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Biomedical subjects

M Prout

Publications and source records attributed to M Prout.

At least 19 recordsLinked to original sources
PubMed2001

CD80 costimulation is required for Th2 cell cytokine production but not for antigen-specific accumulation and migration into the lung.

The CD28 ligands CD80 and CD86 are expressed on APC, and both provide costimulatory function. However, the reason for the expression of two separate CD28 ligands remains unclear. We have previously shown that blockade of CD80 costimulation by Y100F-Ig, a CTL-associated Ag-4 (CTLA4)-Ig mutant that does not bind CD86, inhibits the development of lung inflammatory immune responses, but does not affect blood eosinophilia or Ab production. Each of those responses was inhibited by treatment with CTLA4-Ig, which binds both CD80 and CD86. To clarify the mechanism underlying these observations we have developed a model of lung inflammation using adoptively transferred CD4(+) T cells expressing a Valpha11(+)Vbeta3(+) transgenic TCR specific for I-E(k) and moth cytochrome c. Treatment with Y100F-Ig inhibited the induction of lung eosinophilia in adoptively transferred mice. However, Y100F-Ig did not detectably affect the accumulation of Ag-specific T cells at the site of peptide deposit or in the draining lymphoid tissues. Acquisition of an activated phenotype and expression of adhesion molecules required for migration into the lung were modestly affected. Importantly, treatment with Y100F-Ig diminished the ability of T cells to produce the cytokines IL-4 and IL-5 following intranasal challenge with Ag. All the responses examined were severely inhibited by treatment with CTLA4-Ig. We conclude that T cells require CD80 costimulation for the optimal production of IL-5 following intranasal administration of Ag. Decreased IL-5 production is the most likely explanation for the diminished airway eosinophilia observed.

Abatacept↗
PubMed2000

Th2-dependent airway eosinophilia is regulated by preproenkephalin.

We have used preproenkephalin (PPNK)-deficient mice to study the role of PPNK in the development of airway inflammation. Airway eosinophilia was established by either sensitization followed by airway challenge with OVA or by infection with Nippostrongylus brasiliensis. Both models induce a strong Th2 immune response, characterized by an IL-5-dependent airway eosinophilia. We observed that although the accumulation of lymphocytes in the airways of PPNK-deficient mice was similar to that induced in control mice, IL-5 production and eosinophil infiltration were reduced. We conclude from this work that PPNK has a role in enhancing Th2 cell function and that this molecule may be an important target in asthma immunotherapy.

Animals↗
PubMed2000

Involving minority and underrepresented women in clinical trials: the National Centers of Excellence in Women's Health.

Recent attention to reducing health disparities among population groups has focused on the need to include in clinical studies, especially clinical trials, participants who represent the diversity of the populations to which study results will be applied. While scientists generally applaud the goal of broadening the characteristics of participants in clinical trials, they are faced with multiple challenges as they seek to include historically underrepresented populations in their research. This article examines the historical and sociocultural context of participation by underrepresented groups, especially women and minorities, in clinical trials, identifies major barriers and challenges facing researchers, and suggests strategies for meeting these challenges. The article draws upon the experiences of the investigators affiliated with the National Centers of Excellence of Women's Health (CoEs).

Clinical Trials as Topic↗
PubMed1999

Preproenkephalin is a Th2 cytokine but is not required for Th2 differentiation in vitro.

Preproenkephalin (PPNK) mRNA expression has been detected in many cells of the immune system, including monocytes and lymphocytes. In the present paper, the expression of PPNK mRNA in purified CD4+ Th1 and Th2 lymphocyte subpopulations is investigated and correlated with the presence of the opioid neuropeptides leu- and met-enkephalin. We found that PPNK mRNA and met-enkephalin were present at higher levels in the Th2 cultures compared with the Th1 cultures. Lymphocytes from PPNK-deficient mice were then used to look at the role of PPNK in Th2 lymphocyte differentiation. Lymphocytes from these mice could be driven into a Th2 phenotype, suggesting that cultures containing IL-4 do not require PPNK for Th2 differentiation.

Animals↗
PubMed1999

Implementation of on-site screening sigmoidoscopy positively influences utilization by primary care providers.

