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Biomedical subjects

J W Harris

Publications and source records attributed to J W Harris.

At least 37 records · Page 2Linked to original sources
PubMed2001

Resistance to Varroa destructor (Mesostigmata: Varroidae) when mite-resistant queen honey bees (Hymenoptera: Apidae) were free-mated with unselected drones.

This study demonstrated (1) that honey bees, Apis mellifera L, can express a high level of resistance to Varroa destructor Anderson & Trueman when bees were selected for only one resistant trait (suppression of mite reproduction); and (2) that a significant level of mite-resistance was retained when these queens were free-mated with unselected drones. The test compared the growth of mite populations in colonies of bees that each received one of the following queens: (1) resistant--queens selected for suppression of mite reproduction and artificially inseminated in Baton Rouge with drones from similarly selected stocks; (2) resistant x control--resistant queens, as above, produced and free-mated to unselected drones by one of four commercial queen producers; and (3) control--commercial queens chosen by the same four queen producers and free-mated as above. All colonies started the test with approximately 0.9 kg of bees that were naturally infested with approximately 650 mites. Colonies with resistant x control queens ended the 115-d test period with significantly fewer mites than did colonies with control queens. This suggests that beekeepers can derive immediate benefit from mite-resistant queens that have been free-mated to unselected drones. Moreover, the production and distribution of these free-mated queens from many commercial sources may be an effective way to insert beneficial genes into our commercial population of honey bees without losing the genetic diversity and the useful beekeeping characteristics of this population.

Animals↗
PubMed1999

Leukemia arising out of paroxysmal nocturnal hemoglobinuria.

In paroxysmal nocturnal hemoglobinuria (PNH), one or more hematopoietic stem cells that are defective in GPI anchor assembly as a result of mutation in the PIG-A gene preferentially expand in the bone marrow and give rise to peripheral blood elements that are deficient in GPI anchored protein expression. According to current concepts, 5-15% of PNH patients develop leukocyte dyscrasias which invariably are acute myelogenous leukemia (AML). In this review, the literature from 1962 to the present is analyzed regarding the type of leukocyte dyscrasia, incidence, and cytogenetic features of the abnormal cells that have been reported. Among a total of 119 cases that are well-documented, 104 myeloid dyscrasias involving several categories in addition to AML, as well as 15 lymphoid dyscrasias are described. Of 1,760 patients in 15 series that contain 20 or more patients, 16 (1%) are reported as having developed "acute leukemia." However, of 288 listed as having died, 13 (5%) are recorded as having had "acute leukemia." In 32 of the patients with hematological dyscrasias where karyotypes were analyzed, 7 were found to be normal and 25 found to harbor various alterations with the +8 abnormality present in 8. In 5 of 7 instances evidence indicates that the dyscratic cell arises from the PNH clone. Processes potentially involved in the evolution of the dyscratic cells from PNH clones are discussed.

Female↗
PubMed1998

Sideroblastic anemias: variations on imprecision in diagnostic criteria, proposal for an extended classification of sideroblastic anemias.

Sideroblastic anemias are caused by a diversity of hereditary, congenital, or acquired disorders. Criteria used in describing sideroblastic anemias vary widely among standard medical textbooks and even so have been imprecisely applied in the literature. Recent discoveries concerning the basic pathophysiologic mechanisms involving the molecular biology of nuclear and mitochondrial DNA, erythroid ALA synthase (ALAS-2), and iron transport have made the classification of sideroblastic anemias very complex. We recommend a more precise evaluation and documentation of the components that characterize the sideroblastic abnormality and propose an extended classification of the sideroblastic anemias.

5-Aminolevulinate Synthetase↗
PubMed1997

2.5-million-year-old stone tools from Gona, Ethiopia.

The Oldowan Stone tool industry was named for 1.8-million-year-old (Myr) artefacts found near the bottom of Olduvai Gorge, Tanzania. Subsequent archaeological research in the Omo (Ethiopia) and Turkana (Kenya) also yielded stone tools dated to 2.3 Myr. Palaeoanthropological investigations in the Hadar region of the Awash Valley of Ethiopia, revealed Oldowan assemblages in the adjacent Gona River drainage. We conducted field work in the Gona study area of Ethiopia between 1992 and 1994 which resulted in additional archaeological discoveries as well as radioisotopic age control and a magnetic polarity stratigraphy of the Gona sequence. These occurrences are now securely dated between 2.6-2.5 Myr. The stone tools are thus the oldest known artefacts from anywhere in the world. The artefacts show surprisingly sophisticated control of stone fracture mechanics, equivalent to much younger Oldowan assemblages of Early Pleistocene age. This indicates an unexpectedly long period of technological stasis in the Oldowan.

