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Biomedical subjects

D Stone

Publications and source records attributed to D Stone.

At least 19 recordsLinked to original sources
PubMed1992

Pro-oxidant effects of lipoxygenase-derived peroxides on the copper-initiated oxidation of low-density lipoprotein.

It has been proposed that lipoxygenases, specifically 15-lipoxygenase, may play an important role in promoting the oxidation of low-density lipoprotein (LDL) in the artery wall. It is well known that peroxides are unstable in the presence of transition metals, decomposing to form the alkoxy and peroxy radicals, and so initiating lipid peroxidation. To test whether lipoxygenase-derived peroxides may promote the oxidation of LDL in the presence of copper, the lipoprotein was enriched with lipid peroxides derived from the enzymic action of 5- and 15-lipoxygenases on either linoleic or arachidonic acid. All of these products were found to promote oxidation, whereas the related hydroxy fatty acids had no effect. This suggests that lipoxygenase-derived peroxides associated with the LDL particle may promote peroxidation in the presence of a suitable transition metal catalyst. This result has implications both for the mechanism of the potential pro-oxidant action of lipoxygenases in vivo and for the ex vivo assessment of the oxidizability of LDL samples isolated from different donors.

Arachidonic Acid↗
PubMed1992

The loading of fura-2 into mitochondria in the intact perfused rat heart and its use to estimate matrix Ca2+ under various conditions.

When rat hearts were perfused with a medium containing 10 microM fura-2/AM for 1 hr at 37 degrees C a significant amount of the derived fura-2 could be detected in subsequently isolated mitochondria. This procedure allowed the measurement of matrix free Ca2+ concentration ([Ca2+]m) of mitochondria rapidly isolated from whole hearts by a method which avoids artefactual redistribution of Ca2+. [Ca2+]m in mitochondria prepared from control hearts and incubated with respiratory substrates and EGTA was found to be 172 +/- 23 nM (mean +/- S.E.M.). When hearts were subjected to either increased mechanical work or treatment with 1 microM L-epinephrine (for 2 mins) [Ca2+]m increased to 916 +/- 138 nM and 727 +/- 65 nM respectively. The presence of ruthenium red (2.5 microM) in the perfusion medium prior to and during inotropic intervention diminished these increases in [Ca2+]m(to 316 +/- 28 nM and 218 +/- 18 nM respectively) but did not affect control values. Addition of Na+ ions to incubated mitochondria to enhance mitochondrial Ca2+ egress diminished these increases in [Ca2+]m due to pre-treatment with positive inotropes (compared to controls). These changes in [Ca2+]m were broadly parallelled by changes in the active non-phosphorylated form of pyruvate dehydrogenase (PDH) under all circumstances. These results provide further evidence that the activation of PDH by positive inotropes is accomplished by, and at least in part due to, raised mitochondrial matrix free [Ca2+] and that such increases can be maintained in isolated and suitably incubated mitochondria.

Animals↗
PubMed1992

Correlation of RNA secondary structure and attenuation of Sabin vaccine strains of poliovirus in tissue culture.

Part of the 5' noncoding regions of all three Sabin vaccine strains of poliovirus contains determinants of attenuation that are shown here to influence the ability of these strains to grow at elevated temperatures in BGM cells. The predicted RNA secondary structure of this region (nt 464-542 in P3/Sabin) suggests that both phenotypes are due to perturbation of base-paired stems. Ts phenotypes of site-directed mutants with defined changes in this region correlated well with predicted secondary structure stabilities. Reversal of base-pair orientation had little effect whereas stem disruption led to marked increases in temperature sensitivity. Phenotypic revertants of such viruses displayed mutations on either side of the stem. Mutations destabilizing stems led to intermediate phenotypes. These results provided evidence for the biological significance of the predicted RNA secondary structure.

Base Sequence↗
PubMed1992

Kallmann's syndrome and dilated cardiomyopathy.

A 52-year-old male previously known to have Kallmann's syndrome was admitted with congestive cardiac failure. He was found to have a dilated cardiomyopathy and died despite medical therapy. This report is the first known case of Kallmann's syndrome and dilated cardiomyopathy.

Cardiomyopathy, Dilated↗
PubMed1991

Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.

