Performance of the hypertrophied left ventricle in spontaneously hypertensive rats. Effects of adrenergic stimulation

The performance of isolated hearts from adult male spontaneously hypertensive rats (SHR) and matched normotensive controls (NCR) was investigated in an antegrade perfusion system, where preload and afterload could be varied independently. During electrical pacing of the heart to constant heart rate, increases in afterload, but not in preload, considerably raised cardiac contractility, measured as left ventricular max dP/dt. At afterloads equalling their respective in vivo ones, max dP/dt was similar in SHR and NCR. This indicates that the SHR hearts by myocardial hypertrophy are so well adapted to their raised afterload that an increased inotropic state of the heart is not required. Upon adrenaline addition, SHR and NCR did not differ concerning either "chronotropic sensitivity", i.e. per cent increase in heart rate of the spontaneously beating heart or in "inotropic sensitivity", measured as increase in max dP/dt. However, in this in vitro situation adrenaline increased stroke volume only when the hearts worked at reduced inotropism, induced by lowered temperature (30 degrees C). At maximal inotropic stimulation by adrenaline and occluded outflow, the SHR hearts produced higher systolic pressures than the NCR ones. This reveals an increased maximal contractile capacity of the hypertrophied SHR left ventricle, rather than a reduced one as sometimes suggested.     

The effect of splanchnic nerve stimulation on blood flow distribution, villous tissue osmolality and fluid and electrolyte transport in the small intestine of the cat

The effect of splanchnic nerve activation on intestinal fluid transport and intramural blood flow distribution was examined in the cat. Previous reports from our laboratory have demonstrated that splanchnic nerve activation increases fluid absorption. The present study was performed to elucidate the mechanisms behind this effect. The results showed an increase in net sodium and chloride transport on splanchnic nerve activation whether intestinal blood flow decreased or not. The effect on sodium transport was due to a decrease in lumen to tissue flux. The effect could not be explained by a decrease in local blood flow, as it was present despite constant blood flow in both the villous and crypt regions. No change was seen in the villous osmolality gradient on splanchnic nerve activation. On the basis of these findings, it is proposed that the in vivo effect of splanchnic nerve activation is due to a decrease in fluid and electrolyte secretion, probably occurring in the intestinal crypts.     

The value of deletion analysis for carrier detection in Duchenne muscular dystrophy (DMD)

We performed genetic analysis for carrier detection for several at-risk females in a four-generation Duchenne muscular dystrophy (DMD) pedigree using deletion analysis. We demonstrated that dosage analysis is a suitable alternative method to determine the carrier status of female relatives of DMD patients shown to have a deletion within the DMD gene. Subsequently, we diagnosed an affected male fetus for an at-risk female shown to be a DMD carrier by deletion analysis. The usefulness of deletion and linkage analysis are compared. In this family, linkage analysis was complicated by the unavailability of key family members, two recombination events and by previously undisclosed nonpaternity. We found that dosage analysis was more efficient than linkage for carrier evaluation in this family.     

New insights into the pathogenesis of dilated cardiomyopathy: possible underlying autoimmune mechanisms and therapy

In the present study, autoimmune processes involved in the pathogenesis of dilated cardiomyopathy (DCM) are discussed. Genetic predisposition, persistent viral infection, and molecular mimicry have previously been described as the underlying mechanisms of the disease, and prevalence of autoantibodies (AABs) against several intra- and extracellular cardiotropic targets has been confirmed. These autoantibodies are able to disturb the normal physiological activity of the cardiomyocytes. They also could function as mediators in an activated immune system and direct a great deal of attention to injured tissue via (1) complement activation and (2) genesis of circulatory immunocomplexes (CICs) in association with self-antigens. The number as well as duration of accessible autoantigens or CICs seem to play an important role in activation of the antigen-presenting cells (APCs) and, consequently, promotion of autoimmunity. Since AABs play such a decisive role, their exclusion by immunoadsorption (IA) therapy has been discussed as a new approach in DCM treatment. Hitherto, all performed pilot studies using this approach have shown improvement in cardiac function and quality of life in the vast majority of treated DCM patients. The removal of circulating AABs may downregulate the autoimmune system, moderate the inflammatory signals, and hasten the recovery of the affected tissue.     