Animals↗
PubMed1996

Who owns my body.

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Biomedical Research↗
PubMed1995

The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study.

We compared omeprazole and mephenytoin as probes for the CYP2C19 metabolic polymorphism. Single oral doses of omeprazole (20 mg) or mephenytoin (100 mg) were administered at least 1 week apart to 167 healthy volunteers. Mephenytoin metabolism was measured using the amount of 4'-hydroxymephenytoin and the S/R ratio of mephenytoin in an 8-hour urine collection. Omeprazole hydroxylation was measured using the ratio of omeprazole to 5'-hydroxyomeprazole in serum 2 hours after dosing. All three methods separated poor- or extensive-metabolizer phenotypes with complete concordance. Omeprazole hydroxylation correlated with the S/R ratio of mephenytoin in extensive metabolizers (r2 = 0.681; p < 0.001). Genotyping tests showed that six poor metabolizers of omeprazole were homozygous for a single base pair mutation in exon 5 of CYP2C19. These results support the hypothesis that omeprazole 5'-hydroxylation cosegregates with the CYP2C19 metabolic polymorphism.

Adult↗
PubMed1995

Comparative assessment of small intestinal and colonic permeability in HIV-infected homosexual men.

OBJECTIVES: To investigate both small and large intestinal permeability in HIV-positive subjects, and correlate variation in intestinal mucosal abnormality with immunological and nutritional markers of HIV disease. METHODS: Small and large intestinal permeability studies were performed in 14 HIV-seropositive patients and eight healthy men. Eight out of the 14 patients had diarrhoea and all subjects were negative for enteropathogens. Small intestinal permeability was determined using the lactulose-mannitol test and large intestinal permeability using the colonic absorption of 51Cr-EDTA. In addition, CD4 cell count, beta 2-microglobulin, C-reactive protein estimation and anthropometry were carried out in all subjects. RESULTS: HIV-seropositive subjects had higher lactulose-mannitol ratios (LMR; 0.084 +/- 0.007 versus 0.013 +/- 0.0008) and lower 51Cr activity (1.986 +/- 0.066 versus 3.115 +/- 0.560) than controls (P < 0.0004 and P < 0.05, respectively). Colonic uptake of 51Cr-EDTA was no different between subjects with and those without diarrhoea (2.04 +/- 0.124 versus 1.92 +/- 0.143, P > 0.05). A negative correlation was found between LMR and 51Cr-EDTA, but only for patients with diarrhoea (r = -0.81; P = 0.015). CONCLUSION: Regional variation affecting intestinal absorptive function occurs in patients with HIV-related diarrhoea and is characterized by increased LMR and reduced colonic uptake of 51Cr-EDTA. The pathogenesis and clinical significance of such changes are unknown.

AIDS-Related Opportunistic Infections↗
PubMed1995

A review of recent developments affecting COBRA rights.

Due to the high cost of health care claims and COBRA's status as remedial legislation, COBRA has generated a significant amount of litigation in recent years. While the early COBRA decisions tended to broaden the law in order to provide a remedy to an otherwise uninsured qualified beneficiary, the recent trend in the case law has been to limit the expansion of COBRA rights based on a narrower construction of the statute. Even so, COBRA still represents a legal minefield for employers. As a result, a careful employer will minimize its exposure by monitoring changes in the law and its interpretation and making appropriate modifications to its COBRA documentation and administration. This article discusses some of the more significant recent changes in the law affecting qualified beneficiaries' COBRA rights--and therefore, employers' exposure.

Employment↗
PubMed1995

Tuberculous pancreatic abscess: an unusual manifestation of HIV infection.

Pancreatic tuberculosis is unusual occurring in only 2.7% of autopsy studies of persons with miliary disease. Reports of focal pancreatic tuberculosis are rare, even in patients with the acquired immunodeficiency syndrome (AIDS) in whom abdominal tuberculosis is a frequent feature. We describe two patients infected with the human immunodeficiency virus (HIV) who developed tuberculous pancreatic abscesses. In both this was their AIDS-defining illness.

AIDS-Related Opportunistic Infections↗
PubMed1994

Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8.

