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Biomedical subjects

H Heller

Publications and source records attributed to H Heller.

At least 55 records · Page 3Linked to original sources
PubMed1996

Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting.

The acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS) is a devastating complication of human immunodeficiency virus infection characterized by a disproportionate decrease in lean body mass. The pathogenesis of the AWS is unknown, but recent data suggest that endogenous secretion of the potent anabolic hormone, testosterone; is decreased in 30-50% of men with AIDS. However, it is unknown whether decreased androgen levels are associated with decreased lean body mass and/or functional decreases in muscle strength and aerobic capacity in hypogonadal men with the AWS. In addition, testosterone is known to have stimulatory effects on GH secretion, and the loss of these effects on the GH-insulin-like growth factor I (IGF-I) axis may be an additional mechanism of decreased lean body mass in this population. Twenty hypogonadal subjects (free-testosterone < 12 pg/mL) with weight loss > 10% of preillness weight or absolute weight < 90% ideal body weight (IBW) were enrolled in the study. None of the subjects were receiving Megace. Lean body mass and fat-free mass were determined by potassium-40 isotope analysis (40K) and dual-energy x-ray absorptiometry, respectively, and analyzed with respect to gonadal function by linear regression analysis. Muscle mass was determined by urinary creatinine excretion, and exercise functional capacity was assessed by a 6-min walk test, a sit-to-stand test, and a timed get-up-and-go test. Results also were compared with gonadal function by regression analysis. IGF-I and mean overnight GH levels, determined from frequent sampling (q20 min from 2000-0800 h), were compared with results obtained from age- and sex-matched normal controls. Subjects were 26-58 yr of age (39 +/- 7 yr, mean +/- SD) with a CD4 cell count of 150 +/- 186 cells/mm3. Serum levels of FSH were elevated in 30% of the subjects. Muscle mass was significantly reduced, compared with expected mass for height (23.3 +/- 5.5 vs. 29.3 +/- 1.7 kg, P = 0.0001) and was decreased disproportionately to weight (77% of expected value for muscle mass vs. 93% of expected value for weight). Free-testosterone levels were correlated with total body potassium (R = 0.45, P < 0.05) and muscle mass (R = 0.45, P < 0.05). Total-testosterone levels were correlated with exercise functional capacity (R = 0.64, P = 0.01 for the sit-to-stand test and R = 0.53, P < 0.05 for the 6-min walk test). Mean GH levels were significantly increased (3.03 +/- 1.76 vs. 0.90 +/- 0.37 ng/mL, P < 0.001) and IGF-I levels decreased (167 +/- 66 vs. 225 +/- 69 ng/mL, P < 0.01), compared with age- and sex-matched eugonadal controls. GH levels were inversely correlated with caloric intake (R = -0.60, P = 0.02) and percent fat mass by dual-energy x-ray absorptiometry (R = 0.58, P = 0.02). Six additional hypogonadal subjects receiving Megace for AIDS wasting were analyzed separately. Nutritional status and parameters of body composition were compared in the Megace and non-Megace-treated subjects. No significant differences in caloric intake, lean body mass, fat mass, or muscle mass were demonstrated. These data demonstrate that changes in body composition, including loss of lean body and muscle mass, and deterioration in exercise functional capacity are highly correlated with androgen levels in hypogonadal men with the AWS. Furthermore, our data demonstrate significantly increased GH levels and decreased IGF-I in association with low weight in this population. These data suggest that androgen deficiency combined with classical GH resistance may contribute to the critical loss of lean body and muscle mass in hypogonadal men with the AWS. These data are the first to link muscle and lean body wasting with progressive gonadal dysfunction among the large percentage of men with AIDS wasting who are hypogonadal. This demonstrates the need for additional studies to determine the efficacy of gonadal steroid replacement to increase lean body mass in this population.

Adult↗
PubMed1995

Chromosomal insertion of foreign (adenovirus type 12, plasmid, or bacteriophage lambda) DNA is associated with enhanced methylation of cellular DNA segments.

