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Biomedical subjects

J W Smith

Publications and source records attributed to J W Smith.

At least 37 records · Page 2Linked to original sources
PubMed2001

MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells.

We evaluated cellular mechanisms involved in the activation pathway of matrix prometalloproteinase-2 (pro-MMP-2), an enzyme implicated in the malignant progression of many tumor types. Membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves the N-terminal prodomain of pro-MMP-2 thus generating the activation intermediate that then matures into the fully active enzyme of MMP-2. Our results provide evidence on how a collaboration between MT1-MMP and integrin alphavbeta3 promotes more efficient activation and specific, transient docking of the activation intermediate and, further, the mature, active enzyme of MMP-2 at discrete regions of cells. We show that coexpression of MT1-MMP and integrin alphavbeta3 in MCF7 breast carcinoma cells specifically enhances in trans autocatalytic maturation of MMP-2. The association of MMP-2's C-terminal hemopexin-like domain with those molecules of integrin alphavbeta3 which are proximal to MT1-MMP facilitates MMP-2 maturation. Vitronectin, a specific ligand of integrin alphavbeta3, competitively blocked the integrin-dependent maturation of MMP-2. Immunofluorescence and immunoprecipitation studies supported clustering of MT1-MMP and integrin alphavbeta3 at discrete regions of the cell surface. Evidently, the identified mechanisms appear to be instrumental to clustering active MMP-2 directly at the invadopodia and invasive front of alphavbeta3-expressing cells or in their close vicinity, thereby accelerating tumor cell locomotion.

Antibodies, Monoclonal↗
PubMed2001

Integrin activation controls metastasis in human breast cancer.

Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin alpha v beta 3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin alpha v beta 3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated alpha v beta 3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant alpha v beta 3(D723R), but not alpha v beta 3(WT), in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin alpha v beta 3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

Animals↗
PubMed2001

Unintentional platelet removal by plasmapheresis.

Therapeutic plasmapheresis may remove platelets as well as plasma. Unintentional platelet loss, if not recognized, may lead to inappropriate patient assessment and treatment. A patient with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is reported in whom persistent thrombocytopenia was interpreted as continuing active disease; thrombocytopenia resolved only after plasma exchange treatments were stopped. This observation prompted a systematic study of platelet loss with plasmapheresis. Data are reported on platelet loss during 432 apheresis procedures in 71 patients with six disease categories using three different instruments. Comparing the first procedure recorded for each patient, there was a significant difference among instrument types (P<0.001); platelet loss was greater with the Fresenius AS 104 (17.5%, N = 21) than with the COBE Spectra (1.6%, N = 26) or the Haemonetics LN9000 (2.6%, N = 24). With all procedures, platelet loss ranged from 0 to 71%. Among disease categories, platelet loss was greater in patients with dysproteinemias who were treated for hyperviscosity symptoms. Absolute platelet loss with the first recorded apheresis procedure, in the 34 patients who had a normal platelet count before the procedure, was also greater with the AS 104 (2.23 x 10(11) platelets) than with the Spectra (0.29 x 10(11) platelets) or the LN9000 (0.37 x 10(11) platelets). In 39 patients in whom data were collected on consecutive days, platelet removal by plasmapheresis correlated with a decreased patient platelet count (r = 0.40, P = 0.011). In these 39 patients, the platelet counts were significantly decreased at 24 hours (P = 0.002).

Amnesia↗
PubMed2001

Repeat whole-blood and plateletpheresis donors:unreported deferrable risks, reactive screening tests, andresponse to incentive programs.

BACKGROUND: Evaluating plateletpheresis (PPH) and repeat community whole-blood (RWB) donors' responses to donation incentive programs is essential for developing effective donor retention programs. STUDY DESIGN AND METHODS: Using data from a 1998 anonymous questionnaire sent to 92,581 US blood donors, the prevalence of unreported deferrable risks, screening test reactivity, and response to incentives were compared in RWB and PPH donors by the use of weighted chi-square tests and logistic regression analyses. RESULTS: From 52,650 respondents, 38,884 RWB and 2,028 PPH donors were identified. Levels of screening test reactivity (1%) and unreported deferrable risks (UDRs, 2-3%) were similar in RWB and PPH donors. RWB and PPH donors were strongly encouraged or discouraged by similar incentives. Of the incentives that would encourage a higher proportion of UDR-free RWB donors to return, cholesterol screening and earning a blood credit appealed to >50 percent. Similar results were obtained for cholesterol screening in PPH donors. Community service or education credits, premarital screening, and cash had limited appeal for PPH and RWB donors, respectively, and would be more likely to differentially encourage donors with a UDR to return. CONCLUSION: Incentives that were associated with the greatest donor appeal and that minimized the potential recruitment of more risky donors were identified.

