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Biomedical subjects

D Smith

Publications and source records attributed to D Smith.

At least 289 records · Page 16Linked to original sources

Breast cancer in New South Wales in 1972-1995: tumor size and the impact of mammographic screening.

To examine the use of mammographic screening in women in New South Wales (NSW), we measured uptake of initial mammograms and estimated the proportions of breast cancers that were screen detected. To see if mammographic screening has been associated with reductions in advanced breast cancers and mortality from breast cancer, we analyzed trends in age-specific and age-standardized breast cancer incidence and mortality from 1972 to 1995 and tumor size in 1986, 1989, 1992 and April to September 1995. Between 1984 and the end of 1995, an estimated 72% of NSW women in their 50s and 67% in their 60s had had at least 1 mammogram and, in 1995, an estimated 39% of invasive breast cancers in women in these age groups were detected by mammography. Before 1989, breast cancer incidence increased only slightly (+1.3% annually) but then, from 1990 to 1995, increased more rapidly (+3.1% annually). Between 1986 and 1995, rates of small cancers (< 1 cm) increased steeply by 2.7 times in women 40-49 years of age and 5.6 times in women 50-69 years of age. The incidence of large breast cancers (3+ cm), after little apparent change to 1992, fell by 17% in women 40-49 years of age and 20% in those 50-69 years of age to 1995. Breast cancer mortality increased slightly between 1972 and 1989 (+0.5% annually) but then fell (-2.3% annually) from 1990 to 1995. We concluded that breast cancer rates had been influenced in expected directions by the introduction of mammographic screening in women resident in NSW. We expect that recent falls in incidence of larger breast cancers and breast cancer mortality will become steeper as screening coverage increases in the second half of the 1990s.

Adult↗

HTLV-I-infected T cells evade the antiproliferative action of IFN-beta.

Human T-cell lymphotropic virus type I (HTLV-I)-infected T-cell clones enter the S-phase of the cell cycle in the absence of exogenous IL-2. The pathway by which HTLV-I activates the host T cell may circumvent normal immunoregulatory mechanisms and thus be important for the pathogenesis of HTLV-I-induced diseases. The early control of viral infections is in part mediated by interferons (IFNs), which possess both antiviral and antiproliferative functions. In order to investigate the antiproliferative effect of IFN-beta on HTLV-I-induced T-cell activation, we generated T-cell clones from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis by single-cell cloning under limiting dilution conditions. Here we demonstrate that HTLV-I-induced T-cell proliferation is resistant to the antiproliferative action of IFN-beta. Moreover, HTLV-I-infected T-cell clones continue to constitutively secrete IFN-gamma in the presence of high doses of IFN-beta. HTLV-I-infected T cells express normal levels of IFNAR1 and are able to respond to IFN-beta by phosphorylation of STAT1 on Tyr701, although they display a relative increase in phosphorylation of the transcriptionally inactive STAT1beta when compared with STAT1alpha. Thus, HTLV-I promotes cell cycle progression in G1 by a mechanism that overcomes inhibitory signals, thereby circumventing an innate immune defense mechanism.

Cell Cycle↗

pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines.

A major obstacle for the effective treatment of cancer is the phenomenon of multidrug resistance (MDR) exhibited by many tumor cells. Many, but not all, MDR cells exhibit membrane-associated P-glycoprotein (P-gp), a drug efflux pump. However, most mechanisms of MDR are complex, employing P-gp in combination with other, ill-defined activities. Altered cytosolic pH (pHi) has been implicated to play a role in drug resistance. In the current study, we investigated mechanisms of pHi regulation in drug-sensitive (MCF-7/S) and drug-resistant human breast cancer cells. Of the drug-resistant lines, one contained P-gp (MCF-7/DOX; also referred to as MCF-7/D40) and one did not (MCF-7/MITOX). The resting steady-state pHi was similar in the three cell lines. In addition, in all the cell lines, HCO3- slightly acidified pHi and increased the rates of pHi recovery after an acid load, indicating the presence of anion exchanger (AE) activity. These data indicate that neither Na+/H+ exchange nor AE is differentially expressed in these cell lines. The presence of plasma membrane vacuolar-type H+-ATPase (pmV-ATPase) activity in these cell lines was then investigated. In the absence of Na+ and HCO3-, MCF-7/S cells did not recover from acid loads, whereas MCF-7/MITOX and MCF-7/DOX cells did. Furthermore, recovery of pHi was inhibited by bafilomycin A1 and NBD-Cl, potent V-ATPase inhibitors. Attempts to localize V-ATPase immunocytochemically at the plasma membranes of these cells were unsuccessful, indicating that V-ATPase is not statically resident at the plasma membrane. Consistent with this was the observation that release of endosomally trapped dextran was more rapid in the drug-resistant, compared with the drug-sensitive cells. Furthermore, the drug-resistant cells entrapped doxorubicin into intracellular vesicles whereas the drug-sensitive cells did not. Hence, it is hypothesized that the measured pmV-ATPase activity in the drug-resistant cells is a consequence of rapid endomembrane turnover. The potential impact of this behavior on drug resistance is examined in a companion manuscript.