Pilot detection study of alpha(1) antitrypsin deficiency in a targeted population

Screenings for the genetic disorder alpha(1) antitrypsin deficiency (AAT Deficiency) have been one of two models: large screenings of general populations and small targeted detection programs in high-risk groups. The most appropriate screening and detection methodologies in terms of target populations, subject participation and yield of positive tests, however, have not been well defined. The major objective of this pilot study was to evaluate the effectiveness in terms of participation of two different AAT Deficiency detection programs using a self-administered fingerstick blood test. Individuals ages 30-60 under the care of a pulmonary physician and with a diagnosis of emphysema, COPD, chronic bronchitis, or bronchiectasis were the targeted population. Participants were offered AAT Deficiency testing in the pulmonary physician's office compared with testing offered through mail. Participation (i.e., frequency of subject participation in the detection program) of two different AAT Deficiency detection programs. Non-participation was due to fear of self-administered testing and research studies; women were more likely to participate than men. Eligible subjects were significantly more likely to participate when offered testing by their pulmonary physician in-office (83%) than mail-only (42%) (P < 0.02). Although self-administered genetic testing is available, highest participation in AAT Deficiency detection program was found when offered directly by the physician. This finding may have implications for screening and detection of other genetic diseases. Future studies need to evaluate the yield (i.e., frequency of positive tests) of these detection methodologies in highly targeted populations.     

Molecular analysis of C3 allotypes in patients with nephritic factor.

The autoantibody nephritic factor (NeF) leads to complement consumption in vivo and is associated with type II mesangiocapillary glomerulonephritis (MCGN II) and partial lipodystrophy (PLD). The third component of complement (C3) exists in two common allotypic forms, C3S and C3F, distinguished at the protein level by electrophoresis. An increased frequency of the rarer C3F allele has been reported in several autoimmune conditions, including one small series of patients with NeF. However, patients with NeF have low levels of circulating C3 so that allotyping at the protein level is difficult. The molecular basis of the S/F polymorphism has recently been established: a single base change at the DNA level encodes a single amino acid substitution at the protein level. A second polymorphism, closely linked to the first, is defined by the MoAb HAV 4-1, and is also due to a single base change. These polymorphisms can therefore be analysed at the DNA level. We have used the amplification refractory mutation system (ARMS), a modification of the polymerase chain reaction (PCR), to analyse these two C3 polymorphisms at the DNA level in 26 patients with NeF. The allele frequencies of C3S and C3F were 0.673 and 0.327 (predicted values 0.79 and 0.2, chi 2 = 4.813, P < 0.05), giving a relative risk of 2.1 for the development of NeF conferred by the presence of a C3F allele. The HAV 4-1 allele frequencies were (-) 0.71 and (+) 0.29, i.e. not significantly different than predicted from the linked C3S/F allele frequencies. This is the largest series of patients with NeF yet published, and our data confirm an association between C3F and NeF. Possible mechanisms for for this link are discussed.     

Latent variable discovery in classification models

The naive Bayes model makes the often unrealistic assumption that the feature variables are mutually independent given the class variable. We interpret a violation of this assumption as an indication of the presence of latent variables, and we show how latent variables can be detected. Latent variable discovery is interesting, especially for medical applications, because it can lead to a better understanding of application domains. It can also improve classification accuracy and boost user confidence in classification models.     

No evidence for a correlation between behaviour and the size of the Y chromosome

Y chromosome variation has been studied in three groups of Norwegian males: 35 boys from an adolescent psychiatric hospital; 45 men from a hospital for hard-to-manage or dangerous, psychotic men; and 26 boys from two ordinary school classes.
Y chromosomes with 1, 2, and 3 brightly fluorescing bands were found in all three groups. One boy carried a Y with no bands. The mean values of the Yf/Yq ratio were not significantly different in the three groups (Yf is the length of the distal, brightly fluorescing part of Yq). Two cases of XY/XYY mosaicism were found among the psychotic men.
The study shows that the human species is polymorphic with regard to the size of the Y chromosome, i. e. the number of fluorescent bands in the long arm. No phenotypical manifestation of this polymorphism, particuIarly as regards behaviour, was found.