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Biomedical subjects

D Arnold

Publications and source records attributed to D Arnold.

At least 91 records · Page 5Linked to original sources
PubMed1993

Presentation of numerous viral peptides to mouse major histocompatibility complex (MHC) class I-restricted T lymphocytes is mediated by the human MHC-encoded transporter or by a hybrid mouse-human transporter.

The major histocompatibility complex-encoded transporter associated with antigen processing (TAP) is required for the efficient presentation of cytosolic antigens to class I-restricted T cells. TAP is thought to be formed by the interaction of two gene products, termed TAP1 and TAP2. We find that TAPs consisting either of human subunits, or mouse TAP1 and human TAP2, facilitate the presentation of numerous defined viral peptides to mouse class I-restricted T cells. As human and mouse TAP2 and TAP1 differ in 23 and 28% of their residues, respectively, this indicates that TAP1 and TAP2 can form a functional complex with partners considerably different from those they coevolved with. Moreover, these findings indicate that widely disparate TAPs facilitate delivery of the same peptides to class I molecules. These findings suggest that TAP polymorphism does not greatly influence the types of peptides presented to the immune system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Myoblast transfer in Duchenne muscular dystrophy.

One biceps muscle of 8 patients with Duchenne muscular dystrophy was injected at 55 sites with a total of 55 million viable, purified, and contamination-free normal myoblasts (myoblast transfer). The other biceps of each patient was injected with a placebo to serve as a control. The procedure was blinded to the patients, parents, and investigators. Myoblasts derived from a biopsy specimen of the fathers were cultured and purified under strict conditions and carefully screened for microbial contamination. All patients received cyclophosphamide for immunosuppression for 6 or 12 months. No serious complications were observed after myoblast transfer, indicating that the procedure is safe. The overall therapeutic efficiency of myoblast transfer was poor as judged by the results in maximal voluntary force generation, dystrophin content of the muscle, magnetic resonance imaging of the muscle, and the lack of donor-derived DNA and dystrophin messenger RNA in the injected muscle. An improved efficiency of the take of myoblasts might be achieved by using younger cells and injecting the myoblasts with a myonecrotic agent (to increase the prevalence of regeneration) and a basal laminal fenestrating agent.

Analysis of Variance↗
PubMed1993

Social crisis and epidemic disease in the famines of nineteenth-century India.

The onset of famine in nineteenth-century India resulted in the breakdown of normal social relations and produced a series of often dysfunctional behavioural responses. Survival strategies like the use of 'famine foods' and migration in search of food and work facilitated the spread of such epidemic diseases as cholera, dysentery, malaria, and smallpox. Although many of these diseases are not normally thought of as having a synergistic relationship with malnutrition and hunger, they were linked to it (as the Madras famine of 1876-78 illustrates) through abnormal social and environmental conditions created by drought and an extreme crisis of substance.

Disease Outbreaks↗
PubMed1993

Randomized evaluation of a low fat ad libitum carbohydrate diet for weight reduction.

Restricting dietary fat intake while consuming carbohydrates ad libitum has recently been promoted as a weight loss regimen. Sixty subjects (52 females and eight males) were randomized to low fat ad libitum carbohydrate (low-fat) or low fat with caloric restriction (low-calorie) behaviour modification treatments. Forty-nine subjects completed the 16-20 week programme. Subjects in both groups reported averaging over five exercise sessions per week during treatment. The low-calorie group lost significantly more weight (males 11.8 kg, s.d. 6.4; females 8.2 kg, s.d. 4.2) than the low-fat group (males 8.0 kg, s.d. 1.3; females 3.9 kg, s.d. 3.7). Both groups of subjects lost similar amounts of lean body mass. There was significantly greater loss of body fat in the low-calorie group. A slight reduction in RMR, adjusted for changes in lean body mass, was observed in both groups. Fat intake was reduced from 90 to 30 g per day. Subjects in both groups reduced their total energy intake with the low-calorie group consuming fewer calories per day than the low-fat group. Both groups showed significant and equivalent improvements in eating habits based on microanalysis of eating diaries. Eating in social situations and emotional eating, however, continued to cause adherence problems during treatment for both groups. Follow-up data collected 9-12 months after completion of treatment on 65% of the subjects completing the study showed no significant difference between the two groups in weight losses from baseline (low-fat group 2.6 kg; low-calorie group 5.5 kg).

Adult↗
PubMed1992

Cytokines increase transporter in antigen processing-1 expression more rapidly than HLA class I expression in endothelial cells.

