Biomedical subjects

L Murphy

Publications and source records attributed to L Murphy.

At least 37 records · Page 2Linked to original sources

PubMed2000

Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors.

We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound to thrombin confirmed the amindinohydrazone binding mode.

Administration, Oral↗

PubMed2000

Contractile properties of human renal cell carcinoma recruited arteries and their response to nicotinamide.

BACKGROUND AND PURPOSE: The manipulation of tumour blood supply and thus oxygenation is a potentially important strategy for improving the treatment of solid tumours by radiation. Increased knowledge about the characteristics that distinguish the tumour vasculature from its normal counterparts may enable tumour blood flow to be more selectively modified. Nicotinamide (NA) causes relaxation of preconstricted normal and tumour-supply arteries in rats. It has also been shown to affect microregional blood flow in human tumours. Direct effects of NA on human tumour supply arteries have not previously been reported. This paper describes our evaluation of the effects of NA on two parameters: 'spontaneous', oscillatory contractile activity and agonist (phenylephrine)-induced constriction in the arteries supplying human renal cell carcinomas. MATERIALS AND METHODS: Isolated renal cell carcinoma feeder vessels were perfused in an organ bath with the alpha(1)-adrenoceptor agonist phenylephrine (PE). When the arteries had reached a plateau of constriction, nicotinamide (8.2 mM) was added to the perfusate and changes in perfusion pressure were measured. RESULTS: PE (10 microM) induced a sustained constriction in the majority of the renal cell carcinoma feeder vessels examined, demonstrating that they retain contractile characteristics, at least in response to this alpha(1)-adrenoceptor agonist. In combination with NA (8.2 mM) the constriction was significantly attenuated in half of the preparations. In addition, seven arteries exhibited spontaneous contractile activity which was significantly attenuated by NA in six of them. CONCLUSIONS: NA can significantly attenuate both 'spontaneous' and agonist-induced constrictions in tumour-recruited human arteries, though not all arteries are sensitive.

Adrenergic alpha-Agonists↗

PubMed2000

Empirically supported treatments in pediatric psychology: constipation and encopresis.

OBJECTIVE: To review the empirical research examining behavioral and medical treatments for constipation and fecal incontinence. METHOD: Sixty-five articles investigating intervention efficacy were identified and reviewed. Twenty-three of the studies were excluded because they were case studies or were less well-controlled single-case designs. The intervention protocol for each study was identified and coded, with studies employing the same interventions matched and evaluated according to the Chambless criteria. RESULTS: From the literature base to date, no well-established interventions have emerged. However, four probably efficacious treatments and three promising interventions were identified. Two different medical interventions plus positive reinforcement fit the criteria for the probably efficacious category (one with fiber recommendation and one without). Three biofeedback plus medical interventions fit efficacy category criteria: one probably efficacious for constipation with abnormal defecation dynamics (full medical intervention plus biofeedback for paradoxical contraction), and two fit the promising intervention criteria for constipation and abnormal defecation dynamics (full medical intervention plus biofeedback for EAS strengthening, correction of paradoxical contraction and home practice; and biofeedback focused on correction of paradoxical contraction, medical intervention without fiber recommendation, and positive reinforcement). Two extensive behavioral interventions plus medical intervention also met efficacy criteria for constipation plus incontinence (medical intervention without laxative maintenance plus positive reinforcement, dietary education, goal setting, and skills building presented in a small-group format fits criteria for a promising intervention; and positive reinforcement and skills building focused on relaxation of the EAS during defecation, but without biofeedback, plus medical intervention meets the probably efficacious criteria). CONCLUSIONS: A discussion of the current weaknesses in this research area follows. Specific recommendations for future research are made including greater clarity in treatment protocol and sample descriptions, reporting cure rates rather than success rates, utilization of adherence checks, and investigation of potential differential outcomes for subgroups of children with constipation and incontinence.

Behavior Therapy↗

PubMed2000

Differentiation of islet cells in long-term culture.

Our previous studies in the hamster pancreatic cancer model have shown that exocrine pancreatic cancer arises from ductal/ductular cells, as well as from within the islets, most probably from islet precursor (stem) cells. To identify and characterize these cells, we established a long-term culture from isolated hamster islets and investigated their growth, differentiation, and expression of biomarkers. Islets maintained their original form and structure within the first 14 days in culture. However, beginning at day 7, ductular structures began to form within the islets. At day 21 in culture, acinar cells, intermediary cells, oncocytes, and cells comparable to pancreatic hepatocytes also appeared between ductular and endocrine cells. The number of duct-like cells gradually increased, whereas the number of hormone-producing cells decreased. After 35 days in culture, the exocrine cells disappeared, and undifferentiated cells formed a monolayer. These cells expressed cytokeratins, alpha1-antitrypsin, transforming growth factor-alpha, epidermal growth factor receptor, carbonic anhydrase II, vimentin, laminin, and showed binding to tomato lectin and Phaseolus vulgaris leukoagglutinin. They did not express the regulatory transcriptional factors, insulin-promoting factor 1, NKx6.1, Pax6, and NeuroD. The results thus indicate that islet cells have potential to form exocrine cells. At present, it is not clear whether these cells originate from preexisting stem cells or from transdifferentiated islet cells.