The acute effects of inhaled nitric oxide (NO) (40 ppm in air) on pulmonary (PVR) and systemic (SVR) vascular resistance were compared with those of an intravenous infusion of prostacyclin (24 micrograms/h) in 8 patients with severe pulmonary hypertension and 10 cardiac patients with normal values of PVR. 10 healthy volunteers were studied non-invasively. In the patients with pulmonary hypertension, PVR fell significantly after inhaled NO and after prostacyclin. PVR also fell significantly in the cardiac patients after inhaled NO. Although SVR fell substantially after prostacyclin in patients with pulmonary hypertension, inhaled NO had no effect on SVR in any patient or volunteer. Inhaled NO therefore seems to be both a selective and effective pulmonary vasodilator.

Administration, Inhalation↗
PubMed1991

Reoxygenation-dependent decrease in mitochondrial NADH:CoQ reductase (Complex I) activity in the hypoxic/reoxygenated rat heart.

Reoxygenation of the hypoxic myocardium results in a number of processes, including an O2-dependent increase in total tissue Ca2+ and cell lysis in which mitochondrial electron transport plays a key role. In the present study we have isolated mitochondria from perfused rat hearts subjected to hypoxia and found no change in their respiratory function relative to controls. In contrast, mitochondria isolated immediately after reoxygenation of hypoxic-perfused hearts exhibited a specific and significant decrease in NADH:CoQ reductase (Complex I; EC 1.6.5.3) activity, as measured both polarographically and spectrophotometrically. Isolated cardiomyocytes subjected to a similar protocol of hypoxia/reoxygenation also exhibited a specific decrease in Complex I activity. Myocardial perfusion with media containing Ruthenium Red protected against the reoxygenation-dependent loss of Complex I activity. These observations taken together suggest that mitochondrial Ca2+ uptake on reoxygenation is implicated in the mechanism of the specific loss of Complex I activity.

Animals↗
PubMed1991

Preventability of neonatal cold injury and its contribution to neonatal mortality.

When the body temperature of a small neonate falls below 35 degrees C, lassitude can be noted; severe derangements of cardiovascular, renal, hepatic, immunological, and hematological systems may also occur depending in part on the duration and severity of hypothermia. Diagnosis requires a low-reading thermometer, lacking which the diagnosis can be suspected, but most often is missed. Fatal cases of diagnosed cold injury commonly have terminal pneumonia or sepsis. Prevention involves identification and home visits to high-risk infants; intensive care of those with the diagnosis at Soroka Hospital Medical Center has reduced the case-fatality rate from 30% in 1971 to 3% in 1988-1989. During the same period in our region, the proportion of neonatal deaths occurring in winter months of December, January, and February has dropped from 55 to 27%. The expected proportion is 25%. We hypothesize that excess neonatal mortality during winter months, especially due to pneumonia and sepsis or sudden infant death syndrome (SIDS) is an indicator of missed cold injury syndrome. A preliminary evaluation was made form U.S. data by state, provided by the National Center for Health Statistics, which records no fatalities from cold injury during 1986. Contrasted with this are 26 cold injury deaths in Israel for 1977-1980. In the U.S., though, excess winter neonatal deaths in 1986 from SIDS, pneumonia, and sepsis are reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Cold Temperature↗
PubMed1991

Comparison of a hand-held nebulizer with a metered dose inhaler-spacer combination in acute obstructive pulmonary disease.