Insertion of foreign DNA into an established mammalian genome can extensively alter the patterns of cellular DNA methylation. Adenovirus type 12 (Ad12)-transformed hamster cells, Ad12-induced hamster tumor cells, or hamster cells carrying integrated DNA of bacteriophage lambda were used as model systems. DNA methylation levels were examined by cleaving cellular DNA with Hpa II, Msp I, or Hha I, followed by Southern blot hybridization with 32P-labeled, randomly selected cellular DNA probes. For several, but not all, cellular DNA segments investigated, extensive increases in DNA methylation were found in comparison with the methylation patterns in BHK21 or primary Syrian hamster cells. In eight different Ad12-induced hamster tumors, moderate increases in DNA methylation were seen. Increased methylation of cellular genes was also documented in two hamster cell lines with integrated Ad12 DNA without the Ad12-transformed phenotype, in one cloned BHK21 cell line with integrated plasmid DNA, and in at least three cloned BHK21 cell lines with integrated lambda DNA. By fluorescent in situ hybridization, the cellular hybridization probes were located to different hamster chromosomes. The endogenous intracisternal A particle genomes showed a striking distribution on many hamster chromosomes, frequently on their short arms. When BHK21 hamster cells were abortively infected with Ad12, increases in cellular DNA methylation were not seen. Thus, Ad12 early gene products were not directly involved in increasing cellular DNA methylation. We attribute the alterations in cellular DNA methylation, at least in part, to the insertion of foreign DNA. Can alterations in the methylation profiles of hamster cellular DNA contribute to the generation of the oncogenic phenotype?

Adenoviridae↗
PubMed1995

On the insertion of foreign DNA into mammalian genomes: mechanism and consequences.

We have studied the integration of adenovirus type 12 (Ad12) DNA in transformed and hamster tumor cells over many years. Upon infection of hamster cells with Ad12, viral DNA has been found in association with hamster chromosomes, possibly in part integrated into the host genome. Ad12 DNA integration is not sequence specific. Transcriptionally active sites of the host genome show a preponderance for foreign DNA insertion. We are pursuing the mechanism of Ad12 DNA integrative recombination in a cell-free system prepared from hamster cell nuclear extracts. In a number of Ad12-transformed hamster cell lines or in cell lines carrying foreign DNA, we have located the inserted Ad12 DNA copies on hamster chromosomes by fluorescent in situ hybridization (FISH). Among the consequences of Ad12 DNA integration, we have studied the de novo methylation of the integrated foreign (Ad12) DNA and increases in DNA methylation in several cellular genes and DNA segments in Ad12-transformed and hamster tumor cells. Several lines of evidence argue for the notion that parameters in addition to nucleotide sequence, in particular site of integration and/or the chromatin configuration of the integrated DNA, are important in generating de novo methylation patterns. The de novo methylation of integrated foreign DNA can be interpreted as an old cellular defense mechanism against the activity of foreign genes in an established genome. Pursuing this concept, we have asked for the most likely portal of entry of foreign DNA, supposedly the gastrointestinal tract in most animals. This hypothesis has been tested by feeding mice linearized or circular, double-stranded bacteriophage M13mp18 DNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoviruses, Human↗
PubMed1995

Quantitative and qualitative characterization of apolipoprotein B containing lipoproteins produced by the visceral rat yolk sac in two different in vitro systems: organ culture and isolated epithelial cells in suspension culture.