BACKGROUND & AIMS: Sigmoidoscopy is an effective screening strategy for colorectal cancer that is not widely used by primary care providers. The aim of this study was to assess the impact of "academic detailing" in the form of an outreach educational seminar combined with implementation of on-site sigmoidoscopy services performed by university-based gastroenterologists on provider compliance. METHODS: A controlled trial was initiated at 9 urban neighborhood health centers, including 4 intervention and 5 comparison sites. Baseline data on provider attitudes and practice patterns were collected using a validated questionnaire. Outcome measures included a year 1 follow-up survey of provider attitudes and quarterly review of screening sigmoidoscopy referrals using appointment logs to assess utilization. RESULTS: Overall self-reported compliance rates for screening sigmoidoscopy increased by 36% (baseline, 24%; year 1, 60%) for the intervention group vs. only 7% (baseline, 19%; year 1, 26%) for the comparison group (P = 0. 001). When stratified by site, compliance rates increased at each intervention site (range, 7%-92%) but at only 2 control sites. Use of screening sigmoidoscopy was also significantly greater at the intervention sites (47% vs. 4%; P </= 0.001). CONCLUSIONS: An outreach educational seminar combined with implementation of on-site sigmoidoscopy services is an effective strategy for enhancing provider utilization of screening sigmoidoscopy.

Adult↗
PubMed1999

Medical students' knowledge, attitudes, skills, and practices of cancer prevention and detection.

BACKGROUND: Surveys of U.S. physicians show deficiencies in cancer detection and counseling skills. Thus, there is a compelling need to provide skills teaching during medical school for cancers with preventable mortality and for counseling techniques for smoking prevention and cessation. METHODS: In advance of the integration of initiatives for cancer education into the medical school curriculum, the authors conducted a baseline survey of students' knowledge, attitudes, skills, practices, observation, and training (KASPOT) related to cancer education. Eighty-one percent of Boston University School of Medicine students (n = 499) completed surveys. RESULTS: The students reported higher levels of KASPOT for breast and cervical cancers, compared with skin cancer examination or tobacco use cessation or prevention counseling. More than half of third- and fourth-year students reported that too little emphasis was given to cancer control education. CONCLUSIONS: It appears that students' practice and skills for detection of the most common cancer (skin cancer), and for cancers with the greatest mortality (tobacco-related cancers) are deficient. Revisions in medical students' curricula should seek to address these shortcomings.

Clinical Competence↗
PubMed1999

CTLA-4 blockade enhances the immune response induced by mycobacterial infection but does not lead to increased protection.

The murine immune response to a pulmonary mycobacterial infection is slow to develop, allowing bacterial numbers to increase in the lung for several weeks after infection. We sought to enhance the protective immune response induced during Mycobacterium bovis BCG infection by administering an antibody that blocks the interaction of CTLA-4 with its ligands, CD80 and CD86. We found that injection of anti-CTLA-4 monoclonal antibody (MAb) greatly enhanced and accelerated the immune response, as measured by increased cellularity of the draining mediastinal lymph nodes, and enhanced antigen-inducible proliferation and gamma interferon production by mediastinal lymphocytes in vitro. However, despite the apparently enhanced immune response in the mediastinal lymph node following treatment with anti-CTLA-4 MAb, there was no improvement in clearance of mycobacteria in the lungs, liver, or spleen. Examination of the primary site of infection, the lung, revealed that CTLA-4 blockade had no effect on the number or function of lymphocytes infiltrating the infected lung tissue. Taken together, these data suggest that in vivo CTLA-4 blockade enhances mycobacterial-infection-induced lymphocyte expansion and effector cell cytokine production in the draining lymph node but does not alter the number or function of lymphocytes at the primary site of infection and therefore does not lead to enhanced clearance of the infection.

Abatacept↗
PubMed1997

Autosomal mutations affecting adhesion between wing surfaces in Drosophila melanogaster.

Integrins are evolutionarily conserved transmembrane alpha,beta heterodimeric receptors involved in cell-to-matrix and cell-to-cell adhesions. In Drosophila the position-specific (PS) integrins mediate the formation and maintenance of junctions between muscle and epidermis and between the two epidermal wing surfaces. Besides integrins, other proteins are implicated in integrin-dependent adhesion. In Drosophila, somatic clones of mutations in PS integrin genes disrupt adhesion between wing surfaces to produce wing blisters. To identify other genes whose products function in adhesion between wing surfaces, we conducted a screen for autosomal mutations that produce blisters in somatic wing clones. We isolated 76 independent mutations in 25 complementation groups, 15 of which contain more than one allele. Chromosomal sites were determined by deficiency mapping, and genetic interactions with mutations in the beta PS integrin gene myospheroid were investigated. Mutations in four known genes (blistered, Delta, dumpy and mastermind) were isolated. Mutations were isolated in three new genes (piopio, rhea and steamer duck) that affect myo-epidermal junctions or muscle function in embryos. Mutations in three other genes (kakapo, kiwi and moa) may also affect cell adhesion or muscle function at hatching. These new mutants provide valuable material for the study of integrin-dependent cell-to-cell adhesion.

