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Biomedical subjects

K B Heller

Publications and source records attributed to K B Heller.

At least 19 recordsLinked to original sources
PubMed2000

Plasma levels of orally and subcutaneously administered pentoxifylline in rabbits.

In addition to its ability to improve microcirculation, pentoxifylline also has anti-tumor necrosis factor-alpha (TNF) actions which have prompted investigations into its potential efficacy in disease states involving elevated TNF levels. One such disease entity is AIDS where aberrant TNF seems to mediate axonal degeneration within thecentral nervous system. To this end, we have previously established a rabbit model of TNF-mediated axonal degeneration, and demonstrated that pentoxifylline attenuates this effect. Unfortunately, there has been to date only one limited report on the pharmacokinetics of pentoxifylline in rabbits. Therefore, the present report evaluates plasma levels of pentoxifylline and two of its primary metabolites through high-performance liquid chromatography after both the oral and subcutaneous administration of pentoxifylline. Our results indicate that in rabbits there is a very rapid absorption and metabolism of pentoxifylline after either oral or subcutaneous administration. In comparison with the mouse, the rabbit seems to absorb and metabolize pentoxifylline slower. In contrast to man, the rabbit had lower metabolite plasma levels than the parent drug itself.

Administration, Oral↗
PubMed1999

Immunolocalization of IL-1beta and IL-6 in optic nerves of patients with AIDS.

PURPOSE: Immunohistochemical procedures were employed to test the hypothesis that cytokines such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are involved in AIDS-related optic neuropathy and to determine the primary cell types involved. METHODS: Fixed sections of six human HIV-1 infected optic nerves were immunostained for the presence of IL-1beta and IL-6, using horseradish peroxidase and diaminobenzidine as markers. RESULTS: IL-1beta and IL-6 were found in astrocytes, macrophages, microglia, and endothelial cells. The great majority of astrocytes demonstrated strong immunoreactivity. CONCLUSION: Our findings support the premise that IL-1beta and IL-6 are significant pro-inflammatory mediators in AIDS-related optic neuropathy. This finding supports the theory that HIV infection stimulates the release of IL-1beta and IL-6 in astrocytes, macrophages, and endothelial cells in the optic nerve which ultimately leads to demyelination, astrogliosis, and neuronal destruction.

Acquired Immunodeficiency Syndrome↗
PubMed1998

A histopathologic and morphometric differentiation of nerves in optic nerve hypoplasia and Leber hereditary optic neuropathy.

OBJECTIVES: To characterize and quantitate optic nerve histopathologic and morphometric differences between optic nerve hypoplasia (ONH) as an early and congenital form of intrinsic axonal loss and Leber hereditary optic neuropathy (LHON) as a late and acquired form of intrinsic axonal loss. MATERIALS AND METHODS: Optic nerves from 3 sources were examined: a 42-year-old healthy woman (control), a 53-year-old woman with ONH diagnosed postmortem, and a 74-year-old woman with LHON. The optic nerves were processed, embedded, and stained with a 1% solution of paraphenylene diamine. Histopathologic and morphometric analyses were performed via light microscopy and a semiautomatic computer image analysis system. RESULTS: The ONH showed severe axonal depletion without degenerated profiles in an inferonasal sector, with only a small superotemporal sector having a near normal appearance. The LHON revealed general axonal depletion centrally, fibrocytic scarring, scattered "degeneration dust," and evidence of minimal inflammation, with residual axons limited to superior and temporal peripheral clusters. Morphometric analysis revealed total fiber populations of 98,000 in the ONH optic nerve and 48,000 in the LHON optic nerve, representing 90% and 95% reductions, respectively, compared with the control optic nerve (1.2 million fibers). CONCLUSIONS: Optic nerve hypoplasia and LHON present 2 distinguishable and distinctive patterns of nerve fiber distribution and axonal dropout. The lack of degenerated axons in ONH indicates that any axonal death probably occurred through apoptosis during development. In LHON, degenerated axons and minimal grade of inflammation were obvious, implicating a more "active" pathologic process. This study describes distinctions between these 2 optic neuropathies.

Adult↗
PubMed1998

The role of copper on ethambutol's antimicrobial action and implications for ethambutol-induced optic neuropathy.