Tissue pieces as well as isolated epithelial cells taken from visceral rat yolk sacs at the 18th day of gestation were able to synthesize and to secrete apo B containing lipoproteins floating in the density ranges of VLDL, IDL and LDL. In all three density classes only the high molecular weight apo B was detectable. VLDL secreted from yolk sac tissue or isolated epithelial cells lacked apo E and apo C. Studies with cycloheximide revealed that about 77% of the particles was delivered from a pool of preformed lipoproteins. Evidence was given that also de novo-synthesis of apo B containing lipoproteins took place in the tissue segments and the isolated epithelial cells. Most of apo B mass (90%) and of apo B radioactivity (60%) secreted by the tissue pieces of the visceral yolk sac floated in the density range 1.020-1.064 g/ml, the remainder being found in the d < or = 1.020 g/ml fraction. In contrast, only 40% of apo B mass and 45% of apo B radioactivity delivered from isolated epithelial cells belonged to the d = 1.020-1.064 g/ml fraction. LDL released from yolk sacs and isolated epithelial cells contained more triacylglycerols (41% vs. 25%) and had a larger mean diameter (24 nm vs. 21.8 nm) than those obtained from fetal rat serum, whereas the comparatively small VLDL produced in vitro (mean diameter = 34 nm) contained less triacylglycerols (46% vs. 60.5%) and more protein (20% vs. 10.2%) in comparison with fetal serum VLDL (mean diameter = 42.3 nm). Incubation experiments with [125I]VLDL led to the conclusion that the lipase secreted by yolk sac tissue into the medium could not be responsible for the conversion of VLDL into LDL, thus supporting our view of a direct LDL secretion by visceral rat yolk sacs.

Animals↗
PubMed1995

The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis.

The ubiquitin-mediated degradation of mitotic cyclins is required for cells to exit from mitosis. Previous work with cell-free systems has revealed four components required for cyclin-ubiquitin ligation and proteolysis: a nonspecific ubiquitin-activating enzyme E1, a soluble fraction containing a ubiquitin carrier protein activity called E2-C, a crude particulate fraction containing a ubiquitin ligase (E3) activity that is activated during M-phase, and a constitutively active 26S proteasome that degrades ubiquitinated proteins. Here, we identify a novel approximately 1500-kDa complex, termed the cyclosome, which contains a cyclin-selective ubiquitin ligase activity, E3-C. E3-C is present but inactive during interphase; it can be activated in vitro by the addition of cdc2, enabling the transfer of ubiquitin from E2-C to cyclin. The kinetics of E3-C activation suggest the existence of one or more intermediates between cdc2 and E3-C. Cyclosome-associated E3-C acts on both cyclin A and B, and requires the presence of wild-type N-terminal destruction box motifs in each cyclin. Ubiquitinated cyclins are then rapidly recognized and degraded by the proteasome. These results identify the cyclosome-associated E3-C as the component of the cyclin destruction machinery whose activity is ultimately regulated by cdc2 and, as such, the element directly responsible for setting mitotic cyclin levels during early embryonic cell cycles.

Animals↗
PubMed1994

Investigation of the human oxygen transport system during conditions of rest and increased oxygen consumption by means of fractionation. Effects of oxygen isotopes.

The aim of the study was to assess various pathways of the oxygen transport system at rest and ergometer work by the utility of information derivable from different behaviour of the isotopic oxygen molecules 16O2 and 16O18O during transport. 6 healthy humans were studied at rest and at different levels of ergometer work, ranging from 50 to 250 W. Isotope analysis was performed by applying a reference technique. Samples of inspiratory and expiratory gas, taken during steady state conditions, were analysed by a respiratory mass spectrometer on their 16O18O/16O2 ratios by comparing them with a reference gas of appropriate composition. Ventilatory minute volume, oxygen consumption and end-expiratory oxygen partial pressure were also measured. At rest, the delta IU-value quantifying the isotope effect of the overall oxygen transport amounted to 0.74 +/- 0.08%. During ergometer work, the fractionation factor steadily decreased with increasing oxygen consumption, yielding the regression line delta IU [%] = 0.74 -1.3.10(-4).VO2, where VO2 is oxygen consumption given in ml/min. With respect to oxygen transport from inspiratory gas to tissue, this result suggests: convective processes of oxygen transport become more limiting with increasing oxygen consumption, whereas diffusion does not become a major limiting step up to oxygen consumption rates of 3600 ml/min, otherwise a reverse relationship between fractionation factor and oxygen consumption should have been found.

Biological Transport, Active↗
PubMed1994

Dependency of overall fractionation effect of respiration on hemoglobin concentration within blood at rest.