Animals↗

PubMed1999

Atopic dermatitis: a review of diagnosis and treatment.

Atopic dermatitis is a common, potentially debilitating condition that can compromise quality of life. Its most frequent symptom is pruritus. Attempts to relieve the itch by scratching simply worsen the rash, creating a vicious circle. Treatment should be directed at limiting itching, repairing the skin and decreasing inflammation when necessary. Lubricants, antihistamines and topical corticosteroids are the mainstays of therapy. When required, oral corticosteroids can be used. If pruritus does not respond to treatment, other diagnoses, such as bacterial overgrowth or viral infections, should be considered. Treatment options are available for refractory atopic dermatitis, but these measures should be reserved for use in unique situations and typically require consultation with a dermatologist or an allergist.

Adrenal Cortex Hormones↗

PubMed1999

The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum.

Analysis of Plasmodium falciparum chromosome 3, and comparison with chromosome 2, highlights novel features of chromosome organization and gene structure. The sub-telomeric regions of chromosome 3 show a conserved order of features, including repetitive DNA sequences, members of multigene families involved in pathogenesis and antigenic variation, a number of conserved pseudogenes, and several genes of unknown function. A putative centromere has been identified that has a core region of about 2 kilobases with an extremely high (adenine + thymidine) composition and arrays of tandem repeats. We have predicted 215 protein-coding genes and two transfer RNA genes in the 1,060,106-base-pair chromosome sequence. The predicted protein-coding genes can be divided into three main classes: 52.6% are not spliced, 45.1% have a large exon with short additional 5' or 3' exons, and 2.3% have a multiple exon structure more typical of higher eukaryotes.

Animals↗

PubMed1999

Insulin sensitivity and serum triglyceride level in obese white and black women: relationship to visceral and truncal subcutaneous fat.

Although independent associations of visceral fat with the insulin resistance syndrome were previously reported in obese women, the importance of truncal subcutaneous fat with regard to insulin sensitivity is still controversial. We measured the insulin sensitivity index (S(I)), serum triglyceride (TG) level, and regional fat by two methods: (1) the sum of five truncal and four peripheral skinfolds (TrSUM and PerSUM) in 38 white and black obese nondiabetic premenopausal women, and (2) abdominal visceral (VFM) and subcutaneous fat mass (AbdSCFM) by a combination of magnetic resonance imaging (MRI) and dual x-ray absorptiometry (DXA) in a subset of 26 of these women. After adjusting for the total body fat mass, TrSUM and VFM were independently and negatively related to S(I) (n = 38, P < .012 and n = 26, P < .035, respectively), whereas PerSUM and AbdSCFM were not related (P > .50). Based on multiple regression modeling, TrSUM significantly predicted S(I) independently of the VFM (n = 26, P < .001). Black women had lower S(I) at all levels of TrSUM (n = 38, P = .061 for the slope and P = .03 for the intercept of the regression lines). After adjusting for the total body fat mass, only VFM showed an independent positive relation to serum TG, and race did not affect this relationship (n = 26, P < .001). In conclusion, (1) we confirmed the independent association of the VFM with insulin resistance and elevated TG in obese women; (2) the AbdSCFM measured by a combination of MRI and DXA did not show an independent association with S(I) in obese women; and (3) the independent association of TrSUM with S(I) suggests that truncal subcutaneous fat depots contribute to insulin resistance in obese women independently of the degree of visceral fat.

Absorptiometry, Photon↗

PubMed1999

Disfiguring burn scars and adolescent self-esteem.