This study compared the effect of "standard" dose metaproterenol delivered by hand-held nebulizer (HHN) with two puffs of metaproterenol delivered by a metered dose inhaler (MDI) via a spacer (InspirEase) (MDI-spacer). Seventeen patients with an acute exacerbation of obstructive pulmonary disease were studied. Each patient received both MDI-spacer and HHN. Alternate patients were randomized to either MDI-spacer or HHN as initial treatment. Each subject was tested four different times: before and 30 minutes after the initial aerosol delivery technique, and before and 30 minutes after the alternate aerosol delivery technique. Testing consisted of spirometry, lung auscultation, and measurement of vital signs. The interval between treatments for all subjects was 2.96 +/- 0.27 hours (mean +/- SEM) and was not different for subjects who received therapy via MDI-spacer first or HHN first. The patient population studied demonstrated severe airways obstruction (baseline FEV1 33.3 percent predicted +/- 4.9 percent). There was a statistically significant improvement in FVC and FEV1 after metaproterenol delivered by HHN, but not after MDI-spacer. Metaproterenol treatment with HHN resulted in a greater improvement in FEV1 (p less than .05) than MDI-spacer when the data were reported as absolute improvement (0.19 +/- 0.05 L for HHN) vs (0.06 +/- 0.03 L for MDI-spacer) or reported as percent change (23.2 +/- 6.6 percent for HHN) vs (9.5 +/- 3.4 percent for MDI-spacer). Asthmatic patients exhibited a significantly greater (p less than 0.05) improvement in FEV1 after HHN (23.4 +/- 4.7 percent change) than after MDI-spacer (6.6 +/- 4.5 percent change). Patients with chronic obstructive pulmonary disease (COPD) exhibited a greater improvement in FVC (p less than 0.05) after HHN (25.2 +/- 6.7 percent change) than after MDI-spacer (5.8 +/- 4.7 percent change). We conclude that the "standard" dosage of metaproterenol delivered by HHN results in greater spirometric improvement in patients with acute obstructive pulmonary disease than the conventional dosage of metaproterenol delivered by MDI-spacer. It is likely that this reflects the fact that the recommended dose of metaproterenol delivered by MDI is too low and should be increased.

Acute Disease↗
PubMed1991

Mitochondria, oxygen and reperfusion damage.

Reperfusion of the ischaemic or hypoxic heart elicits a number of oxygen dependent processes such as cell lysis and Ca2+ uptake. It is known that the energisation of mitochondria, which requires oxygen, plays a key role in these processes and that the organelle actively sequesters Ca2+ under these circumstances. In this brief review we discuss how oxidants derived from mitochondrial electron transport may perturb mitochondrial calcium handling on reoxygenation of the hypoxic myocardium. In addition we show that the immunosuppressive agent cyclosporin has little or no effect on the oxygen dependent increase in total cell Ca2+ which occurs when hypoxic myocytes are reoxygenated. This result suggests that the Ca2+ dependent mitochondrial pore, which is known to function under conditions of oxidative stress, does not play a major role in the perturbation of Ca2+ homeostasis which occurs on reoxygenation of hypoxic hearts.

Adenosine Triphosphate↗
PubMed1990

Conservative management of cervical pregnancy with subsequent fertility.

The reported incidence of cervical pregnancies with subsequent fertility is extremely low. We report a case managed conservatively that allowed for future fertility, and ultimately the delivery of a viable infant at term. The conservative management and a review of the literature are discussed.

Adult↗
PubMed1990

Electrocardiographic manifestations of combined hypercalcemia and hypermagnesemia.

Near drowning in the Dead Sea is a potentially lethal accident; the swallowing of the salty water causes acute combined hypercalcemia and hypermagnesemia, and this, rather than aspiration, is considered to be the main pathogenetic fator. The authors reviewed the electrocardiographic data of 37 patients who nearly drowned in the Dead Sea. Common findings in the acute phase included P wave changes, tendency for prolongation of P-R interval, prolongation of QRS complex, infra-His conduction disturbances, tendency for broadening and inversion of T wave, and the appearance of a prominent U wave. Three patients had potentially lethal ventricular tachyarrhythmias. The QaTc interval (beginning of QRS complex to apex of T wave, corrected for heart rate), the expected QaTc calculated from calcium blood level (QaTce), and their difference (DQaTc), were measured or calculated. The QaTc was found within normal limits and did not change during recovery from the Dead Sea water poisoning. The DQaTc correlated significantly with serum magnesium level (p less than 0.001). This correlation signifies that hypermagnesemia normalizes the QaTc interval, which is usually shortened by isolated hypercalcemia. Combined hypercalcemia and hypermagnesemia can be caused by swallowing excessively salty water. The potential cardiac complications require strict monitoring and electrocardiographic follow up study.

Arrhythmias, Cardiac↗
PubMed1990

Interaction of a liver-specific factor with an enhancer 4.8 kilobases upstream of the phosphoenolpyruvate carboxykinase gene.

