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Biomedical subjects

D H Howard

Publications and source records attributed to D H Howard.

At least 19 recordsLinked to original sources
PubMed2002

Differences in pelvic floor area between African American and European American women.

OBJECTIVE: This study tests the null hypothesis that the size of the pelvic opening spanned by the pelvic floor is the same in African American and European American women. STUDY DESIGN: Forty African American female pelvises were age matched with 40 European American female pelvises from the Hamann-Todd collection at the Cleveland Museum of Natural History. The distances between the anchoring points of the pelvic floor to the bony pelvis (pubis anteriorly, ischial spines laterally, and inferior lateral angle of the sacrum posteriorly) were measured on each half of the pelvis. Measurements from left and right halves were averaged. The cross-sectional area of the pelvic floor was calculated from these dimensions. The bi-ischial line divided the total area into anterior and posterior pelvic floor areas. Analyses taking into account differences in stature by dividing individual dimensions by height were also performed. Group differences were compared with the Student t test and the Mann-Whitney rank sum test. RESULTS: African American women had a 5.1% smaller pelvic floor area than European American women (889.6 cm(2) vs 937.0 cm(2), 5.1% P =.037). This was attributable to a 10.4% smaller posterior area (365.3 cm(2) vs 407.6 cm(2), 10.4% P =.016), whereas the anterior areas were similar (524.3 cm(2) vs 529.3 cm(2), P =.61). The following measured distances were smaller in African American women: ischial spine to inferior sacral angle (5.4 cm vs 5.9 cm, P =.016) and bi-ischial diameter (10.0 cm vs 10.6 cm, P =.004). These distances remained significant after height was controlled. CONCLUSIONS: In African American women, the posterior pelvic floor area is 10.4% smaller than in European American women, resulting in a 5.1% smaller total pelvic floor area.

Adult↗
PubMed2001

Hope versus efficiency in organ allocation.

Previous ethical analyses of organ allocation policies have addressed the trade-off between giving organs to urgent versus non-urgent patients, overlooking the process by which patients become urgent in the first place. This article proposes three criteria for assessing the performance of organ allocation rules that take into account the dynamic nature of patient health. An equitable policy is one under which patients' probability of receiving a transplant is equal at listing. Efficiency captures the goal of giving organs to patients when their benefit from transplantation is greatest. Hope implies that patients should believe that they have a reasonable chance of receiving an organ. The sickest first policy, which is currently used to prioritize patients, is hope-preserving, but may be inefficient. As demand grows relative to supply, patients will only receive an organ once they have reached the sickest status category.

Health Care Rationing↗
PubMed2000

Hydroxamate siderophores of Histoplasma capsulatum.

The zoopathogenic fungus Histoplasma capsulatum, like other eukaryotic aerobic microorganisms, requires iron for growth. Under conditions of low iron availability, the fungus secretes hydroxamates that function as siderophores (iron chelators). The experiments to be reported were designed to gather further information on the hydroxamate siderophores of H. capsulatum. The fungus was grown in a synthetic medium deferrated with the cationic exchange resin Chelex 100. Siderophores were detected after 4 days of incubation at 37 degrees C in media containing 0.3 to 1.0 microM iron. The secretion was suppressed by 10 microM iron. The hydroxamates were purified by reverse-phase and size-exclusion chromatography. On the basis of ions observed during electrospray mass spectroscopy, five hydroxamate siderophores were tentatively identified: dimerum acid, acetyl dimerum acid, coprogen B, methyl coprogen B, and fusarinine (monomeric). A polyclonal antibody to dimerum acid was generated. This reagent cross-reacted with coprogen B and fusarinine. Thus, the antibody detects hydroxamates in all three families of siderophores excreted by H. capsulatum.

Antibodies↗
PubMed1999

Acquisition, transport, and storage of iron by pathogenic fungi.

Iron is required by most living systems. A great variety of means of acquisition, avenues of uptake, and methods of storage are used by pathogenic fungi to ensure a supply of the essential metal. Solubilization of insoluble iron polymers is the first step in iron assimilation. The two methods most commonly used by microorganisms for solubilization of iron are reduction and chelation. Reduction of ferric iron to ferrous iron by enzymatic or nonenzymatic means is a common mechanism among pathogenic yeasts. Under conditions of iron starvation, many fungi synthesize iron chelators known as siderophores. Two classes of compounds that function in iron gathering are commonly observed: hydroxamates and polycarboxylates. Two major responses to iron stress in fungi are a high-affinity ferric iron reductase and siderophore synthesis. Regulation of these two mechanisms at the molecular level has received attention. Uptake of siderophores is a diverse process, which varies among the different classes of compounds. Since free iron is toxic, it must be stored for further metabolic use. Polyphosphates, ferritins, and siderophores themselves have been described as storage molecules. The iron-gathering mechanisms used by a pathogen in an infected host are largely unknown and can only be posited on the basis of in vitro studies at present.