Although children with burn scars are reported to have positive self-concepts, social and sexual maturation can be expected to stimulate anxiety, depression and diminished self-esteem in adolescents with disfiguring scars. This study examines complex self-regard of adolescents with burn scars. The following were hypothesized: (1) adolescents with disfiguring burn scars would view themselves as less competent than unburned normative samples; (2) subjects' perceived competence would be incongruent with the importance ascribed to the domains of physical appearance and athletic competence and (3) depression/anxiety would correlate negatively with perceived competence. Subjects were 14 adolescents: 6 male and 8 female, 13-20 years old, at least 2 years post-burn injury (TBSA = 39% +/- 23%). All had scars in at least 2 of the following areas: head/face, neck, chest, hands, genitals. Each subject was administered the Harter Self Perception Profile, a standardized measure of self-competence and value in 8 domains plus a general competence measure. The subjects were also assessed for anxiety/depression by the Child Behavioral Checklist. Overall, adolescents in this sample exhibited a similar or higher degree of self-worth as compared to their peers. However, the athletic competence and physical appearance sub-domains of self-worth for the burn survivors were significantly lower as compared to the normative group. Half of the participants rated the importance of physical appearance to be higher than their level of personal competence in this area, making for distressing emotions. Mood was similar to the normative group and mood correlated significantly with self-worth.

Adolescent↗

PubMed1999

Immunological reconstitution and correlation of circulating serum inflammatory mediators/cytokines with the incidence of acute graft-versus-host disease during the first 100 days following unrelated umbilical cord blood transplantation.

We investigated early immunological reconstitution and the production of circulating inflammatory mediators and their relationship to aGVHD in children during the first 100 days following unrelated UCBT. Nine patients had an underlying malignant disease (ALL, ANLL), and two, non-malignant diseases (SAA, ALD). The median age was 10 years (range: 1.25-21). Seven of 11 patients were alive by day 100, two died from regimen-related toxicity, and two died from severe aGVHD (grade >/=III). Myeloid engraftment (ANC >/=500/mm3 x 2 days) occurred at a median of 24 days (range: 14-55), while platelet engraftment (platelet count >/=20 000/mm3 untransfused x 7 days) was delayed and occurred at a median of 52 days (range: 33-95). The mean cell dose of CD34+ cells was 3.3 +/- 3.51 x 10(5)/kg, and of CD34+/CD41+ cells was 3.94 +/- 3.99 x 10(4)/kg. Acute GVHD (grade II-IV) developed in seven patients (77%), and severe aGVHD (grade III-IV) developed in five patients (55%). Serum levels of IL-2Ralpha, IL-2, IL-4, IL-7, IL-12, and IFNgamma were not significantly different between patients with grades 0-I aGVHD and patients with grades II-IV aGVHD. Evaluation of immunological reconstitution on day 90 post UCBT demonstrated an early recovery of the absolute numbers of B cells (CD19+) and NK cells (CD3-/CD56+). Immunoglobulin levels for IgG, IgM and IgA remained normal throughout the study period. PMN functional studies demonstrated normal superoxide generation, bacterial killing (BK), and chemotaxis (CTX). However, both helper (CD3+/CD4+) and suppressor (CD3+/CD8+) T cell subsets remained low during the first 100 days post UCBT with mean +/- s.e.m. values of 120 +/- 29/mm3 and 10 +/- 50/mm3, respectively (normal = 900-2860/mm3 (CD3/CD4), normal = 630-1910/mm3 (CD3/CD8)). Mitogen response studies showed low blastogenesis to PHA and PWM, with a mean c.p.m. +/- s.e.m. value of 1.7 +/- 0.67 x 10(4) for PHA (NL >/= 75 x 10(3)) and 8.42 +/- 4.1 x 10(3) for PWM (NL >/=25 x 10(3)). In conclusion, serum levels of inflammatory mediators were not predictive nor did they correlate with the severity of aGVHD. Recovery of NK cells, B cells, and PMN functions occurred within the first 90 days post transplant. However, T cell subsets, CD3+/CD4+ and CD3+/CD8+, and T cell functional activity remained significantly decreased and may account for the high incidence of infectious morbidity seen during this immediate post UCBT period.

Acute Disease↗

PubMed1999

Premedical and predental enrichment program for minority students, 1969-1996, at Meharry Medical College.

From 1969 through 1996, Meharry Medical College offered the Biomedical Sciences Program, an eight-week summer premedical and predental enrichment program designed to increase the enrollment of minority students in health professions schools. The program focused on preparing undergraduates to pursue health professions careers by providing specially designed courses in biology, chemistry, mathematics, and scientific communications, as well as interactions with clinical faculty. The curriculum emphasized academic preparation, including structured course work in the classroom, assigned homework every night, and scheduled activities with clinicians. (The program merged with two other outreach programs in 1996 and is now part of the Health Careers Opportunity Pre-Baccalaureate Program.) From 1969 to 1996, 1,015 students participated in the program, and over the years 43% of them responded to tracking surveys. Of these 445 respondents, 70% (310) applied to professional schools, of whom 83% (257) applied to medical, 15% (46) to dental, and 2% (10) to graduate schools. Of the 257 who applied to medical schools, 70% (198) were admitted and all of them graduated. Of the 46 who applied to dental schools, all were admitted and graduated; and of the ten who applied to graduate schools, all were accepted and received PhD degrees in the biomedical sciences. Of particular note, 67% (172) of the applicants who were admitted to professional schools matriculated at Meharry Medical College. These data suggest that the Biomedical Sciences Program used effective strategies that increased the number of underrepresented-minority students entering health professions careers.