Transporter in Ag processing-1 (TAP-1, previously called PSF-1 or Ring-4) is an MHC-encoded gene product that is required for efficient association of intracellular peptide Ag with nascent HLA class I H chain and beta 2-microglobulin, thereby permitting assembly and normal surface expression of the class I molecules. TAP-1 is thought to function as a component of a transmembrane pump, that transports cytoplasmically-derived peptides into the lumen of the endoplasmic reticulum where class I molecules assemble. Synthesis and expression of HLA class I molecules is increased in human endothelial cells by IFN-beta, IFN-gamma, and TNF. We report these same cytokines increase TAP-1 expression. As with class I, TAP-1 is also synergistically increased by combinations of TNF with IFN. Interestingly, cytokine-induced increases in TAP-1 mRNA are markedly more rapid than increases in class I mRNA. This rapid increase in TAP-1 mRNA is reflected in a rapid increase in TAP-1 protein. These results demonstrate that TAP-1 synthesis and class I synthesis are regulated in parallel. The rapidity of the cytokine response of TAP-1 compared to class I further suggests that the constitutive level of TAP-1 expression in endothelial cells is not sufficient to support inducible increases in class I expression.

Animals↗
PubMed1992

Proteasome subunits encoded in the MHC are not generally required for the processing of peptides bound by MHC class I molecules.

Antigen processing provides major histocompatibility complex (MHC) class I molecules with short peptides, which they selectively bind and present to cytotoxic T lymphocytes. The proteolytic system generating these peptides in the cytosol is unidentified, but their delivery into the endoplasmic reticulum is mediated by the TAP1-TAP2 transporter encoded in the MHC class II region. Closely linked to TAP1 and TAP2 are genes for the LMP2 and LMP7 proteins, which resemble components of proteasomes, proteolytic complexes known to degrade cytosolic proteins. This association has led to the common assumption that proteasomes function in this immunological pathway (discussed in ref. 15). We now show that the expression of stably assembled class I molecules and apparently normal peptide processing can be completely restored in the absence of LMP2 and LMP7 in the human lymphoblastoid cell line mutant 721.174 (refs 16, 17). The identity of LMP7 is directly confirmed by reconstitution of a proteasomal subunit after gene transfer. These results therefore dispute the hypothetical involvement of proteasomes in antigen processing, although a more subtle effect of LMP2 and LMP7 cannot be ruled out.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Alternative exon usage and processing of the major histocompatibility complex-encoded proteasome subunits.

The finding that two subunits of the proteasome, LMP2 and LMP7, are encoded in the major histocompatibility complex (MHC) has linked the proteasome which represents a major extralysosomal proteolytic system to the processing of intracellular antigens. Here we describe a second form of the human LMP7 cDNA, LMP7-E2, which has been identified during the characterization of novel genes in the MHC. The analysis of the genome organization of LMP7 revealed that LMP7-E1 and LMP7-E2 arise by alternative exon usage. Using specific antibodies against LMP2 and LMP7, we show that they are co-expressed with class I MHC molecules as well as a putative peptide transporter. The polypeptides encoded by LMP7 and LMP2 undergo proteolytic processing when incorporated into proteasomes, and the LMP7 precursor is derived mainly from LMP7-E2. Furthermore, our data suggest that LMP7 and LMP2 are mutually dependent for their incorporation into the proteasomal complex.

Amino Acid Sequence↗
PubMed1991

Two putative subunits of a peptide pump encoded in the human major histocompatibility complex class II region.

The class II region of the human major histocompatibility complex (MHC) may encode several genes controlling the processing of endogenous antigen and the presentation of peptide epitopes by MHC class I molecules to cytotoxic T lymphocytes. A previously described peptide supply factor (PSF1) is a member of the multidrug-resistance family of transporters and may pump cytosolic peptides into the membrane-bound compartment where class I molecules assemble. A second transporter gene, PSF2, was identified 10 kilobases (kb) from PSF1, near the class II DOB gene. The complete sequences of PSF1 and PSF2 were determined from cDNA clones. The translation products are closely related in sequence and predicted secondary structure. Both contain a highly conserved ATP-binding fold and share 25% homology in a hydrophobic domain with a tentative number of eight membrane-spanning segments. Based on the principle dimeric organization of these two domains in other transporters, PSF1 and PSF2 may function as complementary subunits, independently as homodimers, or both. Taken together with previous genetic evidence, the coregulation of PSF1 and PSF2 by gamma interferon and the to-some-degree coordinate transcription of these genes suggest a common role in peptide-loading of class I molecules, although a distinct function of PSF2 cannot be ruled out.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

In vitro effects of arachidonic acid on the prostaglandin synthesizing system in gastric mucosa.

Self-destruction of the prostaglandin cyclooxygenase has been suggested to be an important factor in the regulation of endogenous prostaglandin synthesis. The present study was done in order to define the role of this substrate-induced inactivation in the regulation of prostaglandin synthesis in gastric mucosa. In tissue homogenate, the prostaglandin synthesizing capacity is rapidly inactivated at 37 degrees C, even in the absence of exogenous arachidonic acid. It was shown that this inactivation can be prevented both by EDTA as a chelator of calcium-ions and by tetracaine, a specific inhibitor of the phospholipase A2. Additional exogenous arachidonic acid again inactivated prostaglandin synthesis in a dose dependent manner. In contrast, the prostaglandin synthesizing capacity in organ cultured mucosal biopsies is well preserved, although the release of endogenous substrate was activated by extracellular calcium and Ca-ionophore A23187. Furthermore, even at high concentrations of exogenous arachidonic acid present in the culture medium, the synthesizing capacity in intact biopsies was only slightly and reversibly reduced. These large differences between intact biopsies and cell free tissue preparations point to very efficient mechanisms controlling the substrate availability for the cyclooxygenase system both from endogenous and exogenous sources in intact gastric mucosa.