Animals↗
PubMed1996

Dominance of insecticide resistance presents a plastic response.

Dominance level of insecticide resistance provided by one major gene (an insensitive acetylcholinesterase) in the mosquito Culex pipiens was studied in two distinct environments. Dominance level was found to be very different environments, varying from almost complete dominance to almost recessive when either propoxur (a carbamate insecticide) or chlorpyrifos (an organophosphorus insecticide) was used. To better understand this plastic response, three environmental parameters were manipulated and their interactions studied. For chlorpyrifos, each parameter had a small effect, but when all parameters were changed, the dominance level was greatly affected. For propoxur, one environmental parameter had a large effect by itself. It was further studied to understand the causal relationship of this plasticity. Recessivity of resistance was associated with more demanding environments. These results are discussed in the context of the various theories of the evolution of dominance. It appears that dominance of insecticide resistance cannot be directly predicted by Wright's physiological theory.

Animals↗
PubMed1994

Cancer and poverty: breaking the cycle.

Poverty contributes to an increase in cancer incidence and mortality. The economically disadvantaged have a higher incidence for several cancers and lower survival rates for all cancer sites combined. A number of factors are responsible for the increased mortality and morbidity from cancer among the poor and include lack of employment, lack of education, inadequate housing, lack of access to medical care, chronic malnutrition, and a fatalistic attitude. Successful strategies must be taken to reverse these trends.

Attitude to Health↗
PubMed1993

The Drosophila Stubble-stubbloid gene encodes an apparent transmembrane serine protease required for epithelial morphogenesis.

The Stubble-stubbloid (Sb-sbd) gene is required for hormone-dependent epithelial morphogenesis of imaginal discs of Drosophila, including the formation of bristles, legs, and wings. The gene has been cloned by using Sb-sbd-associated DNA lesions in a 20-kilobase (kb) region of a 263-kb genomic walk. The region specifies an approximately 3.8-kb transcript that is induced by the steroid hormone 20-hydroxyecdysone in imaginal discs cultured in vitro. The conceptually translated protein is an apparent 786-residue type II transmembrane protein (N terminus in, C terminus out), including an intracellular N-terminal domain of at least 35 residues and an extracellular C-terminal trypsin-like serine protease domain of 244 residues. Sequence analyses indicate that the Sb-sbd-encoded protease could activate itself by proteolytic cleavage. Consistent with the cell-autonomous nature of the Sb-sbd bristle phenotype, a disulfide bond between cysteine residues in the noncatalytic N-terminal fragment and the C-terminal catalytic fragment could tether the protease to the membrane after activation. Both dominant Sb and recessive sbd mutations affect the organization of microfilament bundles during bristle morphogenesis. We propose that the Sb-sbd product has a dual function. (i) It acts through its proteolytic extracellular domain to detach imaginal disc cells from extracellular matrices, and (ii) it transmits an outside-to-inside signal to its intracellular domain to modify the cytoskeleton and facilitate cell shape changes underlying morphogenesis.

Amino Acid Sequence↗
PubMed1992

Comparative studies of Drosophila Antennapedia genes.

The Antennapedia (Antp) homeotic gene of Drosophila melanogaster controls cell fates and pattern formation in the epidermis, nervous system and mesoderm of thoracic segments. Its expression is controlled at the levels of transcription, alternative RNA splicing, polyadenylation and translation. Two nested Antp transcription units extend over 103 kb and produce sixteen different transcripts. We have compared the Antp genes of Drosophila virilis, Drosophila subobscura and D. melanogaster to determine which structural features are conserved and therefore may be important to the gene's function. The overall gene structures are similar. There are many conserved sequence blocks throughout the large introns, at least 15 kb upstream of the first promoter, and at least 3 kb downstream of the last polyadenylation site. Intron and exon sequence conservation around alternative splice sites indicates that alternative protein coding forms may also be conserved. Protein coding potential is perfectly conserved around the C-terminal homeodomain, well conserved in the N-terminal region, and more variable in the middle. The large size of the Antp gene may reflect a large number of control elements necessary for appropriate Antp protein expression. The conservation of transcript complexity suggests functional requirements for the different protein forms.