Education, Predental↗

PubMed1999

Evaluation of the Washington State Workers' Compensation Managed Care Pilot Project I: medical outcomes and patient satisfaction.

OBJECTIVES: This study examined the effect of managed care on medical outcomes and patient satisfaction as part of an evaluation of the Washington State Workers' Compensation Managed Care Pilot. METHODS: One hundred twenty firms (7,041 employees) agreed to have their injured workers treated in managed-care plans. Managed care introduced two changes from the fee-for-service (FFS) delivery system currently used by injured workers in Washington State: (1) experience-rated capitation, and (2) a primary occupational-medicine delivery model. The FFS control group included injured workers employed at 392 firms (12,000 employees). A total of 1,313 workers who experienced occupationally related injuries or illnesses between April 1995 and June 1996 were interviewed by telephone at 6 weeks after injury regarding their medical outcomes and satisfaction with care. Workers whose injuries resulted in four or more lost workdays (n = 372) were also interviewed at 6 months after injury on the same topics. The areas surveyed included functional outcomes and satisfaction with care, providers, and access to providers. RESULTS: The measures of functional outcome reflected no consistent differences between the managed care and the FFS conditions. The workers who attended the managed-care system reported lower levels of satisfaction with care, particularly with access to providers. For example, 58% of managed-care patients reported satisfaction with their attending physician as compared with 69% of FFS patients (P<0.01). CONCLUSIONS: Workers treated through managed-care arrangements were less satisfied with their care, but their medical outcomes were similar to those of workers who received traditional FFS care. The current workers' compensation system in Washington State affords injured workers great latitude in choosing providers. If provider choice is substantially restricted by managed care, worker satisfaction is likely to diminish.

Adult↗

PubMed1999

Evaluation of the Washington State Workers' Compensation Managed Care Pilot Project II: medical and disability costs.

OBJECTIVES: This study examined the effect of managed care on medical and disability costs as part of an evaluation of the Washington State Workers' Compensation Managed Care Pilot (MCP). METHODS: One hundred twenty firms (7,041 employees) agreed to have their injured workers treated in managed care plans. Managed care introduced two changes from the fee-for-service (FFS) delivery system currently used by injured workers in Washington State: experience- rated capitation and a primary occupational medicine delivery network. The FFS control group included injured workers employed at 392 firms (12,000 employees). Medical and disability costs were compared for 1,058 injuries in the managed care group and 1,159 injuries in the FFS group occurring between April 1995 and June 1996. Univariate and multivariate statistical methods were used to analyze the effects of managed care on medical and disability costs. RESULTS: The mean unadjusted medical cost per injury ($587) for the managed care group was 21.5% lower (P = 0.06) than for the FFS group ($748). Adjustment for differences in worker and firm-level characteristics through multivariate analysis had little effect on the unadjusted results, except that the difference in costs between managed care and FFS groups became statistically significant (P<0.01). The major cost differences were for outpatient surgery (cost per surgery) and ancillary services (pharmacy, x-ray, physical therapy, and all other costs). In addition, disability costs, particularly percent on time loss and time-loss cost per injury, were significantly lower (P<0.01) in the managed care group. CONCLUSIONS: The results from the MCP suggest that substantial savings in workers' compensation medical and disability costs may be realized using the type of managed care intervention designed for this study. Delivering occupational health services through managed care arrangements whose design is based on an integrated, occupational health-centered delivery model may offer a viable approach for improving delivery systems, reducing costs and encouraging greater attention to disability prevention.

Adult↗

PubMed1999

Systemic resistance to the antilipolytic effect of insulin in black and white women with visceral obesity.