The principal taxol biotransformation reaction of humans and of human hepatic in vitro preparations is 6 alpha-hydroxylation of the taxane ring, but a separate, minor hydroxylation pathway (metabolite B formation) also exists. Taxol metabolism was studied using membrane fractions from Hep G2 cells infected with recombinant vaccinia viruses that contain complementary DNAs encoding several human cytochrome P450 enzymes. Only P450 2C8 formed detectable 6 alpha-hydroxytaxol. Metabolite B formation was catalyzed by complementary DNA-expressed 3A3 and 3A4, but not by 3A5. Each P450 3A preparation catalyzed felodipine oxidation. The apparent Km and Vmax values for taxol 6 alpha-hydroxylation were 5.4 +/- 1.0 microM and 30 +/- 1.5 nmol/min/nmol P450, respectively, for complementary DNA-expressed P450 2C8; the values were 4.0 +/- 1.0 microM and 0.87 +/- 0.06 nmol/min/mg protein, respectively, for human hepatic microsomes. The inhibition of 6 alpha-hydroxytaxol formation by quercetin was competitive with an apparent Ki of 1.3 or 1.1 microM with 2C8 or hepatic microsomes, respectively; retinoic acid was inhibitory, showing an apparent Ki of 27 microM with hepatic microsomes; inhibition by tolbutamide was complex, weak, and unlikely to be clinically relevant. The correlation between hepatic 2C8 protein content and 6 alpha-hydroxytaxol formation was high (r2 = 0.82), while the correlation with 2C9 content was low (r2 = 0.38). These data show that human biotransformation routes of taxol result from catalysis by specific enzymes of two P450 families and that taxol 6 alpha-hydroxylation is a useful indicator of P450 2C8 activity in human hepatic microsomes.

Biotransformation↗
PubMed1994

Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.

BACKGROUND: To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. METHODS: At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. RESULTS: The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P < 0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun chelation therapy later and used less deferoxamine in relation to their transfusional iron load (P < 0.001). CONCLUSIONS: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.

Adolescent↗
PubMed1994

Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme.

Incubation of taxol with human hepatic microsomal fractions or freshly isolated human liver slices yields three metabolite high performance liquid chromatography peaks, metabolite A, metabolite B, and 6 alpha-hydroxytaxol. These metabolites are formed in patients given taxol, with 6 alpha-hydroxytaxol formation representing the principal biotransformation pathway. Metabolite B and 6 alpha-hydroxytaxol are shown to be products of different, highly regioselective cytochrome P-450 (P450) enzymes, while metabolite A results from stepwise metabolism by each of these enzymes. Correlation of metabolite B formation with P450 3A markers was good (r2 = 0.91-0.94), but the correlation of 6 alpha-hydroxytaxol formation with markers for several P450 enzymes was poor. Chemical inhibitors that selectively inhibited metabolite B formation (troleandomycin, cyclosporine), that selectively inhibited 6 alpha-hydroxytaxol formation (naringenin, quercetin), or that nonselectively inhibited both pathways (felodipine, ketoconazole) were found. Metabolite B formation was selectively reduced by anti-P450 3A4 antibodies. Expressed human P450 3A4 preparations were efficient catalysts of metabolite B formation; no expressed P450 preparation tested showed a capacity for catalyzing taxane 6 alpha-hydroxylation reactions. The combined results of several experimental approaches show that P450 3A4 is the major catalyst of metabolite B formation and that the identity of the P450 enzyme or enzymes responsible for 6 alpha-hydroxytaxol formation cannot be assigned with certainty.

Biotransformation↗
PubMed1994

Isolation, structural determination, and biological activity of 6 alpha-hydroxytaxol, the principal human metabolite of taxol.

The principal biotransformation product of taxol was found to be identical for human hepatic microsomes, human liver slices, and patient bile samples. We have isolated this metabolite from the bile of a patient given taxol, and we report its structure and its cytotoxicity relative to taxol. The NMR and SIMS data presented here indicate that, in humans, taxol is regiospecifically hydroxylated at the 6-position on the taxane ring and that this hydroxyl is stereospecifically placed trans to the hydroxyl at position 7, yielding 6 alpha-hydroxytaxol. This metabolite is apparently not formed in rats. Tests of the growth inhibition potential of 6 alpha-hydroxytaxol versus taxol in two human tumor cell lines showed that the metabolite was approximately 30-fold less cytotoxic than taxol. Thus the cytochrome P-450-mediated biotransformation of taxol to 6 alpha-hydroxytaxol can be classified as a detoxification reaction.