Antineoplastic Agents↗

Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.

The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.

Acute Disease↗

Stability of cutaneous anergy in women with or at risk for HIV infection. HIV Epidemiology Research Study Group.

OBJECTIVE: To study the stability of cutaneous anergy in women with or at risk for HIV infection. DESIGN: Prospective multicenter cohort study METHODS: Interviews, CD4+ lymphocyte counts, and intradermal skin testing with mumps, Candida, and tetanus toxoid antigens were performed on two occasions at a median interval of 74 weeks in 436 HIV-seropositive and 252 seronegative at-risk women; only 10 (2%) HIV-seropositive women were taking highly active antiretroviral therapy at the time of delayed-type hypersensitivity (DTH) testing. Anergy was defined as induration <2 mm to all three antigens. RESULTS: Skin test reactivity at repeat testing was seen in 202 of 233 (87%) HIV-seronegative women who were not anergic at baseline, compared with 10 (53%) of 19 seronegative women who were anergic at baseline (relative risk [RR], 1.7; 95% confidence interval [CI], 1.07-2.5). Anergy at retesting was seen in 108 of 169 (64%) HIV-seropositive women who were previously anergic, compared with 77 of 267 (29%) who were not previously anergic (RR, 2.2; 95% CI, 1.8-2.8). Among initially anergic seropositive women, CD4+ lymphocyte counts were lower at both initial and follow-up testing in those who remained anergic than in those who reacted at follow-up (p < .001). The relative risks for anergy at retesting of initially anergic seropositive women, compared with initially reactive seropositive women, were related to CD4+ level; 2.5 (95% CI, 1.4-4.3) for CD4+ counts < 200 cells/mm3, 2.0 (95% CI, 1.5-1.7) for CD4+ counts 200-500 cells/mm3, and 1.6 (95% CI, 0.9-2.8) for CD4+ counts >500 cells/mm3. CONCLUSIONS: Although anergic HIV-seropositive women may become reactive, cutaneous anergy predicts a higher likelihood of anergy at retesting as well as lower CD4+ counts. Stability of anergy is greatest in HIV-seropositive women with low CD4+ counts.

CD4 Lymphocyte Count↗

Crystallization and preliminary crystallographic analysis of the endo-polygalacturonase from Erwinia carotovora ssp. carotovora.

Crystals of endo-polygalacturonase from Erwinia carotovora ssp. carotovora have been grown from polyethylene glycol 6000 by the hanging-drop method. Polygalacturonase is important in the virulence of this plant pathogen. The protein crystallizes in space group C2 with unit-cell parameters a = 81.3, b = 53.0, c = 103.1 A, beta = 112.6 degrees and with a single molecule in the asymmetric unit. The crystals diffract to 1.9 A.

Bacillus subtilis↗

Prenatal tests: how are women deciding?

Women offered prenatal tests should be given sufficient information to enable them to make an informed decision. We compared the decision-making of 261 women who underwent serum screening for Down syndrome with 63 who did not. A questionnaire completed at 16 weeks' gestation assessed systematic decision-making (the weighing up of pros and cons on the basis of information presented), knowledge, anxiety and demographic information. Those undergoing screening were older but, with age partialled out, they had more knowledge about the test and made decisions less systematically than those not screened.

Adult↗

Selected ion flow tube mass spectrometry of urine headspace.

We describe the use of our selected ion flow tube mass spectrometric technique (SIFT-MS) for the analysis of the headspace above urine. Ammonia, nitric oxide, acetone, ethanol and methanol are identified as the dominant species. As expected, the ammonia is increased in the headspace by making the urine alkaline and the nitric oxide is increased by making the urine acidic. Nitric oxide is abnormally high in the headspace of acidified bacterially infected urine and nitrous acid is also detected. The potential clinical implications of analyses of urine by SIFT-MS are alluded to.

Acetone↗

Analysis of formaldehyde in the headspace of urine from bladder and prostate cancer patients using selected ion flow tube mass spectrometry.