Animals↗
PubMed1998

Does diagnostic accuracy in mammography depend on radiologists' experience?

This study was designed to determine if radiologists' experience in mammography is associated with their performance in correctly interpreting mammograms. Study mammograms (n = 150) were chosen by stratified random sampling from those interpreted as normal, abnormal-benign or abnormal-suspicious for cancer, with oversampling of cancer cases. Ten radiologists who had varying amounts of experience were asked to read the mammograms. Associations between the levels of the radiologists' experience and their accuracy in reading mammograms were assessed. Significant associations (p < 0.05) were found between the frequency of immediate workup recommendations in cancer patients and obtaining feedback, total lifetime mammograms read, number of mammography continuing medical education (CME) credits, and practice type. Radiologists with more experience also noted smaller cancer lesions. However, these experience variables were also associated with increased workup recommendations in the noncancer patients (p < 0.10). In multivariable analysis, obtaining regular feedback and the total lifetime number of mammograms read were independently associate with the number of times immediate workup was recommended in the cancer cases. The most experienced radiologist had the highest sensitivity in diagnosing breast cancer. Further studies are needed to assess whether the current requirements of the U.S. Food and Drug Administration for radiologists who read mammograms ensure acceptable levels of accuracy.

Breast Neoplasms↗
PubMed1997

The impact of clinical history on mammographic interpretations.

OBJECTIVE: To determine whether mammographic interpretations are biased by the patient's clinical history. DESIGN: On 2 occasions, separated by a 5-month wash-out period, 10 radiologists read mammograms for the same 100 women, randomly divided into 2 groups of 50. For 1 group, the clinical history was supplied for the first reading and omitted (except for age) for the second reading. This sequence was reversed in the other group. In addition, 5 cases were shown a third time with a deliberately leading sham history. PATIENTS: Selected with stratified random sampling from 3 categories of diagnostic findings (64 had mammographic abnormalities) and from the definitive designation of breast cancer or no breast cancer (18 had breast cancer). MAIN OUTCOME MEASURES: Radiologists' diagnostic accuracy and directional changes in interpretations and recommendations between the 2 readings. RESULTS: The direction suggested by the history led to small but consistent changes in the interpretations. Overall diagnostic accuracy was not altered, but recommendations were affected for appropriate further diagnostic workup: an alerting history (eg, breast symptoms or family history of breast cancer) increased the number of workups recommended in patients without cancer (P=.01); and a nonalerting history led to fewer recommended workups in the cancer patients (P=.02). The direction of the sham histories led an average of 4 of the 10 radiologists to change previous diagnoses and an average of 1 radiologist to change a previous biopsy recommendation. CONCLUSIONS: Knowledge of the clinical history may alter a radiologist's level of diagnostic suspicion without improving performance in either diagnosis or management recommendations.

Adult↗
PubMed1997

Variation in assimilating functions occurs in spontaneous Candida albicans mutants having chromosomal alterations.

In this study, four clinical isolates and over 100 colony morphology mutants, previously derived spontaneously from strain 3153A during growth on glucose medium, were examined for their utilization of 21 carbon and 3 nitrogen sources at various growth temperatures. The results demonstrated extensive variability in the pattern of assimilation among the mutants and strains, including both the gain and loss of assimilating functions. The persistent alterations in assimilation patterns observed in sequentially produced subclones illustrated an extensive ability of C. albicans populations to constantly produce new combinations of assimilating functions. The variability among spontaneous mutants derived from a single strain explains the well documented variability among natural isolates. From these results we established a relationship between the previously documented broad spectrum of spontaneous chromosomal aberrations in these mutants to the expression of genes controlling the utilization of alternative carbon and nitrogen sources. The existence of cryptic genes, responsible for growth on alternative substrates, was previously deduced from the analysis of other mutants obtained as a response to the restrictive condition on media containing non-assimilating carbon sources. Thus, mutants with altered assimilation functions can arise either on glucose medium or by selection on restricted media. Extensive differences between the patterns of chromosomal aberrations and the distribution of correlated phenotypes in the two groups of mutants indicated that the same phenotypes may be produced by two different mechanisms involving the same or different genes.

Amino Acids↗
PubMed1995

Mechanisms of resistance to fungal infections.

