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Biomedical subjects

J W Smith

Publications and source records attributed to J W Smith.

At least 109 records · Page 6Linked to original sources
PubMed1998

Update on Pneumocystis carinii f. sp. hominis typing based on nucleotide sequence variations in internal transcribed spacer regions of rRNA genes.

Pneumocystis carinii f. sp. hominis isolates from 207 clinical specimens from nine countries were typed based on nucleotide sequence variations in the internal transcribed spacer regions I and II (ITS1 and ITS2, respectively) of rRNA genes. The number of ITS1 nucleotides has been revised from the previously reported 157 bp to 161 bp. Likewise, the number of ITS2 nucleotides has been changed from 177 to 192 bp. The number of ITS1 sequence types has increased from 2 to 15, and that of ITS2 has increased from 3 to 14. The 15 ITS1 sequence types are designated types A through O, and the 14 ITS2 types are named types a through n. A total of 59 types of P. carinii f. sp. hominis were found in this study.

Base Sequence↗
PubMed1998

Determination of copy number of rRNA genes in Pneumocystis carinii f. sp. hominis.

Differential PCR was performed to determine the copy number of rRNA genes in Pneumocystis carinii f. sp. hominis. Two different reference genes, thymidylate synthase (TS) and beta-tubulin (BTU) genes, were used. Primers for the internal transcribed spacer (ITS) region of nuclear rRNA genes and either the TS or BTU gene were mixed together to perform PCR on seven different bronchoalveolar lavage specimens from patients with P. carinii pneumonia. The radioactivity derived from the incorporated radioactive nucleotides of each PCR product band was then used to calculate the copy number of the ITS relative to that of the TS or BTU gene. The copy number ratio between the ITS and the TS gene was determined to be 0.8, and that between the ITS and the BTU gene was also 0.8. These results suggest that the ITS has the same copy number as the TS or BTU gene. Since the copy number of the TS or BTU gene is presumed to be 1, the results also suggest that P. carinii f. sp. hominis has only one copy of the ITS and thus one copy of the nuclear rRNA genes. Therefore, two types of ITS sequences derived from a specimen would indicate that the patient is infected by two types of P. carinii f. sp. hominis.

Bronchoalveolar Lavage Fluid↗
PubMed1998

Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study.

PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.

Adolescent↗
PubMed1998

Preliminary development of an alternative measure of isolation: the construct of institutional isolation.

The Perceptions of Inclusion and Exclusion scale was administered to a sample of 152 university faculty and was used to develop the construct of Institutional Isolation. Preliminary estimates of reliability, factorial, and discriminant data suggest better psychometric characteristics than those of Dean's (1961) General Alienation scale. Institutional isolation reflects employees' sense of adjustment to and acceptance by the organization and is conceptually needed as a precursor to the study of socialization and mentorship. Indeed, further refinement of the scale may provide additional insight into the experiences of particular racial and ethnic groups whose workplace experiences may be less favorable than those of their Euro-American peers.

Employment↗
PubMed1998

Evaluation of potato proteins on the growth performance of early-weaned pigs.

