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Biomedical subjects

M Holmes

Publications and source records attributed to M Holmes.

At least 19 recordsLinked to original sources
PubMed1992

A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021.

BACKGROUND: Pneumocystis carinii pneumonia (PCP) continues to be the most common index diagnosis in the acquired immunodeficiency syndrome (AIDS), but it is not clear which of several available agents is the most effective in preventing a recurrence of PCP. METHODS: We conducted a comparative, open-label trial in 310 adults with AIDS who had recently recovered from an initial episode of PCP and had no treatment-limiting toxic effects of trimethoprim-sulfamethoxazole or pentamidine. All the patients were treated with zidovudine and were randomly assigned to receive either 800 mg of sulfamethoxazole and 160 mg of trimethoprim once daily or 300 mg of aerosolized pentamidine administered every four weeks by jet nebulizer. The participants were followed for a median of 17.4 months. RESULTS: In the trimethoprim-sulfamethoxazole group (n = 154) there were 14 recurrences of PCP, as compared with 36 recurrences (including 1 extrapulmonary recurrence) in the aerosolized-pentamidine group (n = 156). The estimated recurrence rates at 18 months were 11.4 percent with trimethoprim-sulfamethoxazole and 27.6 percent with pentamidine (P < 0.001). The risk of a recurrence (adjusted for initial CD4 cell count) was 3.25 times higher in the pentamidine group (P < 0.001, 95 percent confidence interval, 1.72 to 6.16). There were no significant differences between the groups in survival or in hematologic or hepatic toxicity. Crossovers from trimethoprim-sulfamethoxazole to aerosolized pentamidine were more common than the reverse (27 vs. 4 percent), partly because of the study protocols for the management of leukopenia. There were 19 serious bacterial infections in the trimethoprim-sulfamethoxazole group and 38 in the pentamidine group. The time to a first bacterial infection was significantly greater for those assigned to trimethoprim-sulfamethoxazole (P = 0.017). CONCLUSIONS: In patients with AIDS who are receiving zidovudine, trimethoprim-sulfamethoxazole is more effective than aerosolized pentamidine in conventional doses for the prevention of recurrent pneumocystis infection.

AIDS-Related Opportunistic Infections↗
PubMed1992

Antitumor effects of a bispecific antibody targeting CA19-9 antigen and CD16.

Bispecific murine monoclonal antibodies that target tumor and Fc gamma RIII (CD16) can promote relevant tumor lysis by large granular lymphocytes. For these antibodies to be clinically useful, their properties should be maintained in vivo, where competing human immunoglobulin, shed target antigen, and shed CD16 may be encountered. At a minimum, bispecific antibody antitumor effects should be preserved in whole blood. Furthermore, potentiation of tumor lysis should be reflected by demonstrating the ability of bispecific antibody-retargeted effector cells to infiltrate and mediate lysis of organized tumor. If these characteristics are demonstrated, and there is evidence of in vivo efficacy of bispecific antibody-based therapy in a relevant animal model, further clinical development of such antibodies would be warranted. In this report the ability of CL158 bispecific antibody supernatants to mediate lysis of SW948 tumor growing in monolayer is shown to be preserved in the presence of interleukin 2-activated whole blood. When SW948 cells were grown in vitro as multicellular human tumor spheroids, incubation with interleukin 2-activated lymphocytes (LAK cells) and CL158 led to structural and widespread necrosis. This was dependent on CL158 and resistant to competition by pooled human immunoglobulin or interleukin 2-exposed whole blood. These effects were not promoted by the monospecific antibodies produced by the parent clones of CL158 and were not observed when the IgG2a variant of CA19-9 antibody, which mediates conventional antibody-dependent cellular cytotoxicity, was used instead of its bispecific derivative. To examine the efficacy of bispecific antibody-based treatments on in vivo tumor, scid mice bearing early s.c. SW948 xenografts were treated with interleukin 2 for 5 consecutive days, supplemented by three i.v. injections of 10(7) human LAK cells and various antibodies. Treatment of mice bearing SW948 tumors with LAK cells did not retard tumor growth, but when CL158 was added, significant delays in tumor growth were observed. Tumor growth delay required treatment with both LAK cells and the bispecific antibody. Treatment with the IgG2a variant of CA19-9 antibody, alone or with LAK cells, had no effects on tumor growth. Although the mechanisms of these antitumor effects require further study, it is clear that human LAK cell treatment of animals bearing early, established s.c. tumors is enhanced by the addition of bispecific antibodies with relevant binding characteristics. When compared with the IgG2a isotype variant of CA19-9 monoclonal antibody, this bispecific antibody offers the advantages of preservation of activity in physiological conditions, infiltration and disruption of organized tumor in vitro, and antitumor effects in a relevant xenograft model.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1992