In this study it was investigated in which way varying hemoglobin concentrations within blood influence overall fractionation effect of respiration, meaning a change in composition of isotopic oxygen molecules 16O2 and 16O18O within oxygen transported during entire respiration. Since overall fractionation effect of respiration is known to consist of different fractionating and non-fractionating processes, measuring it under condition of anemia could be useful in relating changes in isotopic compositions of oxygen to limitations of entire oxygen transport caused by one or more of these processes. Experiments were performed on 6 patients suffering from various degrees of anemia of a variety of etiologies and on 6 healthy humans. All test subjects breathed air at rest. Samples from inspiratory and expiratory gas were taken in order to analyse 16O18O/16O2 ratios with the aid of respiratory mass spectrometry. Values of overall fractionation effect decreased with respect to a drop in hemoglobin concentration from 17.6 to 6.6 g/100 ml in terms of a linear relationship (r = 0.79) provided that values of overall fractionation effect were normalized so as to exclude the influence of varying ventilatory conditions. It could be shown that at a value of hemoglobin content of 6.6 g/100 ml, 16O2 was transported in preference to 16O18O with a 0.57% higher rate compared to a value of 0.78% obtained at a hemoglobin concentration of 17.6 g/100 ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗
PubMed1993

Ubiquitin C-terminal hydrolase activity associated with the 26 S protease complex.

In the ubiquitin (Ub) system for protein degradation, proteins ligated to Ub are degraded by an ATP-dependent 26 S protease complex. During or after proteolysis, free Ub is regenerated, but the mechanisms of Ub release remained unknown. It was previously observed that free Ub is released from a Ub-histone conjugate by an ATP-dependent activity present in partially purified preparations of 26 S complex, but the relationship of this activity to protein breakdown was not established. We now show that purified preparations of 26 S complex release free Ub from conjugates that are good substrates for proteolysis, such as conjugates of lysozyme with reductively methylated Ub. The activity that releases free Ub co-migrates with the 26 S protease complex in glycerol density gradient centrifugation, indicating that the responsible Ub C-terminal hydrolase is an integral part of the 26 S complex. Complex-associated hydrolase can also act on adducts in which a single Ub unit is attached to protein, such as a bacterially expressed construct in which the C terminus of Ub is fused to the alpha-NH2 group of a fragment of Ub that contains 60% of its N-terminal region. In all cases, Ub release is insensitive to Ub-aldehyde (an inhibitor of some Ub C-terminal hydrolases) and is stimulated by MgATP. ATP cannot be replaced by beta, gamma-nonhydrolyzable analogs, but it can be substituted by CTP and GTP. The nucleotide specificity of Ub release by the 26 S complex is similar to that observed previously for conjugate proteolysis and nucleotide hydrolysis. It thus seems that the activity of the Ub C-terminal hydrolase associated with the 26 S complex is tightly coupled to the proteolytic action of the complex, and it may have a role in the release of Ub from linkage to amino groups of the protein substrate at the final stages of the Ub proteolytic pathway.

Adenosine Triphosphate↗
PubMed1992

Luetic cervical adenitis in patients with human immunodeficiency virus type 1 infection.

The clinical course of syphilis may be altered in some patients with human immunodeficiency virus type 1 infection. We report two cases of syphilis in patients with human immunodeficiency virus type 1 infection who presented with marked unilateral anterior cervical adenopathy after engaging in oral-genital sex. Neither of the patients had evidence of oropharyngeal chancres. One patient developed a cutaneous rash of secondary syphilis soon after the cervical adenopathy developed. Both patients responded well to antibiotic therapy.

Adult↗
PubMed1991

Brain dysfunction during motor activation and corpus callosum alterations in schizophrenia measured by cerebral blood flow and magnetic resonance imaging.