Amino Acid Sequence↗
PubMed1989

Interacting proteins identified by genetic interactions: a missense mutation in alpha-tubulin fails to complement alleles of the testis-specific beta-tubulin gene of Drosophila melanogaster.

In this paper we demonstrate that failure to complement between mutations at separate loci can be used to identify genes that encode interacting structural proteins. A mutation (nc33) identified because it failed to complement mutant alleles of the gene encoding the testis-specific beta 2-tubulin of Drosophila melanogaster (B2t) did not map to the B2t locus. We show that this second-site noncomplementing mutation is a missense mutation in alpha-tubulin that results in substitution of methionine in place of valine at amino acid 177. Because alpha- and beta-tubulin form a heterodimer, our results suggest that the genetic interaction, failure to complement, is based on the structural interaction between the protein products of the two genes. Although the nc33 mutation failed to complement a null allele of B2t (B2tn), a deletion of the alpha-tubulin gene to which nc33 mapped complemented B2tn. Thus, the failure to complement appears to require the presence of the altered alpha-tubulin encoded by the nc33 allele, which may act as a structural poison when incorporated into either the tubulin heterodimer or microtubules.

Alleles↗
PubMed1989

Ability to form an alliance with the therapist: a possible marker of prognosis for patients with antisocial personality disorder.

Antisocial personality disorder is generally perceived to be refractory to treatment, particularly psychotherapy. In this study, the ability of 48 patients with this disorder to form a working relationship with a psychotherapist or drug counselor was examined in relation to outcome of 24 weeks of treatment evaluated at 7-month follow-up. Some antisocial patients were able to form working relationships with their therapists, and there was a significant association between the ability to form such a relationship and treatment outcome. Measures of this ability, such as the Helping Alliance Questionnaire, may help identify antisocial patients who can benefit from psychotherapy.

Adult↗
PubMed1985

On biological functions mapping to the heterochromatin of Drosophila melanogaster.

We examined the behavior of an autosomal recessive maternal-effect mutation, abnormal-oocyte (abo), that is located in the euchromatin of the left arm of chromosome 2. When homozygous in females, abo results in a marked reduction in the probability that an egg produced by a mutant mother will develop into an adult. However, this probability is increased if the fertilizing sperm delivers to the egg either a normal allele of the maternal-effect gene or a specific type of heterochromatin (called ABO) that is located in small regions of the X and Y chromosome constitutive heterochromatin as well as in some autosomal heterochromatin. These regions, moreover, all react to Hoechst 33258 fluorescent dye identically and specifically. The amelioration of the maternal effect produced by this heterochromatin differs temporally from that caused by the normal allele of the euchromatic gene: the heterochromatin reduces only precellular blastoderm mortality, whereas the normal allele of the euchromatic gene reduces only postblastoderm mortality. Thus, although the genome of the preblastoderm Drosophila embryo is apparently mostly silent, the ABO-containing heterochromatin functions at this early time. Finally, preliminary data indicate that abo is but one member of a cluster of linked genes, each of which interacts with its own normal allele and with a different, locus-specific, heterochromatic factor. From these observations, it appears that Drosophila heterochromatin contains developmentally important genetic elements, and that a functional concomitant of heterochromatic location is gene action at a developmental stage during which the activity of the euchromatic genome is as yet undetectable. Some general implications of these inferences are considered.

Animals↗
PubMed1978

Identification of some urinary metabolites of propantheline bromide in man.

The peak plasma concn. of total radioactivity occurred 6 h after a single oral dose of [carboxyl-14C; methyl-2H3] propantheline bromide was administered to a healthy man. At this time 10% of the dose was present in the total plasma volume. 2. A total of 71% dose of radioactivity was excreted in urine in 96 h after dosage, 59% dose being excreted in the first 24 h. About 5.3% of the orally administered propantheline bromide was excreted unchanged. 3. T.l.c. analysis and g.l.c.-mass spectrometry showed xanthanoic acid, hydroxyxanthanoic acid(s), and propantheline as urinary metabolites of the drug. 4. A glucuronide of xanthanoic acid, a hydroxylated propantheline and the (2-hydroxyethyl)diisopropylammonium ion were tentatively identified as urinary metabolites. Hydrolysis of propantheline and conjugation of the resulting xanthanoic acid appear to be the major routes of metabolism of this compound. 5. A mean elimination half-life of 9.2 h was obtained for the total radioactivity by pharmacokinetic analysis of plasma and urine levels of 14C.

Adult↗