In the past year, significant advances have been made in our understanding of immune defenses to fungal infections, which may be instrumental in the development of rational approaches to immunodiagnosis and therapy of these infections. The highlights have been the result of the direct application of advances in molecular biology and basic immunology, particularly cytokine research, leading to improved definition of fungal antigens and increased understanding of the roles of functionally distinct T-cell subsets, the activity of which may be either host-protective or disease-promoting.

Animals↗
PubMed1994

Variability in radiologists' interpretations of mammograms.

BACKGROUND: Despite the proved value of mammography in screening for breast cancer, its efficacy depends on radiologists' interpretations. The variability in such interpretations is not well understood. METHODS: Using a technique of stratified random sampling, we selected 150 mammograms obtained in 1987: 27 from women with histopathologically confirmed breast cancer and 123 from women with no evidence of breast cancer after three years of follow-up examinations. Ten radiologists, who were unaware of the diagnoses and research hypothesis, each interpreted the 150 mammograms. Disagreement was analyzed within pairs of the 10 radiologists, as well as for the group of 150 women as a whole. RESULTS: The diagnostic consistency between pairs of radiologists was moderate, with a median weighted percentage of agreement of 78 percent (weighted kappa, 0.47). The frequency of the radiologists' recommendations for an immediate workup ranged from 74 to 96 percent for mammograms from the women with cancer and from 11 to 65 percent for films from the women without cancer. A substantial disagreement in management recommendations--in which one radiologist recommended routine follow-up and another recommended a biopsy for the same patient--occurred in 3 percent of the pairwise comparisons but in 25 percent of the comparisons for the group of women as a whole. When two or more radiologists recommended a biopsy for the same patient, a disagreement in the stated location (right or left breast) occurred in 2 percent of the pairwise comparisons among the radiologists but in 9 percent of comparisons for the group of women as a whole. Because some disagreement was likely, given that 10 radiologists read each film, the pairwise comparison is a more conservative estimate of disagreement. CONCLUSIONS: Although mammography is of value in screening women for breast cancer, radiologists can differ, sometimes substantially, in their interpretations of mammograms and in their recommendations for management. Efforts to improve accuracy and reduce variability in interpretation may increase the effectiveness of mammography in detecting early breast cancers.

Breast Diseases↗
PubMed1994

Recombinant murine gamma interferon stimulates macrophages of the RAW cell line to inhibit intracellular growth of Histoplasma capsulatum.

Macrophages of the RAW 264.7 cell line, activated by pretreatment with recombinant murine gamma interferon, inhibit the intracellular growth of Histoplasma capsulatum. Growth inhibition occurred by a mechanism that was operative only when L-Arg metabolism was allowed to occur. When activated macrophages were cultured in the absence of L-Arg or in the presence of NG-monomethyl-L-Arg, a competitive inhibitor of L-Arg metabolism, activation to the antihistoplasma growth-inhibitory state did not occur. An increase in levels of NO2-, an end product of L-Arg metabolism, was detected only after activation of RAW 264.7 cells to the growth-inhibitory state. In contrast, only baseline levels of NO2- were detected when L-Arg was excluded or when NG-monomethyl-L-Arg was added to the culture medium. Nitric oxide (NO.), a reactive intermediate product of L-Arg metabolism, was implicated as the relevant antihistoplasma effector molecule. When H. capsulatum yeast cells were cultured for 24 to 28 h in a system designed to generate soluble NO., a dose-dependent cytotoxic effect was observed.

Animals↗
PubMed1994

Expression of inducible nitric oxide synthase by stimulated macrophages correlates with their antihistoplasma activity.

The antihistoplasma activity of recombinant murine gamma interferon (rMuIFN-gamma)-treated macrophages of the RAW 264.7 cell line depends on the generation of nitric oxide (NO.) from L-arginine. Macrophages of the P388D1 cell line treated with rMuIFN-gamma do not produce NO. or inhibit the intracellular growth of Histoplasma capsulatum. NO. is generated by the inducible enzyme nitric oxide synthase (iNOS) formed by stimulated macrophages. Northern (RNA) blot analysis of RAW 264.7 cells revealed the expression of iNOS mRNA after exposure to rMuIFN-gamma. In contrast, rMuIFN-gamma-treated P388D1 cells did not produce detectable levels of iNOS. These data suggest that the failure of P388D1 cells to generate NO. and to restrict the intracellular growth of H. capsulatum is due to a lack of expression of iNOS following treatment with rMuIFN-gamma.

Amino Acid Oxidoreductases↗
PubMed1994

Antihistoplasma effect of activated mouse splenic macrophages involves production of reactive nitrogen intermediates.