The principal side effect of the antimycobacterial agent ethambutol (EMB) is an optic neuropathy with clinical features very similar to a mitochondrial hereditary optic neuropathy (Leber's). The mechanism of EMB-induced optic neuropathy may be EMB's chelation of copper, thereby precluding normal cytochrome c oxidase activity and mitochondrial metabolism in the optic nerve. Before attempting to use therapeutic copper to replenish endogenous stores in an attempt to preclude EMB-induced optic neuropathy, we wished to determine whether EMB is still effective against mycobacteria in the presence of copper. EMB and copper, alone and in combination, were tested against six strains of Mycobacterium tuberculosis and five strains of Mycobacterium avium using a radiometric broth macrodilution assay. Copper did not effect EMB's antimicrobial actions against either species of mycobacteria. This in vitro study suggests that if copper were given to patients to prevent EMB-induced optic neuropathy, it would not compromise EMB's bacteriostatic properties.

Antitubercular Agents↗
PubMed1998

Recurrent miscarriage: causes, evaluation, and treatment.

Recurrent miscarriage or fetal loss syndrome (also known as fetal wastage syndrome) is characterized by recurrent spontaneous abortion. There are many syndromes associated with recurrent fetal loss, including anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects. Many of these syndromes are treatable, leading to normal term pregnancy, if the clinician is astute and vigorously pursues a thorough evaluation of why the patient has suffered unexplained, spontaneous miscarriages. There is no uniform agreement on how many spontaneous, unexplained miscarriages are needed to diagnose recurrent fetal loss; we generally pursue an evaluation for causation if a women has had 2 or more such events. In this article, we discuss the common reasons for recurrent fetal loss, plus diagnostic procedures to consider in pinpointing the problem, such as cytogenetic studies, blood coagulation protein/platelet tests, hysterosalpingography, sonography, and magnetic resonance imaging. We also describe management strategies that often lead to successful pregnancy outcome when the underlying problem is addressed. For example, in the case of thrombotic defects, a common cause of recurrent fetal loss, we report a 100% success rate in achieving a normal-term delivery among women who took low-dose (81 mg/day) aspirin preconception followed by postconception low-dose (5000 units q 12 h) heparin.

Abortion, Habitual↗
PubMed1997

An immunohistochemical study of TNF-alpha in optic nerves from AIDS patients.

PURPOSE: Both in vitro and in vivo studies have implicated a role for tumor necrosis factor (TNF-alpha) in the pathology of demyelinating diseases. The purpose of this study was to address the hypothesis that TNF-alpha is a mediator of AIDS-related optic nerve injury and to determine the cell types involved in the proliferation of TNF-alpha in the AIDS optic nerve. METHODS: Ten optic nerves from seven patients with AIDS, and three from persons who were HIV negative were stained, using the indirect immunoperoxidase method. Six of the ten AIDS optic nerves were positive for cytomegalovirus (CMV), but the remainder did not have abnormal fundus findings. RESULTS: In all the optic nerves from AIDS patients with or without CMV retinitis, the vast majority of astrocytes stained strongly for TNF-alpha. Microglial cells (MPS-derived macrophages) varied from not staining to staining strongly positive for TNF-alpha. However, oligodendrocytes were not labeled positively for TNF-alpha. Some endothelial cells also stained for TNF-alpha. Examination of normal optic nerves and controls did not reveal any cell type that stained positively for TNF-alpha. CONCLUSIONS: The present study supports the contention that TNF-alpha is a major mediator of AIDS-associated optic neuropathy. HIV infection induces the production of TNF-alpha in macrophages and astrocytes, which probably causes demyelination and other neuronal damage.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Pentoxifylline suppression of TNF-alpha mediated axonal degeneration in the rabbit optic nerve.

In AIDS patients, axonal degeneration in the optic nerve occurs as a histopathological manifestation of the optic neuropathy. Direct infection of neurons by HIV is unlikely, and the axonal injury may be an indirect effect mediated by cytotoxic factors such as tumor necrosis factor-alpha (TNF-alpha) which we have previously demonstrated to cause axonal degeneration in the rabbit optic nerve. To test the suppressive effects of pentoxifylline in preventing TNF-alpha-mediated axonal degeneration, we applied pentoxifylline to an established rabbit model that demonstrates an AIDS-like optic neuropathy using intravitreal TNF-alpha injections. Degenerated axonal profiles were numerous in control rabbit optic nerve (mean 1879) and reduced in rabbits receiving the medium dose of pentoxifylline (300 mg PO BID, mean 439, p < 0.001) and the highest dose of pentoxifylline (600 mg PO BID, mean 120, p < 0.007). High dose pentoxifylline reduced TNF-alpha-induced axonal losses to less than 10% that seen without pentoxifylline pretreatment. Lower doses of pentoxifylline had a lesser but significant protective effect. Our results suggest that TNF-alpha-mediated axonal degeneration can be suppressed by high doses of pentoxifylline. Pentoxifylline may therefore be useful in AIDS patients demonstrating neurological or neuro-ophthalmological symptoms.