Adult↗
PubMed2001

Multicenter evaluation of PCR methods for detecting CMV DNA in blood donors.

BACKGROUND: CMV DNA screening may be a useful adjunct to serologic tests in distinguishing potentially infectious blood donations from those that are "CMV-safe." However, there is currently no consensus on the optimal assay method for accurate detection of CMV DNA in donors. STUDY DESIGN AND METHODS: A blinded multicenter evaluation of seven CMV PCR assays was performed by five laboratories by using coded sets of analytical controls and donor blood samples. RESULTS: Five assays displayed sufficient sensitivity for donor screening, as judged by consistent detection of a minimum of 25 CMV genome equivalents (geq) in analytical controls constructed to contain from 1 to 100 CMV geq in background DNA from 250,000 cells, while the other two assays displayed inadequate sensitivity. Three sensitive assays, two based on nested PCR directed at the UL93 and UL32 regions of the CMV genome and another test (Monitor Assay, Roche), did not detect CMV DNA in samples from any of 20 pedigreed CMV-seronegative, Western blot-negative (S-/WB-) donors. Two other assays based on nested PCR occasionally detected CMV DNA in S-WB- samples, and one sensitive nested PCR assay directed at UL123 detected CMV DNA in a large proportion (85%) of S-WB- samples. CONCLUSION: Seven CMV PCR assays currently used for research and/or diagnostic applications displayed marked variations in sensitivity, specificity, and reproducibility when applied to coded analytical and clinical control samples containing cellular DNA from the equivalent of 250,000 WBCs. These results will be useful in the selection of assays with performance characteristics appropriate to donor screening objectives. They may also help explain discrepant findings from previous studies that used PCR to determine CMV DNA prevalence in seronegative and seropositive blood donors.

AIDS-Related Opportunistic Infections↗
PubMed2001

The utility of lung biopsy in recipients of stem cell transplantation.

BACKGROUND/PURPOSE: Pulmonary infiltrates in recipients of stem cell transplantation often present as diagnostic dilemmas. Although lung biopsy may establish the diagnosis of parenchymal disease, it remains unclear whether such a procedure results in a significant change in the patient's treatment and outcome. This study evaluates the efficacy of lung biopsy in recipients of stem cell transplantation. METHODS: The medical records of 15 stem cell transplant recipients who underwent 18 lung biopsies were reviewed. The indications for stem cell transplantation were leukemia in 10 patients, lymphoma in 2, histiocytosis in 1, neuroblastoma in 1, and Ewing's sarcoma in 1. The results of the lung biopsies were correlated to the clinical management and outcomes. RESULTS: The overall mortality rate was 67% (10 patients). Eight of the 9 patients who required mechanical ventilatory support at the time of lung biopsy died. The pathologic diagnoses were pneumonitis in 6 biopsies, fibrosis in 6, brochiolitis obliterans organizing pneumonia in 3, hemorrhage in 2, and infarction in 1. Therapy was changed in 1 patient who improved after a course of steroids for bronchiolitis obliterans organizing pneumonia. Lung biopsy cultures were positive in 6 patients but rarely resulted in changes in antibiotic therapy. CONCLUSIONS: Results of very few lung biopsies performed in stem cell transplant recipients redirected therapy. Furthermore, the ultimate outcome of these patients were not improved by the results of lung biopsies.

Adolescent↗
PubMed2001

Evaluation of a combined calcium sodium alginate and bio-occlusive membrane dressing in the management of split-thickness skin graft donor sites.