We conducted five experiments to evaluate conventional and low-glycoalkaloid potato protein (CPP and LGPP, respectively) in diets for early-weaned pigs. In Exp. 1, 150 weanling pigs (initially 4.4 +/- .9 kg and 15.5 +/- 2 d of age) were fed either a control diet containing 3% spray-dried animal plasma (SDAP) or diets with additional SDAP (2.5 or 5% added; 5.5 or 8% total) or CPP (2.6% or 5.1%) substituted on a total lysine basis. From d 0 to 14 after weaning, increasing SDAP increased (linear, P < .05) ADG and ADFI, whereas increasing CCP had no effect on growth performance. In Exp. 2, 180 weanling pigs (initially 5.9 +/- 1.2 kg and 20 +/- 2 d of age) were fed diets containing a LGPP replacing 25, 50, 75, or 100% of the 7% dietary SDAP on a digestible lysine basis. From d 0 to 7 after weaning, increasing LGPP increased and then returned to control levels ADG and ADFI (quadratic, P < .01) and gain:feed ratio (quadratic, P < .05). In Exp. 3, 175 weanling pigs (initially 5.5 +/- 1.1 kg and 20 +/- 3 d of age) were fed either a control diet containing 20% dried whey, 17.5% dried skim milk, and 4% select menhaden fish meal (SMFM) or diets consisting of lactose and either 3.5 and 7.0% SDAP or 4.0 and 8.0% LGPP added at the expense of dried skim milk on a digestible lysine basis. From d 0 to 7 after weaning, ADG and ADFI increased (linear, P < .05) with increasing SDAP. With increasing LGPP, ADG and ADFI increased and then decreased (quadratic, P < .10 and P < .05, respectively). Gain:feed ratio (G/F) was not affected by SDAP and was improved (linear, P < .05) for pigs fed increasing LGPP. In Exp. 4, 270 weanling pigs (initially 6.2 +/- 1.6 kg and 20 +/- 3 d of age) were used to compare three diets that contained either 2.5% spray-dried blood meal (SDBM), 4.8% SMFM, or 3.92% CPP; test feedstuffs were substituted on a total lysine basis and diets were fed from d 7 to 28 after weaning. Pigs fed CPP had decreased (P < .05) ADG and G/F compared with those fed the other protein sources. In Exp. 5, 255 weanling pigs (initially 5.3 +/- 1.2 kg and 17 +/- 2 d of age), were used to compare five diets that contained either 2.5% SDBM, 5.51% SMFM, 4.17% CPP, 4.17% LGPP or 8.34% LGPP; feedstuffs were substituted on a digestible lysine basis and diets were fed from d 7 to 28 after weaning. No differences (P > .10) were observed in growth performance among pigs fed any of the protein sources within the experiment. However, pigs fed the LGPP had numerically greater ADG and better G/F than those fed CPP. In conclusion, these results suggest that LGPP can be an effective replacement for a portion of the SDAP in diets for weanling pigs.

Amino Acids↗
PubMed1998

A phase II study of carboplatin, cisplatin, interferon-alpha, and tamoxifen for patients with metastatic melanoma.

The purpose of this trial was to determine the toxicity and antineoplastic activity of cisplatin, carboplatin, tamoxifen, and interferon-alpha (IFN-alpha) in patients with advanced melanoma. Eleven patients with metastatic melanoma were enrolled. The patients received carboplatin 400 mg/m2 i.v. on day 0; cisplatin 25 mg/m2 i.v. on days 7, 14, and 21; tamoxifen 20 mg p.o. b.i.d. on days 0-27; and interferon-alpha 5 million units/m2 subcutaneously 3 times per week. Cycles were repeated every 28 days. Patients were assessed for tumor response at the end of 2 cycles. Toxicity was severe, with 14 of 24 cycles given requiring some form of dose reduction. Carboplatin dose reductions were related to bone-marrow toxicity, whereas IFN-alpha caused fatigue, arthralgias, myalgias, and fever. The overall response rate was 18% (2 partial responses [PRs]). The combination of cisplatin, carboplatin, tamoxifen, and IFN-alpha is active in advanced melanoma; however, the toxicity is unacceptable.

Adult↗
PubMed1998

A series of function blocking antibodies against the alpha v beta 3 integrin bind allosteric to the ligand binding site and induce ligand dissociation.

The alpha v beta 3 integrin plays a critical role in bone resorption, angiogenesis, and tumor cell invasion. A blockade of this receptor has therapeutic potential in osteoporosis, vascular restenosis, and cancer. In this report, we characterize the mechanism by which six monoclonal antibodies inhibit the function of alpha v beta 3. All six antibodies interact with a common site that is partially comprised of residues 164-202 within the beta 3 subunit. This domain is physically separate from the RGD binding site, and appears to regulate ligand binding allosterically. Thus, the blocking antibodies function, in part, by inducing the dissociation of ligand from alpha v beta 3. Although this family of antibodies is able to virtually abolish alpha v beta 3-mediated cell adhesion, they only block about one-half of soluble ligand binding to the integrin. This observation is consistent with the idea that two functionally distinct populations of alpha v beta 3 are present on the cell surface. The unique mechanism of action of these antibodies provides new insight in the structure-function relationships of alpha v beta 3, and also suggest that such antibodies are likely to behave differently than RGD mimetics if used as drugs.