Sixteen unmedicated (14 never-medicated, 2 with washout periods of 1-2 weeks) schizophrenic patients displaying positive symptoms (e.g., formal thought disorder, hallucinations, delusions) without negative symptoms (e.g., flattening of affect, loss of energy, anhedonia--type I patients), 15 unmedicated (with washout periods from 1 week to 2 years) patients with marked negative symptomatology [type II patients; criterion score below 15/above 35 on the Munich version of the Scale of Assessment of Negative Symptoms (SANS), respectively], and 31 matched normal controls were investigated using regional cerebral blood flow [rCBF; dynamic single-photon emission computerized tomography (SPECT) with Xenon-133 as tracer] and magnetic resonance imaging (MRI; spin-echo technique, T1 weighted, midsagittal cuts). rCBF measurements were performed during both resting conditions and simple motor activation. Separately, on the same day, we performed a planimetric evaluation of the callosal-brain ratio in all subjects using MRI. In accordance with previous results on a smaller sample, we found signs of diffuse bilateral rCBF hyperactivation in type I patients, as compared with signs of nonreactivity in type II schizophrenics. Both activation patterns were different from a strictly contralateral sensorimotor rCBF activation seen in normal persons (only 8 studied with SPECT). The planimetry of relative callosal area did not reveal differences compared to normal persons, when type I/II patients were taken together. However, the threefold increased variance as compared with that found in normal persons suggested biological heterogeneity in patients. We found an increase of relative callosal size in type I as compared with type II patients. In the light of some recent findings linking lack of laterality of several brain functions to increased callosal size, we propose lack of laterality/diffuse hyperactivation and increased callosal size to be connected with positive symptomatology/good prognosis schizophrenia, and vice versa.

Activities of Daily Living↗
PubMed1990

A ubiquitin-protein ligase specific for type III protein substrates.

A previously studied species of ubiquitin-protein ligase contains specific sites for the binding of basic (Type I) and bulky hydrophobic (Type II) NH2-terminal amino acid residues of protein substrates. We now describe another enzyme that ligates ubiquitin specifically to proteins that have NH2-terminal residues other than the above two categories (Type III substrates). The new species of ligase, that we call E3 beta, is separable from the formerly described ligase (termed E3 alpha) by affinity chromatography on protein substrate columns. E3 beta was partially purified from extracts of rabbit reticulocytes and was shown to be required for the breakdown of Type III proteins. Apart from its different substrate specificity, it resembles E3 alpha in some physical properties, in a requirement for ubiquitin carrier protein (E2) for conjugate formation, and in its action to ligate multiple ubiquitin units to the substrate protein. The denatured derivative of bovine pancreatic ribonuclease is a specific substrate for E3 alpha, while that of ribonuclease S-protein is a good substrate for E3 beta. Since S-protein is formed by the removal from ribonuclease of NH2-terminal S-peptide, it is suggested that E3 beta interacts with an NH2-terminal determinant exposed in ribonuclease S-protein.

Animals↗
PubMed1990

Assessment of stratified inhomogeneity within distal alveolar space with respect to oxygen uptake.

Investigations were made as to whether or not there is a limitation of oxygen transport by stratified inhomogeneity in distal alveolar gas. Experiments were performed on 2 subjects. Single breath manoeuvres were carried out with similar phases of inspiration and expiration but varying breath-hold times. The inspiratory gas contained a small amount of oxygen labeled carbon dioxide, C18O2. End-expiratory gas was analysed on its residual C18O2 partial pressure by mass spectrometry. For evaluating a stratificational conductance, compartment model analysis was applied on the breath-hold data. Stratificational conductance has been found to be higher than 553 ml.mmHg-1. min-1. When transferred to oxygen transport, this means that stratificational conductance is more than 10 times higher than oxygen diffusing capacity. It can be concluded that (i) stratified inhomogeneity in distal alveolar space does not exhibit a limiting factor of oxygen uptake in lungs, (ii) a contribution of stratificational effects to sloping alveolar plateau is expected to be of minor importance.

Adult↗
PubMed1990

Oral physostigmine treatment for patients with presenile and senile dementia of the Alzheimer's type: a double-blind placebo-controlled trial.

Twelve patients aged 53 to 89 years with presenile or senile dementia of the Alzheimer's type participated in a treatment trial of oral physostigmine. Patients first received the drug during an open dose-finding phase. In a double-blind crossover design phase, the patients' memory performance during treatment with an optimal memory-enhancing dose was compared with memory performance during placebo treatment. Response to medication was assessed by the Delayed Recognition Span Test, the Selective Reminding Test, and the Alzheimer's Disease Assessment Scale. Intergroup differences in response to physostigmine were nonsignificant. Age at onset of the disease did not differentiate partial responders from nonresponders.