Model of the dynamics of receptor potential in a mechanoreceptor.

Mechanoreceptors are physiological units that convert mechanical stimuli to neural responses. An important one in the skin is the Pacinian corpuscle, which consists of a nerve ending surrounded by a capsule that is made up of alternating layers of fluid and elastic shells. In this paper a capsule model is coupled to a model for the dendrite via a variable representing the hoop strain imposed by the capsule on the receptor membrane of the dendrite. The transient behavior of the receptor potential due to step and periodic displacement-type stimuli imposed on the outer membrane of the capsule is investigated, and the results are compared to those of analogous experiments. The model is used to develop hypotheses concerning the role of the capsule as a filter for mechanical stimuli.

Animals↗
PubMed1992

Sensory nerves in adult rats regenerate and restore sensory function to the skin independently of endogenous NGF.

We have investigated the possible roles of NGF, and of impulse activity, in the regeneration of sensory nerves. Unexpectedly, the ability of crushed axons to regrow and to restore functional recovery of three sensory modalities in adult rat skin (A alpha-mediated touch, A delta-mediated mechanonociception, and C-fiber-mediated heat nociception) was totally unaffected by anti-NGF treatment. This finding applied even when the anti-NGF dosage was almost eight times that which entirely blocked collateral sprouting of the undamaged axons of both classes of nociceptive nerves (the A alpha-axons do not sprout in adult animals). In the same anti-NGF-treated animal, regeneration would proceed normally on the one side, while collateral sprouting was prevented on the other. Light microscopic and EM examination revealed that in the denervated skin the regenerating axons utilized the same dermal perineurial pathways followed by collaterally sprouting axons. Regeneration within these antibody-accessible pathways progressed normally during anti-NGF treatment, extending 1-2 cm beyond the former field borders, that is, into territory whose invasion by collaterally sprouting axons was totally blocked. The blood-nerve barrier is absent within the degenerating peripheral nerve trunk, a putative NGF source for regenerating fibers but not for sprouting ones. The NGF-independent regeneration was also found to be unaffected when putative spinal cord sources of NGF were eliminated by dorsal root excision. Anti-NGF treatment also failed to block regeneration across 4 mm excision gaps in the nerve trunk. The daily anti-NGF regime continued to be effective for at least 8 weeks, at which time newly evoked collateral sprouting could still be blocked. Exogenous NGF, in doses that evoke collateral sprouting de novo in normal skin, failed to influence regeneration. Finally, an electrical stimulus regime, which markedly reduces the latency of collateral sprouting, failed to affect the time to arrival of regenerating axons at the skin, or the rate of their arborization in it. We conclude that, in striking contrast to their collateral sprouting, the regeneration of nociceptive axons occurs independently of endogenous NGF and is unaffected by impulse activity. These findings further support the proposal that these two growth behaviors have basically different biological functions in the organism.

Animals↗
PubMed1992

Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat.

