PubMed Health⌕ Search

Biomedical subjects

S Karp

Publications and source records attributed to S Karp.

At least 19 recordsLinked to original sources
PubMed2001

Improving patient recruitment to multicentre clinical trials: the case for employing a data manager in a district general hospital-based oncology centre.

One of the most frequently cited reasons for poor recruitment to multicentre randomized clinical trials is the additional workload placed on clinical staff. We report the effect on patient recruitment of employing a data manager to support clinical staff in an English district general hospital (DGH). In addition, we explore the effect data managers have on the quality of data collected, proxied by the number of queries arising with the trial organizers. We estimate that the cost of employing a data manager on a full-time basis is 502 per patient recruited but may amount to 326 if the appointment is part-time. Data quality is high when full responsibility lies with a data manager but falls when responsibility is shared. Whether the costs of employing a data manager to recruit patients from a DGH are worth incurring depends on the value placed on the speed at which multicentre trials can be completed, how important it is to broaden the research base beyond the traditional setting of teaching hospitals, and the amount of evaluative data required.

Clinical Trials as Topic↗
PubMed2001

BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation.

During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs. We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of IHH: Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This role of BMP signaling is independent of the Ihh/PTHrP pathway.

Animals↗
PubMed2001

Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation.

Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone development. Smoothened (Smo) is a transmembrane protein that transduces all Hh signals. In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes. Animals generated by this means develop shorter long bones when compared to wild-type littermates. In contrast to Ihh mutants (Ihh(n)/Ihh(n)), chondrocyte differentiation proceeds normally. However, like Ihh(n)/Ihh(n) mice, proliferation of chondrocytes is reduced by about 50%, supporting a direct role for Ihh in the regulation of chondrocyte proliferation. Moreover, by overexpressing either Ihh or a constitutively active Smo allele (Smo*) specifically in the cartilage using the bigenic UAS-Gal4 system, we demonstrate that activation of the Ihh signaling pathway is sufficient to promote chondrocyte proliferation. Finally, expression of cyclin D1 is markedly downregulated when either Ihh or Smo activity is removed from chondrocytes, indicating that Ihh regulates chondrocyte proliferation at least in part by modulating the transcription of cyclin D1. Taken together, the present study establishes Ihh as a key mitogen in the endochondral skeleton.

Animals↗
PubMed1997

The need for comprehensive data on educational affiliations between academic health centers and managed care organizations.

Because of the emerging dominance of managed care, it is important to encourage the development of partnerships and affiliations between academic health centers (AHCs) and managed care organizations (MCOs) to train tomorrow's physicians to operate effectively in the new health care environment. But to what extent do such relationships exist now. In 1996, the authors sought to identify existing databases on the availability and extent of existing education partnerships and affiliations between AHCs and MCOs and the availability of such information to policymakers, the educational community, students, and residents. Despite a thorough search of the literature and interviews with representatives of education and practice organizations and with other experts in the medical education and managed care fields, the authors found no centralized or even partly centralized database on opportunities for training in managed care settings or on AHC-MCO partnerships. However, anecdotal evidence revealed eight such partnerships, each different from the others, that can serve as models for future partnerships; these are described. The authors speculate about why there are not more data describing AHC-MCO partnerships. They conclude by stating that the health care and health education industries have a variety of professional associations that could work together to assemble and make available such data to help build the educational and information infrastructure needed to train future physicians.

Academic Medical Centers↗
PubMed1996

Access of Native Americans to renal transplantation in Arizona and New Mexico.