The optimal treatment of the split-thickness skin graft (STSG) donor site remains an unresolved issue. This study was conducted to evaluate the combined use of calcium sodium alginate and a bio-occlusive membrane dressing in the management of STSG donor sites. This study was a prospective evaluation of all patients requiring an STSG over a 6-month period ending October 1998. There were 57 patients with a mean age of 61 years. All skin grafts were harvested with an electric dermatome from the anterior thigh and were 0.012 to 0.016 inches thick. Donor sites were dressed with calcium sodium alginate followed by a bio-occlusive dressing. Postoperatively, the skin graft donor site dressing was removed and replaced. The mean skin graft area was 114 cm2. The first dressing change occurred, on average, 3 days postoperatively. All dressings were taken down and the wounds reevaluated 7 days postoperatively. Fifty-two patients (91%) had achieved complete reepithelialization by this time. Five patients (9%) required an additional dressing. All wounds were healed completely by postoperative day 10. Donor site discomfort was minimal and limited to the time of dressing change. There were no wound-related complications. The average cost of dressing supplies was $48.00 per patient and $23.00 per dressing. This method of managing STSG donor sites allowed for unimpeded reepithelialization without wound complication. The bio-occlusive dressing eliminated the pain typically associated with fine mesh gauze dressings. The absorptive property of the calcium sodium alginate eliminated the problem of seroma formation and leakage seen routinely with the use of a bio-occlusive dressing alone. These results confirm that this technique is both efficacious and cost-effective.

Adult↗
PubMed2001

The influence of a competitor on the geographic mosaic of coevolution between crossbills and lodgepole pine.

The geographic mosaic theory of coevolution posits that the form of selection between interacting species varies across a landscape with coevolution important and active in some locations (i.e., coevolutionary hotspots) but not in others (i.e., coevolutionary coldspots). We tested the hypothesis that the presence of red squirrels (Tamiasciurus hudsonicus) affects the occurrence of coevolution between red crossbills (Loxia curvirostra complex) and Rocky Mountain lodgepole pine (Pinus contorta ssp. latifolia) and thereby provides a mechanism giving rise to a geographic mosaic of selection. Red squirrels are the predominant predispersal seed predator and selective agent on lodgepole pine cones. However, in four isolated mountain ranges east and west of the Rocky Mountains, red squirrels are absent and red crossbills are the main predispersal seed predator. These isolated populations of pine have apparently evolved without Tamiasciurus for about 10,000 to 12,000 years. Based on published morphological, genetic, and paleobotanical studies, we infer that cone traits in these isolated populations that show parallel differences from cones in the Rocky Mountains have changed in parallel. We used data on crossbill and conifer cone morphology and feeding preferences and efficiency to detect whether red crossbills and lodgepole pine exhibit reciprocal adaptations, which would imply coevolution. Cone traits that act to deter Tamiasciurus and result in high ratios of cone mass to seed mass were less developed in the isolated populations. Cone traits that act to deter crossbills include larger and thicker scales and perhaps increased overlap between successive scales and were enhanced in the isolated populations. In the larger, isolated mountain ranges crossbills have evolved deeper, shorter, and therefore more decurved bills to exploit these cones. This provides crossbills with higher feeding rates, and the change in bill shape has improved efficiency by reducing the concomitant increases in body mass and daily energy expenditures that would have resulted if only bill size had increased. These parallel adaptations and counter adaptations in red crossbills and lodgepole pine are interpreted as reciprocal adaptations and imply that these crossbills and pine are in coevolutionary arms races where red squirrels are absent (i.e., coevolutionary hotspots) but not where red squirrels are present (i.e., coevolutionary cold-spots).

Animals↗
PubMed2001

Activities and conformational fitting of 1,4-naphthoquinone derivatives and other cyclic 1,4-diones tested in vitro against Pneumocystis carinii.

Atovaquone is a chemotherapeutic agent used to treat pneumonia caused by Pneumocystis carinii in some immunocompromised patients. A set of cyclic 1,4-diones were tested in vitro for ability to inhibit growth of P. carinii, including 22 variously substituted 1,4-naphthoquinones, one bis-1,4-naphthoquinone, and three other quinones. For comparison, the antipneumocystic primaquine and its 5-hydroxy-6-desmethyl metabolite were also tested. At 1.0 microg/ml, seven compounds inhibited growth by at least 39%, with atovaquone at 92%; of these seven, five are 2-hydroxy-1,4-naphthoquinones, while one is a 2-chloro- and another is a 2-methyl-1,4-naphthoquinone. At 0.1 microg/ml, however, the most active compound tested was the primaquine metabolite, which inhibited growth by more than 42% at this concentration. To ascertain a structure-activity relationship, all 1,4-naphthoquinones were compared conformationally by means of computer-based molecular modeling (Spartan) incorporating the Sybyl force field. Without exception, for all 21 monomers tested, the substituent at position 3 of the 1,4-naphthoquinone favored activity most strongly when it simultaneously occupied (i) space centered at about 3 A from position 3, without projecting steric bulk from the area encompassed by atovaquone's cyclohexyl ring, and (ii) roughly planar space at about 7.3 A from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents.