We have investigated the co-involvement of endogenous NGF and impulses in the collateral sprouting of cutaneous sensory nerves in adult rats, specifically the A delta-axons involved in mechanonociception and the C-fibers that mediate heat nociception. Their collateral sprouting was measured by the progressive expansion, respectively, of the behaviorally defined "pinch" and "heat" fields into surrounding denervated skin (the light-touch A alpha-fibers do not sprout in adult mammals). The expansions of such "isolated" fields were totally prevented in animals injected daily with anti-NGF serum, but developed normally after treatment was discontinued. Light microscopic and EM examination of the skin confirmed that the effect of the anti-NGF treatment was attributable to its prevention of collateral sprouting. Initiation of treatment would also rapidly halt sprouting already in progress. Finally, intradermal injections of purified NGF protein would not only increase the rate of nociceptive fiber sprouting, but also evoke sprouting de novo within normally innervated skin (again, A alpha-axons were unaffected). We conclude that the collateral sprouting of intact nociceptive nerves following partial denervation of skin is entirely dependent on endogenous NGF. The observed latency of this sprouting was 10-12 d; we estimate, however, that at least 2 d of field expansion is required for its reliable detection. Thus, about 8-10 d are required for NGF levels in the skin to rise to effective levels, and for the neurons to respond and initiate sprouting. From indirect findings, the NGF component of this sprouting latency appears to be about 2 d. In accord with earlier findings, the remaining "initiation time" was reduced by 5-6 d if the neurons were briefly excited, even 2 d prior to the isolation of their fields. Unexpectedly, this phenomenon of "precocious sprouting" requires that endogenous NGF be available; the sprouting latency reverted to normal values when the conditioning impulses were evoked during a 2 d anti-NGF "umbrella." In contrast to the impulse-sensitive neuronal mechanisms involved in the initiation of sprouting, those underlying the sprouting rate were unaffected by nerve activity and were entirely dependent on the level of endogenous NGF. We suggest that interactions like that revealed in these studies between a sprouting agent and impulses that seem to prime the neuron's response to it contribute to plasticity within the nervous system.

Animals↗
PubMed1991

Capturing and clustering women's judgment policies: the case of hormonal therapy for menopause.

Two hundred sixty-five women estimated the likelihood that they would take estrogen plus progestin to alleviate menopausal symptoms when faced with hypothetical cases varying in degree of hot flashes and risk of osteoporosis and cancer. Clustering of their judgment policies revealed four groups of women with respect to their approach to this decision. These groups of women were significantly different from each other on educational level, perceived experience of stress, and attitudes toward menopause and use of medications. Willingness to take hormonal therapy across all cases was related to attitudes about, and knowledge of, menstruation, perceived stress, mother's experience with menstrual problems, severity of symptoms, and use of vitamins. While there have been previous attempts to cluster rater policies, the current study represents a novel attempt to understand the differences between people who appear to have different policies about a decision problem, in this case, whether or not to take hormone therapy to counter menopausal symptoms.

Attitude↗
PubMed1991

Intussusception in cystic fibrosis.

Two cases of acute intussusception in older children with cystic fibrosis are reported. Both cases presented with symptoms and signs consistent with meconium ileus equivalent, which delayed the final diagnosis. Both cases required abdominal surgery but made full and uneventful recoveries.

Cystic Fibrosis↗
PubMed1991

Human papillomavirus, gonorrhea, syphilis, and cervical dysplasia in jailed women.

We assessed the prevalence of human papillomavirus (HPV) by cervicovaginal lavage and Southern blot and inquired about behavioral risk factors for cervical disease and sexually transmitted diseases by interview in 114 female detainees at a large New York City jail. Of the women screened, 8% had abnormal Pap smears, 35% had HPV, 7% had gonorrhea, and 22% had serologic syphilis. Given the high rates of HPV infection and cervical cytology, Pap smears should be a routine intake procedure for incarcerated women.