Lower rates of transplantation among minority groups are a nationally recognized phenomenon. Native Americans (NA) nationally have nearly four times the risk of end-stage renal disease (ESRD) as compared with white (W) Americans and are significantly overrepresented in the Network 15 ESRD population. To understand more about NA and W transplant rates, we looked at all reported Arizona (AZ) and New Mexico (NM) resident cases from the Network No. 15 data base. Age of onset, sex, primary diagnosis, payment source, transplant donor source, and other factors were examined. NA experienced a slightly earlier onset of ESRD than W, and diabetes mellitus was the primary ESRD diagnosis for 63-73% of NA and for 34-39% of W. Because age distribution and frequency of diabetes mellitus of the NA ESRD population differ from those of W in the Network, age-specific and diagnosis-specific transplant rates were examined. Age-adjusted transplant rates per 100 ESRD patients for AZ were 16.4 (NA) and 21.0 (W) and for NM 14.2 (NA) and 22.4 (W). Diagnosis-specific age-adjusted transplant rates for patients with the primary diagnoses of diabetes mellitus and glomerulonephritis, the two most common causes of ESRD among NA, showed a large difference between W and NA rates. Age-adjusted rates for diabetes were: AZ 8.4% (NA) and 14.5% (W); NM 9.8% (NA) and 15.9% (W). Age-adjusted rates for patients with glomerulonephritis were: AZ 23.7% (NA) and 28.0% (W); NM 22.3% (NA) and 33.0% (W). In all comparisons and in both the W and NA ESRD populations, women were transplanted at lower rates than men. NA experienced a greater delay from onset of treated ESRD to transplant than W. Payment source and transplant donor source did not appear to be significantly different between NA and W. The lower transplant rates in NA versus W in Network No. 15 cannot be explained by age- or diagnosis-specific factors.

Adolescent↗
PubMed1994

Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor.

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory agent produced primarily by activated monocytes and macrophages. TNF-alpha is synthesized as a precursor protein of M(r) 26,000 (26K) which is processed to a secreted 17K mature form by cleavage of an Ala-Val bond between residues 76-77. The enzyme(s) responsible for processing pro-TNF-alpha has yet to be identified. Here, we describe the capacity of a metalloproteinase inhibitor, GI 129471, to block TNF-alpha secretion both in vitro and in vivo. The inhibition is specific to TNF-alpha; the production of other secreted cytokines, such as the interleukins IL-1 beta, IL-2, or IL-6, is not inhibited. The mechanism of inhibition occurs at a post-translational step in TNF-alpha production. Our data suggest that TNF-alpha processing is mediated by a unique Zn2+ endopeptidase which is inhibited by GI 129471 and would represent a novel target for therapeutic intervention in TNF-alpha associated pathologies.

Animals↗
PubMed1992

Altering the cellular mechanical force balance results in integrated changes in cell, cytoskeletal and nuclear shape.

Studies were carried out with capillary endothelial cells cultured on fibronectin (FN)-coated dishes in order to analyze the mechanism of cell and nuclear shape control by extracellular matrix (ECM). To examine the role of the cytoskeleton in shape determination independent of changes in transmembrane osmotic pressure, membranes of adherent cells were permeabilized with saponin (25 micrograms/ml) using a buffer that maintains the functional integrity of contractile microfilaments. Real-time videomicroscopic studies revealed that addition of 250 microM ATP resulted in time-dependent retraction and rounding of permeabilized cells and nuclei in a manner similar to that observed in intact living cells following detachment using trypsin-EDTA. Computerized image analysis confirmed that permeabilized cells remained essentially rigid in the absence of ATP and that retraction was stimulated in a dose-dependent manner as the concentration of ATP was raised from 10 to 250 microM. Maximal rounding occurred by 30 min with projected cell and nuclear areas being reduced by 69 and 41%, respectively. ATP-induced rounding was also accompanied by a redistribution of microfilaments resulting in formation of a dense net of F-actin surrounding retracted nuclei. Importantly, ATP-stimulated changes in cell, cytoskeletal, and nuclear form were prevented in permeabilized cells using a synthetic myosin peptide (IRICRKG) that has been previously shown to inhibit actomyosin filament sliding in muscle. In contrast, both the rate and extent of cell and nuclear rounding were increased in permeabilized cells exposed to ATP when the soluble FN peptide, GRGDSP, was used to dislodge immobilized FN from cell surface integrin receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Actomyosin↗
PubMed1991

Exfoliative dermatitis secondary to tobramycin sulfate.

We report a case of exfoliative dermatitis clearly linked to intravenous and intraperitoneal administration of tobramycin. Despite the complicated drug regimen with which the patient was treated, tobramycin was implicated by rechallenge with the drug once before its role was understood and again at an outside hospital.

Drug Eruptions↗
PubMed1989

Acquired congenital heart block. Pattern of maternal antibody response to biochemically defined antigens of the SSA/Ro-SSB/La system in neonatal lupus.