Administration, Oral↗
PubMed1989

Binding sites of ubiquitin-protein ligase. Binding of ubiquitin-protein conjugates and of ubiquitin-carrier protein.

It was found previously that the enzyme ubiquitin-protein ligase (E3) contains specific protein substrate binding sites that are responsible for the selection of proteins for degradation by the ubiquitin system. In the present study, we have tried to gain more insight into the mode of action of E3 by the characterization of other binding sites of this enzyme. Following the ligation of ubiquitin to 125I-lysozyme, the conjugates produced are very tightly bound to E3, as indicated by size analysis on glycerol density gradient centrifugation. The strong binding of ubiquitin-protein conjugates to the enzyme may account for the apparently processive addition of multiple molecules of ubiquitin to the protein substrate. Both the protein substrate moiety and the ubiquitin moiety participate in the interaction of ubiquitin-protein conjugates with E3, as indicated by competition with specific agents and by the comparison of the binding of ubiquitin-conjugated protein to that of free protein. In addition to the binding of its substrates and products, E3 also appears to interact with some of the enzymes with which it acts in concert. When E3 is incubated with the ubiquitin-carrier protein E2, a complex is formed between the two enzymes as analyzed on glycerol gradients. The formation of an E2.E3 complex may facilitate the transfer of activated ubiquitin from E2 to the protein substrate bound to the ligase.

Adenosine Triphosphate↗
PubMed1988

Maze-learning behavior in early adrenalectomized rats.

Rats adrenalectomized (ADX) on day 11 of life display enhanced brain growth due, at least in part, to a stimulation of cell proliferation and myelinogenesis. The present study investigated some functional consequences of this treatment. Rats were ADX or sham-operated (SHAM) on postnatal day 11 and then tested in adulthood for their problem-solving ability in a Hebb-Williams maze. The mean number of errors committed by ADX rats was lower than that of the SHAM controls on every test problem of the maze. ADX subjects also left the start box more quickly and ran the maze faster than the controls. When a subset of these same subjects was tested for running wheel activity, the ADX animals showed greater baseline running behavior and also learned more readily to respond to a fixed-interval schedule of reinforcement. The remaining animals were subjected to carcass analysis, which revealed that ADX rats under the food-restricted conditions necessary for maze testing had a lower percentage of body fat and a higher relative water content than SHAMs. Although there may be some relationship between enhanced maze-learning performance and altered activity or motivation in the ADX animals, the overall results suggest that the performance of these subjects reflects a real difference in learning ability. The neural mechanisms underlying this difference remain to be elucidated.

Adrenal Glands↗
PubMed1988

[Changes in the sensitivity of the cornea in patients with intracerebral tumors. Studies of patients with meningioma of the cranial base and neurinoma of the trigeminal nerve and the vestibulocochlear nerve using the Draeger esthesiometer].

The center of the cornea was measured preoperatively in 29 patients suffering from intracranial tumors (acoustic neuroma, trigeminus neuroma, basal meningioma). These measurements were made with the Draeger electronic-optical esthesiometer; the results were supplemented by an analysis of tumor diameters determined by computer tomography. In each case one-half of the patients with acoustic neuromas and medial meningiomas of the wing of the sphenoid bone manifested a reduction in sensitivity at the center of the ipsilateral cornea (normal: 0.8 to 1.7 x 10(-5) N). The diameters of the sensitivity-reducing acoustic neuromas ranged from 15 mm to 45 mm. It may be deduced both from the topographic conditions at the skull base in the vicinity of the porus acusticus internus and from the conditions associated with a pressure-induced lesion of a peripheral nerve that medial acoustic neuromas as small as 10.1 mm in diameter can lead to a reduction in the conductivity of the ipsilateral trigeminal nerve. Only when they attain a diameter of 28.4 mm and when the proportions of the skull base are equally spacious do the acoustic neuromas regularly cause an ipsilateral corneal hypesthesia.

Adult↗