Animals↗
PubMed1991

Toxicity of potassium cyanide added to fresh fruit and juice.

To investigate the toxicity of potassium cyanide in fresh fruit and juice, male and female Wistar rats were orally dosed with fruit homogenates or juices containing 3 x LD50 of potassium cyanide. These were given in single doses at various intervals after spiking. The dosing solutions were analysed for cyanide using a cyanide test kit. There was a good correlation between the toxic signs in rats and the cyanide remaining in dosing solutions. The toxicity of spiked apple and honeydew melon diminished with time, while spiked grape and both grape and apple juices maintained their toxicity during the 4-hr studies. The pH of the samples both before and after spiking seemed to be an important factor in determining the toxicity.

Administration, Oral↗
PubMed1991

A behavioral taxonomy of obese female participants in a weight-loss program.

To create a behavioral classification of obesity, 2-wk baseline food diaries were obtained from 236 obese women entering weight-loss programs. Subjects monitored food intake along with the social, environmental, and emotional context in which each meal occurred. Variables representing situation-specific eating behaviors were statistically extracted from greater than 11,000 eating episodes. Hierarchical cluster analysis identified five distinct groups of subjects on the basis of similarity of eating patterns. The five groups were (1) moderately healthy eating habits, (2) chronic food restrictors, (3) alternating diet-binge eaters, (4) emotional overeaters, (5) unrestricted meal overeaters. The five groups differed on questionnaire measures of emotional adjustment and eating behavior but did not differ on dropout rates, amount of weight lost, or exercise compliance. The chronic food restrictors had significantly less lean body mass, lower resting metabolic rates, and higher waist-to-hip ratios than did the unrestricted meal overeaters.

Adult↗
PubMed1991

Correlative multidisciplinary approach to the study of mitochondrial encephalomyopathies.

Mitochondrial encephalomyopathies can be caused by defects in the mitochondrial respiratory complexes. The clinical phenotypes are quite protean but in many instances a characteristic or suggestive clinical presentation permits a tentative bedside diagnosis. The diagnosis can be verified by laboratory investigations. The major laboratory hallmarks of mitochondrial encephalomyopathies include: ragged red fibers on muscle biopsy, a specific defect or deficiency in a mitochondrial respiratory enzyme complex, mtDNA abnormalities, reduced anaerobic threshold by bicycle ergometry, impaired cellular energy state by MRS and characteristic brain imaging abnormalities. Monitoring of some of these parameters along with the clinical phenotype will aid in the evaluation of therapeutic trials.

Brain Diseases↗
PubMed1990

Different changes in spontaneous field potential oscillations precede epileptiform bursting in hippocampal slices perfused with penicillin or reduced magnesium.

Power spectra were used to analyse spontaneous field potentials (SFPs) recorded in the CA3 distal apical dendritic region of guinea pig hippocampal slices perfused with either penicillin or reduced Mg2+. High concentrations of penicillin (2000 IU/ml) progressively converted the low amplitude, irregular oscillations observed in control medium to higher amplitude, low frequency, rhythmic oscillations at approximately 2-3 Hz just prior to the onset of spontaneous, synchronized bursting. Low concentrations (50-300 IU/ml) increased the power of frequencies below 10 Hz and suppressed higher frequencies in a dose-dependent fashion. Although Mg2(+)-free medium also increased the magnitude of the SFPs prior to the onset of synchronous bursting, the changes were smaller than with penicillin and the frequency distribution was completely different. Low concentrations of Mg2+ (0.0-0.5 mM) increased the power across all frequencies, however, the maximal effect was on frequencies between 5 and 25 Hz. The transition from normal to epileptiform activity may proceed through at least 2 distinct intermediate states. When recurrent inhibition is blocked (penicillin), synchronous synaptic activity precedes the onset of bursting, whereas non-specific increases in excitability and activation of NMDA receptors (reduced Mg2+) produce an asynchronous transition state.

Action Potentials↗
PubMed1990

The pharmacokinetics of chloramphenicol in plasma and saliva of dairy cows.

In the present study the pharmacokinetics of chloramphenicol were investigated in bovine plasma and saliva. The method of detection of chloramphenicol, a radio-immunoassay, requires only small sample volumes, no further clean-up, and a large number of samples can be processed simultaneously. This enabled the collection of a larger number of samples over a longer period of time than in previous studies. The intention was to obtain a complete pharmacokinetic profile of chloramphenicol, to evaluate it according to common open-compartment models, and to compare it with the results of previous studies. The radio-immunoassay results were confirmed by analysing a number of samples distributed over the concentration range of interest by a gas-chromatographic method with electron-capture detection. The suitability of saliva was evaluated as a possible means of monitoring compliance with the ban on chloramphenicol in the Federal Republic of Germany in milk-producing animals.

Animals↗