The molecular basis of autoantibody reactivity with components of the SSA/Ro-SSB/La particle exhibited by sera of mothers of infants with severe and permanent manifestations of neonatal lupus (NLE) was investigated using immunoblotting and immunoprecipitation. The characteristics of NLE that were studied included congenital complete heart block (CCHB), second degree heart block, and hepatic fibrosis. Antibodies specific for one or more components of the SSA/Ro-SSB/La particle were found in sera from all 20 mothers of permanently affected infants. However, no antibody specific for a single peptide of this particle was common to all sera. Using tissue extracts from a human cell substrate, 80% of these sera had antibodies to one or more components of the SSA/Ro particle demonstrable by immunoblotting. The predominant antibody response in the NLE group was to the newly recognized 52-kD SSA/Ro peptide component. In contrast, antibodies to the 60-kD SSA/Ro component although present, were the least represented and not significantly increased in frequency among mothers of these infants, compared with a group of 31 mothers with autoimmune diseases such as systemic lupus erythromatosus (SLE) but who had healthy offspring. Antibodies directed to the 48-kD SSB/La antigen were demonstrated in 90% of the NLE mothers often accompanying antibodies against the 52-kD SSA/Ro component. The combination of antibodies to 48- and 52-kD structures was significantly increased in the NLE group, with an odds ratio of 35. The type of cell or tissue substrate was shown to influence detectability of antibodies. The 52-kD SSA/Ro peptide and the 48-kD SSB/La peptide were abundant in cardiac tissues from fetuses aged 18-24 wk, further supporting the possible relevance of these peptides to heart block.

Autoantibodies↗
PubMed1985

Plasma vitamin C and uterine cervical dysplasia.

Plasma concentrations of vitamin C were determined in a case-control study of women (n = 80) who had sought a Papanicolaou test in the Bronx Municipal Hospital Center. Controls (n = 34) were women having negative cytologic tests, negative colposcopic findings, and no known gynecologic dysfunction. Cases (n = 46) were defined as women who had either one positive or two consecutive suspicious Papanicolaou smears in a 12-month period. The mean concentration of vitamin C in the plasma was significantly lower in the cases than in the controls (0.36 versus 0.75 mg/dl, p less than 0.0001). Cases were further stratified according to the histopathologic diagnosis. The data direct attention to a possible etiologic association of vitamin C in human cervical epithelial abnormalities. A clinical trial with vitamin C intervention is suggested.

Adult↗
PubMed1983

Serum complement 'supergenes' of the major histocompatibility complex in man (complotypes).

The loci for the complement proteins C2 and BF, and the two loci for C4 are closely linked to one another. In many hundreds of meioses no crossing over has been detected between these loci. In addition, the alleles of these four loci occur in specific combinations not predicted by their gene frequencies in much the same way as alleles of the Rh and MNS systems. These units are termed complotypes. There are 14 complotypes with frequencies in excess of 1% in our study population of normal sixth chromosomes from Caucasians. Since they are also intimately associated with HLA-DR, comploytypes may also be of importance in screening programs for transplantation.

Chromosome Mapping↗
PubMed1975

Excess leukemia in cohorts of children born following influenza epidemics.

Two series of data from the California State Department of Health and one from Children's Hospital of Los Angeles were analyzed to determine whether an association exists between influenza epidemics and incidence of leukemia in children born following such outbreaks. Of leukemic children born in areas for which information on past influenza activity was available, the population-based Alameda County Cancer Registry recorded 89 cases during 1960-1969, the California Tumor Registry recorded 653 cases during 1950-1970, and Children's Hospital recorded 575 cases during 1957-1972. Flu epidemics were identified and flu cohorts constructed such that leukemic children who could have been in utero during a flu epidemic constituted a flu cohort. Based on the total number of leukemia cases reported and the proportion of at-risk weeks contributed by the flu cohort, expected numbers of leukemia cases from the flu cohort were computed for each age. In each series, there was an excess of leukemia cases in the flu cohort, contributed primarily by the 0-4 age group. Trimester analysis indicated that the greatest excess occurred in children who were in the first trimester of gestation during a flu epidemic. Incidence data from the Cancer Incidence System of the San Francisco Bay Area Resource for Cancer Epidemiology and the Third National Cancer Survey show a relative risk of 3.4 for this group. Due to sources of misclassification in this study, such as analysis of flu cohorts rather than individuals whose mothers actually had influenza during pregnancy, the results tend to be diluted. If influenza is a causative factor, the actual increase in leukemia risk is likely to be much greater than this analysis indicates.

Adolescent↗