, liver, and lung. hAPN protein was specifically expressed on epithelial cells of the proximal convoluted renal tubules, bronchi, alveolar sacs, and intestinal villi. The hAPN expression pattern within transgenic mouse tissues matched that of mouse APN and was similar in mice heterozygous or homozygous for the transgene. Primary embryonic cells and bone marrow dendritic cells derived from hAPN-transgenic mice also expressed hAPN protein. Although hAPN-transgenic mice were resistant to HCoV-229E in vivo, primary embryonic cells and bone marrow dendritic cells were infected in vitro. hAPN-transgenic mice are valuable as a source of primary mouse cells expressing hAPN. This hAPN-transgenic line will also be used for crossbreeding experiments with other knockout, immune deficient, or transgenic mice to identify factors, in addition to hAPN, that are required for HCoV-229E infection.

[Premature atherosclerosis in a 17-year-old male with diabetes mellitus and familial dyslipoproteinemia]. / Aterosclerosis prematura en un joven de 17 años con diabetes mellitus y una dislipoproteinemia familiar.

A 17-year-old male was admitted with an acute myocardial infarction. A coronarography showed 90% occlusion in of the descendent anterior artery. A coronary angioplasty was done with excellent response. As coronary risk factors he had diabetes mellitus for 5 years and dyslipidemia with a phenotype IIb and hypo-alpha-lipoproteinemia. The case is discussed in regard to the possible etiopathogenic causes for his premature atherosclerosis.

Mechanism of tumorigenesis of renal carcinomas associated with the constitutional chromosome 3;8 translocation.

PURPOSE: Members of a family carrying a constitutional balanced translocation [t(3;8) (p14;q24)] have a high risk of developing multiple, bilateral clear-cell renal carcinomas. Two genetic mechanisms of carcinogenesis for this malignancy have been proposed: (1) disruption of a gene at the translocation breakpoint and (2) mutation of the von Hippel-Lindau tumor-suppressor gene at 3p25. This study further evaluates the role of the von Hippel-Lindau gene in the etiology and pathogenesis of t(3;8)-associated renal carcinomas. METHODS: Two new t(3;8)-associated renal carcinomas were tested for mutations in the von Hippel-Lindau gene by single-stranded conformational polymorphism analysis followed by direct DNA sequencing, for loss of alleles on chromosomes 3p and 8, and for methylation abnormalities in the first cloned exon of the von Hippel-Lindau gene. RESULTS: A missense mutation in the von Hippel-Lindau gene was found in one of the two t(3;8)-associated renal carcinomas. This mutation would produce a stop codon and a truncated protein. Both tumors showed a loss of alleles on the derivative 8 chromosome. When these results were combined with the results of our previous studies, two of the four t(3;8)-associated renal carcinomas, which were examined for molecular genetic changes, showed different von Hippel-Lindau somatic mutations. All renal tumors from the 3;8 translocation family showed loss of the translocated portion of chromosome 3. CONCLUSIONS: These results support a mechanism of tumorigenesis in the chromosome (3;8) translocation family that involves the loss of both copies of the von Hippel-Lindau gene.

¿Han quedado obsoletos los análisis de glucosuria? / Is the urine glucose test obsolete

El control metabólico de la diabetes mellitus realizado por los pacientes se ha llevado a cabo durante muchos años con exámenes de orina. La necesidad de un estricto control, en voga durante los últimos años, pone énfasis en el monitoreo del azúcar sanguíneo en el hogar. Se desea evaluar el estaod y la tecnología de los exámenes de glucosuria en la actualidad, a fin de observar cuál debe ser su papel en el trtamiento diario. El manejo renal de la glucosa depende de la concentración de azúcar, el índice de filtración glomerular y la reabsorción tubular. La mayor parte de los 180 g de glucosa filtrados diariamente en los glomérulos se reabsorbe en los túbulos por un proceso activo. Los métodos actuales utilizados por los pacientes diabéticos para medir el azúcar en la orina en los EEUU son: tabletas Clinitest, Testape, Diastix y Chemstrip uG. Se revisa cada uno de ellos, señalando sus beneficios e inconvenientes, así como sus falsas reacciones piositivos y negativas. Debido a su simplicidad y rango más amplio, parece ser que Chemstrip uG es el mejor en la actualidad, aunque también es uno de los más caros. La recolección de orina para estas determinaciones pueden ser cuantitativa o semicuantitativa. En la práctica diaria los exámenes de glucosuria tienen algunos problemas serios: variaciones en el umbral renal de paciente a paciente y en el mismo paciente, disociación temporal entre el azúcar de sangre y el la orina, variaciones con el estado de hidratación, falsas reacciones positivas y negativas, requiriendo además del paciente esfuerzo, técnicas cuidadosas y gastos