The mechanism by which recombinant murine gamma interferon (rMuIFN-gamma) and bacterial lipopolysaccharide (LPS) activate mouse resident splenic macrophages to inhibit the intracellular growth of the fungus Histoplasma capsulatum was examined. Growth inhibition depended on L-arginine metabolism. The growth inhibitory state normally induced by rMuIFN-gamma and LPS in resident splenic macrophages did not occur when the macrophages were cultured in the presence of NG-monomethyl-L-arginine, a competitive inhibitor of L-arginine metabolism. Resident splenic macrophages treated with rMuIFN-gamma and LPS produced nitrite (NO2-), an end product of L-arginine metabolism. When macrophages were cultured in the presence of NG-monomethyl-L-arginine together with rMuIFN-gamma and LPS, only baseline levels of NO2- were detected. Spleen cells from H. capsulatum-infected mice produced high levels of NO2- in culture. The production of NO2- correlated with in vitro inhibition of the intracellular growth of H. capsulatum. Anti-tumor necrosis factor alpha antibody did not block NO2- production by the immigrant splenic macrophages and did not abolish the antihistoplasma activity.

Animals↗
PubMed1994

Chromosomal alterations of Candida albicans are associated with the gain and loss of assimilating functions.

We have demonstrated that a normal laboratory strain of Candida albicans spontaneously produces mutants which acquire the ability to assimilate certain carbon sources that are not utilized by the parental strain. The examination of mutants acquiring the ability to utilize either sorbose or D-arabinose revealed a few additional phenotypic changes, including the gain and loss of the capacity to assimilate other carbon sources. The change of assimilation patterns resembled the polymorphic variation of assimilation patterns found among different wild-type strains of C. albicans. Most importantly, these sorbose- and D-arabinose-positive mutants were associated with chromosomal rearrangements, with each class of positive mutants having alterations of specific chromosomes. These findings demonstrated for the first time that chromosomal alterations in C. albicans are involved in genetic variation of fundamental functions of this asexual microorganism.

Arabinose↗
PubMed1993

Multiple chromosomal and phenotypic changes in spontaneous mutants of Candida albicans.

Previous studies have revealed the occurrence of multiple chromosomal alterations among spontaneous colony form mutants and clinical isolates of Candida albicans. In this report we show that such karyotype alterations are also seen in spontaneous and induced non-germinative mutants of the fungus. To determine if phenotypic changes other than colony form and microscopic morphology accompanied the rearrangements of the electrophoretic karyotype, we studied the following characteristics of the non-germinative and some of the colony form mutants: formation of pseudohyphae, chlamydospore production, germ tube formation, colony morphology, auxotrophy, growth at various temperatures, and colony morphology and pigment formation on selected media (bismuth sulphite and Phloxine B). We established that phenotypic and karyotypic variability among spontaneous, non-germinative mutants was no different than such variability among spontaneous colony form mutants. Thus, non-germination may represent another phenotypic consequence of genomic instability in C. albicans. The variability in different phenotypic attributes that occurred amongst the mutants was not associated with any given karyotype. Moreover, neither the low nor the high phenotypic variabilities observed were explained by the relatively high number of alterations in a limited number of chromosomes.

Candida albicans↗
PubMed1993

Gamma interferon cooperates with lipopolysaccharide to activate mouse splenic macrophages to an antihistoplasma state.

Inhibition of the intracellular growth of Histoplasma capsulatum by murine resident red pulp splenic macrophages was examined. Splenic macrophages, unlike resident peritoneal macrophages, required a prolonged preincubation (18 h) with recombinant murine gamma interferon (rMuIFN-gamma) for activation. To be fully activated, the splenic macrophages required incubation with rMuIFN-gamma in combination with 0.1 microgram of lipopolysaccharide (LPS) per ml. Splenic macrophages stimulated with rMuIFN-gamma, LPS, or rMuIFN-gamma and LPS produced tumor necrosis factor alpha (TNF-alpha), but recombinant murine TNF-alpha (rMuTNF-alpha) did not activate macrophages when used alone or as a second signal with rMuIFN-gamma. Anti-TNF-alpha antibody did not block IFN-gamma-LPS activation of splenic macrophages to any significant extent. One hundred micromolar ferrous sulfate antagonized IFN-gamma-LPS activation of splenic macrophages, indicating that iron was involved in the fungistatic activity of cytokine-stimulated phagocytes. Our results indicate that (i) splenic macrophages differ significantly from peritoneal macrophages in their requirements for activation and (ii) the mechanism by which splenic macrophages exert their antifungal effects involves iron.

Animals↗