Antifungal Agents↗
PubMed2001

Internal transcribed spacer regions of rRNA genes of Pneumocystis carinii from monkeys.

Analysis of sequence variations among isolates of Pneumocystis carinii f. sp. macacae from 14 Indian rhesus monkeys (Macaca mulatta) at the internal transcribed spacer (ITS) regions of the nuclear rRNA gene was undertaken. Like those from P. carinii f. sp. hominis, the ITS sequences from various P. carinii f. sp. macacae isolates were not identical. Two major types of sequences were found. One type of sequence was shared by 13 isolates. These 13 sequences were homologous but not identical. Variations were found at 13 of the 180 positions in the ITS1 region and 28 of the 221 positions in the ITS2 region. These sequence variations were not random but exhibited definite patterns when the sequences were aligned. According to this sequence variation, ITS1 sequences were classified into three types and ITS2 sequences were classified into five types. The remaining specimen had ITS1 and ITS2 sequences substantially different from the others. Although some specimens had the same ITS1 or ITS2 sequence, all 14 samples exhibited a unique whole ITS sequence (ITS1 plus ITS2). The 5.8S rRNA gene sequences were also analyzed, and only two types of sequences that differ by only one base were found. Unlike P. carinii f. sp. hominis infections in humans, none of the monkey lung specimens examined in this study were found to be infected by more than one type of P. carinii f. sp. macacae. These results offer insights into the genetic differences between P. carinii organisms which infect distinct species.

Animals↗
PubMed2001

Effects of choice white grease or poultry fat on growth performance, carcass leanness, and meat quality characteristics of growing-finishing pigs.

Eighty-four crossbred gilts were used to evaluate the effects of dietary choice white grease (CWG) or poultry fat (PF) on growth performance, carcass characteristics, and quality characteristics of longissimus muscle (LM), belly, and bacon of growing-finishing pigs. Pigs (initially 60 kg) were fed a control diet with no added fat or diets containing 2, 4, or 6% CWG or PF. Diets were fed from 60 to 110 kg and contained 2.26 g lysine/Mcal ME. Data were analyzed as a 2 x 3 factorial plus a control with main effects of fat source (CWG and PF) and fat level (2, 4, and 6%). Pigs fed the control diet, 2% fat, and 4% fat had greater (P < 0.05) ADFI than pigs fed 6% fat. Pigs fed 6% fat had greater (P < 0.05) gain/feed (G/F) than pigs fed the control diet or other fat levels. Subcutaneous fat over the longissimus muscle from pigs fed CWG had more (P < 0.05) moisture than that from pigs fed PF. Feeding dietary fat (regardless of source or level) reduced (P < 0.05) the amount of saturated fats present in the LM. Similarly, 4 or 6% fat decreased (P < 0.05) the amount of saturated fats and increased unsaturated fats present in the bacon. No differences (P > 0.05) were observed for ADG, dressing percentage, leaf fat weight, LM pH, backfat depth, LM area, percentage lean, LM visual evaluation, LM waterholding capacity, Warner-Bratzler shear and sensory evaluation of the LM and bacon, fat color and firmness measurements, or bacon processing characteristics. Adding dietary fat improved G/F and altered the fatty acid profiles of the LM and bacon, but differences in growth rate, carcass characteristics, and quality and sensory characteristics of the LM and bacon were minimal. Dietary additions of up to 6% CWG or PF can be made with little effect on quality of pork LM, belly, or bacon.

Adipose Tissue↗
PubMed2001

Effect of region and herd size on dairy herd performance parameters.

Differences in selected Dairy Herd Improvement (DHI) performance parameters among regions and herds of different size categories were evaluated. DHI records from herds in 37 states were grouped into North, Midsouth, and South regions, and six herd size categories (20 to 49, 50 to 99, 100 to 149, 150 to 249, 250 to 449, and > or = 450 cows). The North region had higher income over feed costs (IOFC); milk, fat, and protein rolling herd averages; summit milk; standardized 150-d milk; and percentage of cows in milk, than the other regions. These variables were lowest for the South region. Cost/45.4 kg of milk, days open, days dry, and somatic cell counts were lowest in the North region and were highest in the South. Percentage of cows entering and leaving the herd were highest in the Midsouth and were lowest in the South. Larger herds had higher total feed cost, IOFC, milk, fat, and protein rolling herd averages, summit milk, standardized 150-d milk, percentage of cows entering and percentage leaving the herd than smaller herds. Larger herds had lower somatic cell counts than smaller herds. Cost/45.4 kg of milk, days dry, days open, days in milk, and percentage of cows in milk did not show clear trends among different herd sizes. There were significant interactions between region and herd size for some of the variables.