Allosteric Site↗
PubMed1997

Identification of a region in the integrin beta3 subunit that confers ligand binding specificity.

Many integrin adhesion receptors bind ligands containing the Arg-Gly-Asp (RGD) peptide motif. Most integrins exhibit considerable specificity for particular ligands and can distinguish among the many conformations of RGD. In this study we identify the domain of the integrin beta subunit involved in determining ligand binding specificity. Chimeras of beta3 and beta5, the most homologous integrin beta subunits, were expressed with alphav on the surface of human 293 cells. The ligand binding phenotype of each chimera was assessed using the ligands Fab-9 and fibrinogen, both of which have a binding preference for alphavbeta3. The results of the study show that when exons C and D of the beta3 subunit (residues 95-233) are substituted into beta5, the chimera gained the ability to bind Fab-9 with an affinity close to that of wild-type alphavbeta3. This chimera was able to mediate cell adhesion to fibrinogen. Furthermore, the swap of only a 39-residue segment of this larger domain, beta3 residues 164-202, into the backbone of beta5 enabled the chimeric integrin to bind soluble Fab-9. This small domain is highly divergent among the integrin beta subunits, suggesting that it may play a role in determining ligand selection by all integrins.

Amino Acid Sequence↗
PubMed1997

Evidence that the integrin beta3 and beta5 subunits contain a metal ion-dependent adhesion site-like motif but lack an I domain.

The amino-terminal domain of each integrin beta subunit is hypothesized to contain an ion binding site that is key to cell adhesion. A new hypothesis regarding the structure of this site is suggested by the crystallization of the I domains of the integrin alphaL and alphaM subunits (Lee, J.-O., Rieu, P., Arnaout, M. A., and Liddington, R. (1995) Cell 80, 631-638; Qu, A., and Leahy, D. J. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 10277-10281). In those proteins, an essential metal ion is bound by a metal ion-dependent adhesion site (MIDAS). The MIDAS is presented at the apex of a larger protein module called an I domain. The metal ligands in the MIDAS can be separated into three distantly spaced clusters of oxygenated residues. These three coordination sites also appear to exist in the integrin beta3 and beta5 subunits. Here, we examined the putative metal binding site within beta3 and beta5 using site-directed mutagenesis and ligand binding studies. We also investigated the fold of the domain containing the putative metal binding site using the PHD structural algorithm. The results of the study point to the similarity between the integrin beta subunits and the MIDAS motif at two of three key coordination points. Importantly though, the study failed to identify a residue in either beta subunit that corresponds to the second metal coordination group in the MIDAS. Moreover, structural algorithms indicate that the fold of the beta subunits is considerably different than the I domains. Thus, the integrin beta subunits appear to present a MIDAS-like motif in the context of a protein module that is structurally distinct from known I domains.

Amino Acid Sequence↗
PubMed1997

The cell adhesion domain in plasma vitronectin is cryptic.

Vitronectin (Vn) is a major adhesive glycoprotein in blood. However, many of the functions of Vn are regulated by its conformational state and degree of multimerization. Here, the ability of native and denatured Vn to bind to integrin adhesion receptors was compared. Three lines of evidence suggest that the native, plasma form of Vn is not an adhesive glycoprotein. (i) Antibodies that bind in close proximity to the cell adhesion domain of Vn fail to bind to native Vn present in unfractionated plasma. (ii) Denatured Vn binds to both glycoprotein IIb/IIIa and alphavbeta3 in a dose-dependent manner. In contrast, native Vn is unable to bind either integrin. (iii) Thermal denaturation of native Vn, or its complexation with type 1 plasminogen activator inhibitor, exposed the cell adhesion domain of Vn. Thus, while plasma Vn is unable to bind integrins and is not an adhesive glycoprotein, the conformationally altered from of the protein binds avidly to both alphavbeta3 and glycoprotein IIb/IIIa. The data presented here indicate that such conformational changes in Vn are likely to occur in areas of tissue injury and thrombosis.