Adult↗
PubMed1991

Characterization of the molecular basis of the alpha 1-antitrypsin F allele.

alpha 1-Antitrypsin (alpha 1AT), the major serum inhibitor of neutrophil elastase, is a highly polymorphic serum protein associated with characteristic isoelectric-focusing (IEF) patterns for most variants. To characterize the molecular basis of the anodal F variant, the DNA sequence of the coding exons of an FZ individual was determined. The F allele differed from the normal M1(Val213) alpha 1AT allele by a single nucleotide transversion of cytosine to thymidine, which results in the amino acid substitution Arg223 CGT----Cys TGT. Inheritance of the F mutation was confirmed by family analysis using allele-specific amplification. In the context that the normal alpha 1AT molecule has only one cysteine residue, a mutation resulting in the addition of a second cysteine may influence the three-dimensional form of the protein and/or permit interaction with other plasma proteins with free-SH groups and may be responsible for the observation that the major F alpha 1AT bands often migrate as doublets in IEF gels.

Alleles↗
PubMed1990

Women's use of information regarding hormone replacement therapy.

For perimenopausal women, an important decision is whether or not to use hormone replacement therapy (HRT). The decision is complex because HRT involves judgment in weighing gains and losses related to physiological risk. Gains involve relief of hot flashes and prevention of osteoporosis; losses include cancer mortality and side effects of medication. A policy-capturing study of 283 perimenopausal women showed that the factor of most frequent concern was relief of hot flashes. Cluster analyses identified four major groups. Group 4 had an n of 9 and the lowest R2, making interpretation of data questionable. The largest group responded to hot flashes alone; the second to hot flashes and osteoporosis; and the third to hot flashes, somewhat to osteoporosis, but also to side effects of estrogen/progestin therapy. Results indicate nursing interventions should anticipate differences in women's concerns and tailor counseling appropriately.

Climacteric↗
PubMed1989

Informal versus formal supports for impaired elderly people: determinants of choice on Israeli kibbutzim.

Among 269 functionally impaired elderly people residing on 53 Israeli kibbutzim, those cared for principally by informal caregivers were compared with those cared for principally by formal caregivers. The major findings were that the variables differentiating between primary reliance on formal versus informal care are similar to those that have been found in other studies, and that the availability of formal resources was not accompanied by withdrawal of informal supports.

Aged↗
PubMed1989

Factors relating to institutional risk among elderly members of Israeli kibbutzim.

Characteristics of 269 functionally impaired elderly persons and their primary caregivers were examined in relation to long-term care planning. Contrary to expectation, there were no differences in rates of institutional risk between those elderly residents of Israeli kibbutzim cared for primarily by formal caregivers and cared for by informal caregivers. Lack of informal caregivers emerged as an important risk factor for institutional risk, even in the service-rich environment of kibbutzim.

Aged↗
PubMed1989

Characterization of the intracellular mechanism causing the alpha-1-antitrypsin Nullgranite falls deficiency state.

The alpha-1-antitrypsin (alpha 1AT) Null alleles are those for which no alpha 1AT can be detected in the serum attributable to the gene. The intracellular consequences of the various substitution, deletion, and insertion mutations causing the Null state can be categorized into two groups: those associated with detectable alpha 1AT mRNA transcripts and those with no detectable alpha 1AT mRNA transcripts. To classify the intracellular mechanism associated with the Nullgranite falls allele (Tyr160 TAC, C deletion, 5' frameshift----Stop160 TAG), a Nullgranite falls homozygote was evaluated. Genotypic diagnosis of the Nullgranite falls homozygous state was determined using the polymerase chain reaction and Nullgranite falls specific primers. Total cellular RNA extracted from alveolar macrophages of the index case was compared to that from a normal M1 homozygote for the presence of alpha 1AT mRNA transcripts using Northern blot analysis and hybridization to either a 32P-labeled full length alpha 1AT cDNA probe or (as a control) a 32P-labeled gamma-actin cDNA probe. Although the macrophages of both the Nullgranite falls homozygote and the normal showed gamma-actin mRNA transcripts in comparable amounts, Nullgranite falls macrophages contained no detectable alpha 1AT mRNA transcripts whereas the normal had the expected 1.8 kb alpha 1AT mRNA transcripts. Thus, the Nullgranite falls allele can be classified along with Nullbellingham as a Null allele associated with no detectable alpha 1AT mRNA. These observations highlight the marked heterogeneity in the molecular processes causing the Null state, despite an identical phenotype at the clinical level.

Adult↗