Animal Feed↗
PubMed2000

A redox site involved in integrin activation.

Integrin adhesion receptors contain an on/off switch that regulates ligand binding affinity and cell adhesion. The switch from "off" to "on" is commonly referred to as integrin activation. The objective of this study was to gain insight into the nature of the on/off switch in platelet integrin alpha(IIb)beta(3). Here, we show that a select group of the cysteines, located within the extracellular cysteine-rich domain of the beta subunit, remain unpaired. These unpaired cysteine residues exhibit the properties of a redox site involved in integrin activation. Alterations to the redox site prevent the inter-conversion between resting and active integrin. Altogether, the study establishes integrin as a direct target for redox modulation, revealing an unappreciated link between cell adhesion and redox biology.

Amino Acid Sequence↗
PubMed2000

Trends in incidence and prevalence of major transfusion-transmissible viral infections in US blood donors, 1991 to 1996. Retrovirus Epidemiology Donor Study (REDS)

CONTEXT: Evaluating trends in blood donor infectious disease rates is essential for monitoring blood supply safety and donor screening effectiveness. OBJECTIVE: To determine changes over time in blood donor population infection rates of human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis C virus (HCV), and hepatitis B virus (HBV). DESIGN: Cross-sectional survey data from the National Heart, Lung, and Blood Institute-sponsored Retrovirus Epidemiology Donor Study. SETTING: Five blood centers in different regions of the United States. PARTICIPANTS: A total of 1.9 million volunteer blood donors with 1 or more nonautologous donations from January 1991 to December 1996. MAIN OUTCOME MEASURES: Changes in rates of HIV, HTLV, HCV, and HBV infections were evaluated by comparing yearly prevalence estimates (per 100,000 donations) for first-time allogeneic donors and period-specific incidence rates (IRs) (per 100,000 person-years) for repeat allogeneic donors between 1991 and 1996 (for HCV, from about March 1992 to June 1996). RESULTS: Prevalence of HIV decreased in first-time donors from 0.030% to 0.015% (P=.006) and HCV prevalence decreased from 0.63% to 0.40% (P<.001). Trends were not statistically significant for the proportion of first-time donors with hepatitis B surface antigen (HBsAg) or HTLV. For repeat donors, IRs did not change significantly, indicating a stable but low level of seroconversion. The overall IRs (95% confidence intervals) per 100,000 person-years were 2.92 (2.26-3.70) for HIV, 1.59 (1.12-2.19) for HTLV, 3.25 (2.36-4.36) for HCV, and an estimated 10.43 (7.99-13. 37) for HBV (based on an HBsAg rate of 2.66 [2.04-3.41] with presumed false-positive results considered negative). The HBV IR estimate with presumed false-positive results considered positive (for comparability to previous analyses) was 17.83 (14.60-21.56). CONCLUSION: The decrease in HIV and HCV prevalence rates, combined with the previously documented lower rates of infection in first-time donors compared with the general population, suggests the continued benefit of behavioral risk factor screening. JAMA. 2000;284:229-235

Blood Banks↗
PubMed2000

Differential effects of a dihydropyridine calcium channel antagonist on the components of ethanol tolerance.

The dihydropyridine calcium channel antagonist, nimodipine, was found to decrease the extent of tolerance that developed to the ataxic action of ethanol in experimental designs in which the tolerance was not context-specific, when ethanol was given by liquid diet. When ethanol was given by injection, so that cues were present for the effects of ethanol during the chronic treatment, tolerance to the ataxic actions of ethanol was unaffected. Nimodipine, however, decreased the tolerance to the hypothermic actions of ethanol, when the ethanol was given by injection. When the rats were given practice sessions on the motor task while under the influence of the ethanol, during the chronic treatment, nimodipine did not affect tolerance to the ataxic actions of ethanol. When nimodipine was given before the motor task learning and ethanol after the practice sessions, the tolerance to the ataxic effect of ethanol was increased. A similar schedule of drug treatment with the NMDA antagonist CGP37849 given before the practice sessions, and ethanol afterwards, resulted in decreased tolerance to ethanol. It is suggested that these changes in ethanol tolerance may be explained by dual actions of nimodipine in, firstly, decreasing the form of tolerance to ethanol that is not dependent on contextual cues and, secondarily, in increasing the learning of a motor task.

2-Amino-5-phosphonovalerate↗