We have previously identified a series of five DNase-I hypersensitive (HS) sites within and around the rat phosphoenolpyruvate carboxykinase (PEPCK) gene. The far upstream region has now been sequenced, and the tissue-specific HS site has been mapped more precisely at 4,800 base pairs upstream of the transcription start site of the PEPCK gene. DNA fragments that include the HS site were cloned upstream of various promoters to test whether these regions modulate transcription of the chloramphenicol acetyltransferase reporter gene. Chloramphenicol acetyltransferase activity was enhanced when the DNA fragment encompassing the upstream HS site was linked to various lengths of the PEPCK promoter or to the heterologous simian virus 40 promoter. This upstream region in conjunction with the proximal promoter, which may contain a tissue-specific element, conferred maximum activation in H4IIE hepatoma cells, which express the endogenous PEPCK gene. When these experiments were performed in XC cells, in which the gene is not expressed, transcriptional activation by the upstream element was still significant. Evidence of a specific protein-DNA interaction, using DNA mobility shift and DNase I footprinting assays, was obtained only when using H4IIE cell nuclear extracts. Competition assay showed that the interacting factor may be similar or identical to the liver-specific factor HNF3. We suggest that this protein factor binds to DNA within the HS site and interacts with the proximal promoter region to control tissue-specific high-level expression of the PEPCK gene.

Animals↗
PubMed1989

Activity of bleomycin in iron- and copper-deficient cells.

Three models were used to examine the requirement of bleomycin (Blm) for iron (Fe) to carry out its antitumor or cytotoxic activity. Mice were made iron deficient by dietary means. Animals with depressed iron stores in liver and low plasma and ascites fluid iron supported Ehrlich tumor growth as well as mice maintained on a control diet. Bleomycin was equally effective against this tumor in iron-deficient mice as it was against the tumor in iron-sufficient controls. Likewise, nutrient copper deficiency did not change the efficacy of the drug. Ehrlich cells in culture were treated with a non-growth inhibiting concentration of the chelating agent, 1,10-phenanthroline before or during their exposure to bleomycin. Again, the treated cells were as sensitive to drug as controls, despite the fact that this ligand reduces cellular iron and zinc and can extract iron from Fe(II)Blm. Lastly, it was demonstrated that iron-depleted Euglena gracilis cells growing at reduced rates were as sensitive to growth inhibition by bleomycin as control cells.

Animals↗
PubMed1989

Hypoxia-reoxygenation induced increase in cellular Ca2+ in myocytes and perfused hearts: the role of mitochondria.

Reoxygenation of isolated rat cardiac myocytes following a period of hypoxia and substrate deprivation resulted in a 1.5-2-fold increase in the total Ca2+ content which could be inhibited by 1 microM antimycin A or ruthenium red (50% inhibition at 2.5 microM). This increase in Ca2+ content was not accompanied by any release of creatine kinase into the medium. Treatment of reoxygenated cells with digitonin also resulted in an antimycin A-sensitive increase in Ca2+ but this was inhibited by a lower concentration of ruthenium red (50% inhibition at 0.25 microM) and was associated with a substantial release of creatine kinase from the cells. It is concluded that the reoxygenation-stimulated increase in Ca2+ is dependent on functioning mitochondria and does not occur as a result of physical damage to the sarcolemma. In a parallel series of experiments, the effects of antimycin A and ruthenium red on the reoxygenation-induced increase in Ca2+ and release of cytosolic contents in the perfused heart (the oxygen paradox) were also investigated. As was observed with the isolated myocytes, each of the compounds significantly reduced the magnitude of the Ca2+ increase that occurred on reoxygenation: the compounds also reduced the extent of release of cell contents in the perfused heart. The implications of these results for the series of events occurring on reoxygenation of the hypoxic myocardium are discussed.

Animals↗
PubMed1989

Epidemiologic characteristics of scabies in the Israel Defense Force.

Scabies is not a notifiable disease in most countries. As a result the data on its epidemiologic characteristics are limited. In the Israel Defense Force, compulsory reporting of individual cases has been required for years, and in this study the epidemiology of the disease is examined for the years 1968-1988. A moderate epidemic occurred between 1969 and 1973, and was followed by a return to the previous low incidence. In 1982 a massive outbreak began, and peaked from 1985-1986. From 1987 to 1988, the incidence of infestation has markedly declined. A seasonal pattern of morbidity was evident during epidemic periods only; maximum incidence occurred during the winter months. These data are compared with those described in other countries and provide a more complete picture of the epidemiology of scabies based on individually reported cases.

Adolescent↗