Animals↗
PubMed1990

Hereditary cranium bifidum and symmetric parietal foramina are the same entity.

Cranium bifidum is literally "cleft skull." Numerous reports describe the anatomy of this defect, and crude estimates of the population prevalence suggest it is a relatively infrequent occurrence. McKusick's catalog contains only one family with cranium bifidum but several familial reports of symmetrical parietal foramina. Available information indicates that cranium bifidum and symmetrical parietal foramina are inherited in an autosomal dominant fashion and occur in orientals, blacks, whites, and native Americans. Here we report on a family with serial radiographs that document ontogenic development of parietal foramina in late childhood and adulthood from apparent cranium bifidum and parietal foramina during infancy and early childhood. We conclude that these are the same entity, differentiated only by the time during life in which the defect is demonstrated.

Cranial Sutures↗
PubMed1990

Partial trisomy 18 with minimal anomalies: lack of correspondence between phenotypic manifestations and triplicated loci along chromosome 18.

A 2-year-old boy with microcephaly, developmental delay, and minimal anomalies was found to have an extra submetacentric chromosome equivalent to 18pter----q12. Review of the phenotypes produced by various triplicated 18 regions supports the hypothesis that no one chromosome 18 region is sufficient to produce the phenotype of trisomy 18. The mild phenotype of trisomy 18p, the variable phenotype of trisomy 18pter----q12, and the discontinuous phenotype of triplication for band 18q12 alone emphasizes that the contribution of triplicated loci to the phenotype is neither additive nor invariant.

Child, Preschool↗
PubMed1989

Enhancement of transbilayer mobility of a membrane lipid probe accompanies formation of membrane leaks during photodynamic treatment of erythrocytes.

In order to further characterize membrane alterations in human erythrocytes subjected to photodynamic treatment the passive transbilayer mobility of a phospholipid analogue was studied in cells illuminated for various lengths of time in the presence of the photosensitizer, aluminum chlorotetrasulfophthalocyanine. These measurements were combined with the characterization of the membrane leaks for polar solutes occurring under the same conditions with respect to their apparent size, number and ion selectivity. The time-dependent photodynamic enhancement of leaks for K+ as well as choline or erythritol was paralleled by a marked increase of the transbilayer reorientation rate of the amphiphilic lipid probe, palmitoyllysophosphatidylcholine from 0.05% min-1 in native cells to 0.32% min-1 after 60 min illumination. The asymmetric orientation of native phospholipids was not affected by this treatment. The leak permeability proved to be due to the formation of pores with apparent radii of about 0.45 nm after 60 min illumination, and of 0.75 nm after 90 min. The number of pores per cell was calculated to be less than 1, the pores are slightly cation-selective (PK/PCl approximately 3:1). Since photodynamic treatment did not induce lipid peroxidation under the prevailing experimental conditions, protein modification must be the primary cause of both, leak permeability and flip enhancement. Since it is also likely that the leak permeability arises from oxidation of intrinsic membrane proteins, the results raise the interesting possibility that oxidative alteration of intrinsic membrane proteins may lead to enhanced transbilayer mobility of lipids.

Cell Membrane Permeability↗
PubMed1987

Peroxidative membrane damage in human erythrocytes induced by a concerted action of iodoacetate, vanadate and ferricyanide.

Human erythrocytes incubated without substrate in the presence of iodoacetate (0.2 mM), vanadate (0.5 mM) and ferricyanide (5 mM) form aqueous membrane leaks of equivalent radii of 0.5-0.8 nm leading to complete colloid-osmotic lysis within 180 min. All three components are indispensable for the effect. Inosine but not glucose markedly enhances the rate of hemolysis. These effects are due to oxidative damage, as indicated by concomitant destruction of polyunsaturated fatty acids and suppression of both effects by radical scavengers. Hemoglobin is not oxidized under these conditions. GSH and membrane SH levels remain almost normal, and no crosslinking or irreversible aggregation of membrane proteins is observed. In the absence of O2 no membrane damage can be observed. It is proposed that radical formation originates from reduction of O2 by NADPH, analogous to processes described in microsomal membranes. NADH seems not to be involved, since leak formation occurs in spite of the blockage of NADH formation by iodoacetate. Vanadate and ferricyanide are probably required to amplify the peroxidative reaction sufficiently to overcome the cellular antioxidative capacity.

Erythrocyte Membrane↗
PubMed1987

Progressive oxidative membrane damage in erythrocytes after pulse treatment with t-butylhydroperoxide.