Bile↗
PubMed1994

Inhibition of hemoglobin S polymerization by N-terminal band 3 peptides: new class of inhibitors: solubility studies.

Two synthetic peptides corresponding to the N-terminal amino acids (AA) of band 3 were designed to inhibit deoxyhemoglobin S (deoxy S) polymerization through two different mechanisms. Peptide I, an N:1-15AA fragment, was employed to bind to the 2,3-diphosphoglycerate (2,3-DPG) receptor locus of single deoxy S molecules with 5-7 AA extending internally and the remaining 10-8 AA projecting external to hemoglobin (Hb) S, thereby inhibiting polymerization by steric hindrance. Peptide II consisted of two N:1-8AA + K (lysine) sequences linked by a coupler through the lysine, and it was employed to bind to the 2,3-DPG loci of two deoxy S molecules, tethering them together to form "binary hemoglobin complexes" incapable of entering the polymer chains. Decreased polymerization would result from reduction in effective concentration of deoxy S. Binding of peptides to the 2,3-DPG receptor loci was demonstrated by a progressive rightward shift in the hemoglobin oxygen binding curves as a function of increasing peptide concentrations. Inhibition of deoxy S polymerization was studied by equilibrium solubility measurements of purified, stripped solutions of Hb S. Physiologically significant inhibition was demonstrated for both peptides with near-maximum increases in solubility achieved by Peptide II at 1:1 peptide:Hb S ratios. These peptides represent a new class of inhibitors of deoxy S polymerization.

Amino Acid Sequence↗
PubMed1993

Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major.

To examine the relationship between hepatic iron stores and plasma ferritin concentration in individuals treated with red cell transfusion and iron chelation therapy, 37 patients with sickle cell anemia and 74 patients with thalassemia major were studied. In each patient, hepatic iron stores were measured by an independently validated noninvasive magnetic method, and plasma ferritin was determined by immunoassay. The correlation between hepatic iron and plasma ferritin was significant both in patients with sickle cell anemia (R = 0.75, P < 0.0001) and in those with thalassemia major (R = 0.76, P < 0.0001). Regression analysis showed no significant difference between the two groups in the linear relationships between hepatic iron stores and plasma ferritin. Considering all 111 transfused patients as a group, the coefficient of correlation between hepatic iron stores and plasma ferritin was highly significant (R = 0.76, P < 0.0001). Regression analysis found that variation in body iron stores, as assessed by magnetic determinations of hepatic iron, accounted for only approximately 57% of the variation in plasma ferritin, suggesting that the remainder was the result of other factors, such as hemolysis, ineffective erythropoiesis, ascorbate deficiency, inflammation, and liver disease. The 95% prediction intervals for hepatic iron concentration, given the plasma ferritin, were so broad as to make a single determination of plasma ferritin an unreliable predictor of body iron stores. Variability resulting from factors other than iron status limits the clinical usefulness of the plasma ferritin concentration as a predictor of body iron stores.

Adolescent↗
PubMed1993

Band 3 peptides inhibit deoxy S polymerization: viscosity studies.

We have previously obtained evidence that N-terminal band 3 peptides inhibited deoxyhemoglobin S (deoxy S) polymerization as determined by equilibrium solubility assays. An N:1-15AA fragment binds to the 2,3-diphosphoglycerate (2,3-DPG) receptor locus of deoxy S with five to seven amino acids (AA) extending internally, while ten to eight AA remained external to deoxy S and inhibited polymerization by steric hindrance. A true mirror-image peptide, corresponding to two N:1-8AA + lysine (K) linked by coupler, binds to the 2,3-DPG loci of two deoxy S molecules, tethering them together to form "binary complexes" incapable of entering the polymer chains. The reduction in the concentration of deoxy S available for extended chain formation decreased polymerization. We now report time:viscosity profiles of the sol-gel transformation of purified solutions of deoxy S with and without peptides and studies of the gel solidity at equilibrium. Samples with peptides had longer lag times than controls of similar deoxy S concentrations. The mirror-image peptide was a more effective inhibitor than the N:1-15AA peptide. When the mirror-image peptide was present in peptide:hemoglobin molar ratios of 0.25-1:1, the increases in lag time were equivalent to decreasing the deoxy S concentrations by 15-25%, comparable to projected major therapeutic effects. Gel solidity, determined by yield temperature, was less in the sample with mirror-image peptide compared to control. These results support the proposed mechanisms of inhibition of deoxy S polymerization by band 3 peptides.

Amino Acid Sequence↗