Antibodies, Monoclonal↗
PubMed1997

Utility of bone marrow culture and biopsy in the diagnosis of disseminated infections in AIDS.

Bone marrow examination (BME) has been used as a diagnostic test of last resort in HIV infected patients. Identifying factors that would increase the diagnostic yield of BME would be useful. A retrospective cohort study was done to determine the predictive value of BME for disseminated infection in 133 patients with HIV infection in a 4-year period at an active HIV clinical center. Thirty-two percent of the cases had evidence of a disseminated infection on BME but only 10% of cases had a diagnosis made exclusively by BME. Multivariate analysis demonstrated that a positive result was more likely in those patients with fewer than 50 CD4 cells/mm3 and those with a hematocrit of less than 25% (P<0.01). BME can be a useful, low-risk diagnostic procedure in selected patients with HIV infection who are ill with a low CD4 count and/or have a hematocrit less than 25%. A diagnosis can usually be made by other means, suggesting that this test should be limited to those in whom other diagnostic modalities have been exhausted.

AIDS-Related Opportunistic Infections↗
PubMed1997

Superior patency of perforating antecubital vein arteriovenous fistulae for hemodialysis.

A comprehensive review of vascular access procedures at one institution over a 10-year period was performed to assess primary hemodialysis (HD) access patency. A total of 427 operations were performed between January 1983 and January 1993. There were 147 Brescia-Cimino fistulae (B-C fistula), 111 perforating antecubital vein (PAV) fistulae, and 28 synthetic graft fistulae. There were 134 patients who were not considered candidates for arteriovenous fistula (AVF) formation and received only central venous HD access. Seven external fistulae in burn patients were deleted from the study. No patient in this study had undergone prior HD access. Primary failure was defined as fistula thrombosis, inadequate flow for hemodialysis, or a complication requiring ligation. Kaplan-Meyer life table analysis was used to determine primary fistula patency. The results were as follows: PAV fistulae had a primary patency rate of 80% at a median follow up of 36 months (1-124 months); the B-C fistula was 66% at a median 27 months (1-120 months), and the synthetic graft fistula was 64% at median 7 months (1-40 months). The primary patency rate of the PAV fistula was significantly better than the B-C fistula (p = 0.0015) or the synthetic graft fistula (p = < 0.0001). In conclusion, the PAV fistula has an excellent patency rate and appears to be a viable option for AV access after a failed B-C fistula or when a B-C fistula is not technically feasible.

Adolescent↗
PubMed1997

Allostery and proteolysis: two novel modes of regulating integrin function.

Integrins are involved in transmitting signals between the cytoplasm and the extracellular matrix. Importantly, the transfer of information is bi-directional: signals flow inside-out and outside-in. Here, I discuss two potential modes by which integrin function is likely to be regulated. It is hypothesized that the integrin cytoplasmic tails are proteolytic substrates, and that cleavage of the cytoplasmic domain regulates the ligand binding affinity of integrins. It is also hypothesized that the ligand binding site is allosterically regulated by separate divalent ion binding sites that independently control ligand association and dissociation rate. Both hypotheses are suggested by reports in the literature and can be tested experimentally.

Cytoplasm↗
PubMed1997

Maternal immunization to Gov system alloantigens on human platelets.

BACKGROUND: Immunization to platelet alloantigens can occur during pregnancy or after the transfusion of blood components. Platelet alloantibodies can cause neonatal alloimmune thrombocytopenia and posttransfusion purpura. Transfusion-induced alloimmunization to a novel platelet alloantigen system, Gov, expressed on the 175-kDa glycosyl phosphatidylinositol-anchored platelet glycoprotein, CD109, was previously described. This report describes three unrelated patients who were alloimmunized to Gov(a) or Gov(b) during pregnancy. STUDY DESIGN AND METHODS: Platelets were typed by using radioimmunoprecipitation for HPA-1a, -3a, -5a, -5b, Gov(a), and Gov(b) and by polymerase chain reaction-restriction fragment length polymorphism for HPA-1a, -1b, -3a, and -3b. Maternal sera were screened for platelet antibodies by using radioimmunoprecipitation and the antigen capture assay. RESULTS: Patients 1 and 2 were investigated after the diagnosis of neonatal alloimmune thrombocytopenia in their children, and alloantibodies specific for Gov(b) and Gov(a), respectively, were detected in maternal serum. Serum from patient 3, who had mild idiopathic thrombocytopenia purpura with no detectable autoantibody, was found to contain alloantibodies to Gov(b) and to HPA-5b, presumably as a result of immunization during pregnancy. Platelet typings confirmed that the patients were at risk for alloimmunization to the respective antigen. CONCLUSION: This report of three cases of maternal alloimmunization to antigens in the Gov system indicates that immunization can occur via placental transfer of antigen and that Gov system alloantibodies may be associated with neonatal alloimmune thrombocytopenia.