This study was designed to determine the role of visceral adipose tissue (VAT) accumulation in systemic fat metabolism and to compare this in black and white women who differ in their manifestations of upper body obesity. Systemic glycerol and free fatty acid (FFA) turnover rates (rates of appearance, Ra) were measured in the basal state and during a pancreatic euglycemic clamp in nondiabetic, premenopausal, obese black and white women with a wide range of VAT accumulation. The slopes of the regression equations predicting basal and insulin-suppressed RaGlycerol and RaFFA from VAT area, age, and fat mass or fat-free mass did not significantly differ between black and white women. VAT area was the best predictor of the %-suppressed RaGlycerol and RaFFA during the pancreatic clamp (partial r = 0.76, P < 0.0001 and partial r = 0.60, P < 0.05, respectively). Basal R(a)Glycerol, but not RaFFA, was lower in black than in white women (P < 0.05). During the clamp, black women showed greater insulin suppression of RaGlycerol than of RaFFA (P < 0.0001) and greater insulin suppression of RaGlycerol (P < 0. 05) but similar suppression of RaFFA compared with white women. These differences were independent of age, fat mass, or fat-free mass and were partly explained by a lower VAT in black women. Thus, in both races, VAT accumulation was associated with systemic resistance to the antilipolytic effect of insulin and, in obese black women, systemic lipolysis measured as glycerol turnover rate was more responsive to insulin suppression than were systemic FFA turnover rates.

Adipose Tissue↗

PubMed1999

Creating alternative immunization clinics to maintain and improve community immunization rates.

Immunization campaigns are among the most effective means for improving community health, yet underimmunized groups leave communities at risk for vaccine-preventable diseases. In 1993, the Childhood Immunization Initiative (CII) was implemented to address this risk. The goal of the CII, to achieve immunization coverage 90% or greater among 2-year-old children, was reached nationwide by 1996. However, individual states ranged from 81% to 99% for specific vaccines (Centers for Disease Control and Prevention, 1997b). The work of the CII is ongoing and was expanded in 1996 to address the immunization needs of adolescents. The purpose of this article is to present a model for providing immunization services in alternative sites, in which the community health nurse takes the service to the people. Building linkages with local communities, preparing the clinic site and supplies, arranging for staffing of an alternative clinic, and evaluation after service provision are key elements to a successful outreach clinic.

Community Health Centers↗

PubMed1998

Establishment of tumor cell culture (ILA) derived from hamster pancreatic islets treated with BOP.

ILA cells were established from tumors induced by the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) in hamster islets. The proliferation, morphology, karyotype, immunoreactivity with certain antibodies and growth factor secretion of these tumor cells were compared with the same parameters in tumor cells induced by BOP in hamster ductal cells (TAKA-1-BOP) established in a previous study. Minor differences were found in the morphology and ultrastructure of the 2 cell lines. Contrary to TAKA-1-BOP cells, ILA cells did not express cytokeratins 8.13, 13 or 18 but did express DU-PAN-2 and TAG-72, 2 known human pancreatic cancer-associated antigens. No endocrine cell markers were expressed. A significant difference also was found in the chromosomal pattern in that there were more abnormalities and marker chromosomes in ILA cells than in TAKA-1-BOP cells and the Y or X chromosomes were missing in ILA cells. ILA cells produced TGF-alpha, IGF-I, bombesin and gastrin and expressed specific binding sites for hEGF. TGF-alpha secretion from ILA cells was much greater than that from TAKA-1-BOP cells. Our results indicate that pancreatic cancer cells grown in vitro are not a single clone. We conclude that there are some genetic and biological differences between tumors arising from pancreatic duct and islets and that pancreatic ductal adenocarcinomas originating from islets have a profound malignant potential.

Adenoma, Islet Cell↗

PubMed1998

In vitro evaluation and crystallographic analysis of a new class of selective, non-amide-based thrombin inhibitors.

We describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-amino acid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the active-site catalytic apparatus and is anchored to the enzyme via a single network of hydrogen bonds to Asp189 of the S1 pocket.

Amides↗

PubMed1998

Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.

Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve our understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino-acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.

Chromosome Mapping↗

PubMed1998

NEEDLY, a Pinus radiata ortholog of FLORICAULA/LEAFY genes, expressed in both reproductive and vegetative meristems.

The LEAFY/FLORICAULA genes from Arabidopsis and Antirrhinum are necessary for normal flower development and play a key role in diverse angiosperm species. A homologue of these flower meristem-identity genes, NEEDLY (NLY), has been identified in Pinus radiata. Although the NLY protein shares extensive sequence similarity with its angiosperm counterparts, it is lacking the proline-rich and acidic motifs thought to function as transcriptional activation domains. NLY already is expressed during vegetative development at least 5 years before the transition to the reproductive phase. Expression of NLY in transgenic Arabidopsis promotes floral fate, demonstrating that, despite its sequence divergence, NLY encodes a functional ortholog of the FLORICAULA/LEAFY genes of angiosperms. Expression of the LFY::NLY transgene can largely complement the defects in flower development caused by a severe lfy allele.

Amino Acid Sequence↗