Development of membrane damage in erythrocytes in the presence of the radical-forming oxidant t-butylhydroperoxide is a well established fact (see, for example, Deuticke et al. (1986) Biochim. Biophys. Acta 854, 169-183). We have now demonstrated that a mere pulse treatment of erythrocytes (5-15 min) with this agent leads to subsequent development of progressive oxidative membrane damage in spite of the absence of exogenous oxidant. Damage comprises the occurrence of ion leakiness and subsequent colloid-osmotic lysis, enhancement of the transbilayer mobility of phospholipid analogues, and lipid peroxidation. There is, however, only very little concomitant oxidation and precipitation of hemoglobin. Defect formation is not due to oxidation of SH-groups nor is it directly related to lipid peroxidation, since it can be suppressed by thiourea without concommitant inhibition of lipid peroxidation. This 'spontaneous' development of membrane damage can be antagonized by metabolic substrates and by desferrioxamine, indicating that lack of protective metabolic resources as well as the presence of catalytic metal (iron) complexes are required for the development of membrane damage. This progressive development of injury in cells only temporarily exposed to an exogenous oxidant may be regarded as a more appropriate model for oxidative membrane damage under pathophysiological conditions in vivo than cells exposed to continuous damage by exogenous oxidants.

Erythrocyte Membrane↗
PubMed1986

Leak formation in human erythrocytes by the radical-forming oxidant t-butylhydroperoxide.

Oxidative damage of human erythrocytes by the lipoperoxide analogue, t-butylhydroperoxide, has been characterized with regard to ion-permeable leaks formed in the membrane. The formation of these leaks is not correlated with oxidative denaturation of hemoglobin and its precipitation at the membrane. It is also not related to the oxidation of membrane protein SH-groups. A close, although not simply proportional correlation could be demonstrated between leak formation and phospholipid peroxidation as monitored by occurrence of malondialdehyde. The two processes showed similar dependences on exposure time, concentration and temperature. Both were stimulated by the addition of azide as a ligand of ferric heme iron, and suppressed by the anti-oxidant, butylated hydroxytoluene. The leak pathway permits solute permeation with a temperature dependency of bulk diffusion in water and discriminates nonelectrolytes according to size. Discrimination among alkali chlorides corresponds to their free solution mobility; sodium halides are discriminated more effectively. Apparent radii of about 0.5-0.7 nm can be assigned to the defects, while apparent numbers of defects per cell as low as 0.1-0.2 suggest that the defects are dynamic in nature.

Azides↗
PubMed1984

Oxidative stress of human erythrocytes by iodate and periodate. Reversible formation of aqueous membrane pores due to SH-group oxidation.

Human erythrocytes were exposed to oxidative stress by iodate and periodate. Oxidation causes a time- and concentration-dependent increase in membrane permeability for hydrophilic molecules and ions. The induced leak discriminates nonelectrolytes on the basis of molecular size and exhibits a very low activation energy (Ea = 1-4 kcal.mol-1). These results are reconcilable with the formation of aqueous pores. The pore size was approximated to be between 0.45 and 0.6 nm. This increase in permeability is reversible upon treatment with dithioerythritol. Blocking of membrane thiol groups with N-ethylmaleimide protects the membranes against leak formation. The oxidation causes dithioerythritol-reversible modification of membrane proteins as indicated by the gel electrophoretic behavior. These modifications can also be suppressed by blocking the membrane thiol groups with N-ethylmaleimide. About half of the membrane methionine is oxidized to acid hydrolysis-stable derivatives. A fast saturating increase in diene conjugation was observed in whole cells but not in isolated membranes, with only minor degradation of fatty acid chains. The oxidation of cell membrane lipids as well as oxidation of cell surface carbohydrates are not involved in leak formation. Taken together with earlier data (Deuticke, B., Poser, B., Lütkemeier, P. and Haest, C.W.M. (1983) Biochim. Biophys. Acta 731, 196-210), these findings indicate that formation of disulfide bonds by different oxidative mechanisms results in leaks with similar properties.

Carbohydrates↗
PubMed1980

Substrate specificity and transport properties of the glycerol facilitator of Escherichia coli.

The specificity of the glycerol facilitator (glpF) of Escherichia coli was studied with an osmotic method. This transport system allowed the entry of polyols (glycerol and erythritol), pentitols, and hexitols. The analogous sugars were not transported. However, urea, glycine, and DL-glyceraldehyde could use this pathway to enter the cell. The glpF protein allowed the rapid efflux of preequilibrated xylitol. Glycerol surprisingly did not inhibit the uptake of xylitol, and xylitol only slightly reduced the uptake of glycerol. The observation and the insensitivity of the xylitol transport to low temperature suggest that the facilitator behaves as a membrane channel.

Bacterial Proteins↗