Adult↗
PubMed1997

Increased prevalence of infectious diseases and other adverse outcomes in human T lymphotropic virus types I- and II-infected blood donors. Retrovirus Epidemiology Donor Study (REDS) Study Group.

Disease associations of human T lymphotropic virus types I and II (HTLV-I and -II) infection were studied in 154 HTLV-I-infected, 387 HTLV-II-infected, and 799 uninfected blood donors. Adjusted odds ratios (ORs) and 99% confidence intervals (CIs) were derived from logistic regression models controlling for demographics and relevant confounders. All subjects were human immunodeficiency virus type 1-seronegative. HTLV-II was significantly associated with a history of pneumonia (OR, 2.6; 99% CI, 1.2-5.3), minor fungal infection (OR, 2.9; 99% CI, 1.2-7.1), and bladder or kidney infection (OR, 1.6; 99% CI, 1.0-2.5) within the past 5 years and with a lifetime history of tuberculosis (OR, 3.9; 99% CI, 1.3-11.6) and arthritis (OR, 1.8; 99% CI, 1.2-2.9). Lymphadenopathy (> or =1 cm) was associated with both HTLV-I (OR, 6.6; 99% CI, 2.2-19.2) and HTLV-II (OR, 2.8; 99% CI, 1.1-7.1) infection, although no case of adult T cell leukemia/lymphoma was diagnosed. Urinary urgency and gait disturbance were associated with both viruses. This new finding of increased prevalence of a variety of infections in HTLV-II-positive donors suggests immunologic impairment.

Adolescent↗
PubMed1997

Current practices of preoperative bowel preparation among North American colorectal surgeons.

In North America, the rate of infections following colorectal surgery decreased after the introduction of oral antibiotic bowel preparation against colonic microflora. Eight hundred eight board-certified colorectal surgeons were surveyed for their current bowel preparation practices before elective procedures. The 471 responders (58%) all use mechanical preparation: oral polyethylene glycol solution (70.9% of the respondents), oral sodium phosphate solution with or without bisacodyl (28.4%), and "traditional" methods of dietary restriction, cathartics, and enemas (28.4%). Most surgeons (86.5%) add oral and parenteral antibiotics to the regimen; 11.5% add only parenteral antibiotics, 1.1% add only oral antibiotics, and 0.9% add no antibiotics. Generally (77.8% of cases), oral neomycin and erythromycin or metronidazole are combined with a perioperative parenteral antibiotic. Most individuals start the preparation as outpatients the day before surgery, and the parenteral drugs are added to the regimen 1-2 hours before the procedure. The use of outpatient bowel preparation is increasing; however, patient selection is critical, and education is needed to reduce the rate of complications.

Anti-Bacterial Agents↗
PubMed1997

Dihydropteroate synthase polymorphisms in Pneumocystis carinii.

Sulfa drugs are widely used in the treatment and prophylaxis of Pneumocystis carinii pneumonia. The nucleotide sequences of the sulfa target enzyme, dihydropteroate synthase (DHPS), differed substantially in human-, rat-, and mouse-derived P. carinii. Sequence variation also existed in the DHPSs from human-derived isolates. Six nucleotide changes were found in 6 human isolates; each was nonsynonymous and resulted in an amino acid change. Several of these changes were in highly conserved regions and are similar to those that cause sulfa resistance in other organisms. These data suggest that the human-derived P. carinii DHPS may be evolving under positive selective pressure from sulfa drugs.

Amino Acid Sequence↗