We have used selected ion flow tube mass spectrometry (SIFT-MS) to determine the concentration of formaldehyde in the headspace of urine from patients suffering from bladder and prostate cancer and from several healthy subjects as controls. We address the potential problems associated with the use of ion chemistry to quantify formaldehyde in the presence of the relatively large number densities of water molecules and show that formaldehyde can be quantified in urine headspace using analysis by SIFT-MS. These studies show that formaldehyde is clearly elevated in the headspace of the urine from the cancer patients as compared with urine from the healthy controls. Thus, with further improvements in the methodology and the sensitivity of our SIFT-MS technique, formaldehyde quantification in urine headspace using this new analytical method could be a valuable non-invasive indicator of the presence of early-stage tumours in the body.

Formaldehyde↗

Quantification of breath isoprene using the selected ion flow tube mass spectrometric analytical method.

We have used our selected ion flow tube mass spectrometric method (SIFT-MS) to study isoprene levels in the alveolar breath of 29 healthy volunteers during normal working hours at the varying states of nutrition occurring during this period. Quantification of the breath isoprene was achieved using O(2)(+) precursor ions to avoid complications which can arise when using H(3)O(+) precursor ions for isoprene analysis. The present data indicate that the spread of the alveolar isoprene levels in this sample of healthy individuals is 22 to 234 ppb and that the mean value is 83 ppb with a standard deviation of 45 ppb. These levels are compared with those previously determined using other techniques and are seen to be at the low end of the values previously reported. The present studies are a prelude to an investigation of the proposed correlation of breath isoprene levels with psychological, physical and biochemical stress.

Adult↗

Association of HLA alleles and clinical features in patients with synovitis of recent onset.

OBJECTIVE: To determine how HLA alleles are associated with the clinical disease patterns of patients with synovitis of recent onset. METHODS: The HLA alleles A, B, C, DRbeta1, and DQbeta1 were determined in a cohort of 211 patients (mean age 42 years, 64% female, 79% white) with recent-onset synovitis in 1 or more peripheral joints. At a mean disease duration of 33 weeks, 98 patients (46%) met the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), 38 (18%) met the European Spondylarthropathy Study Group criteria for spondylarthropathy (SpA), and 75 (36%) were classified as having undifferentiated arthropathy (UA). Controls were racially matched healthy individuals (n = 244). RESULTS: Shared epitope (SE) alleles were significantly more common in rheumatoid factor-positive (RF+) patients fulfilling the ACR RA criteria than in other patients with early arthritis (65% versus 35%; P < 0.001). In addition, the RA patients had by far the highest frequency of radiographic erosions (52% and 39% in RF+ and RF- RA, respectively, versus 3% and 9% in SpA and UA patients, respectively; P < 0.0001). The presence of SE alleles was a particularly strong predictor of early erosions in the RF- RA patients (odds ratio [OR] 6.8, 95% confidence interval [95% CI] 1.2-45). The presence of 2 SE alleles or an associated DQbeta1*0301 (DQ7) or DQbeta1*0302 (DQ8) allele appeared to modestly increase the risk of early erosions, although these DQ alleles were in strong linkage disequilibrium with DRbeta1*0401, both in the patient and in the control populations. B27 was linked with the presence of SE alleles in the patients, including those patients fulfilling the RA criteria, but not in the controls (12% versus 3%; P < 0.001). Enthesitis was present in 23 (11%) of 211 patients, was highly associated with B27 (OR 4.2, 95% CI 1.5-11.5), and surprisingly, was not a feature specific only to the SpA group. The B8-DR3 haplotype was significantly increased in the patient subgroups compared with controls (17% versus 7%; P < 0.01), although the clinical significance of this association is unclear. CONCLUSION: This study of HLA associations in a diverse cohort of early synovitis patients emphasizes the complex degree of genetic interaction between alleles at several major histocompatibility complex loci, which regulates clinical phenotypes. In particular, SE and B27, while predisposing patients to characteristic clinical syndromes, had an unexpected degree of association in this cohort, perhaps explaining the overlap in clinical features in many patients.

Adult↗

Quality of life in systemic lupus erythematosus patients during more and less active disease states: differential contributors to mental and physical health.

OBJECTIVE: To identify determinants of mental and physical health as a function of disease state in patients with systemic lupus erythematosus (SLE). METHODS: A sample of 129 SLE patients (mean age 42.01 years; SD 11.09) was recruited from 9 immunology/rheumatology clinics across Canada. Patients completed questionnaires assessing psychological distress, social support, coping, stress, and health-related quality of life. Physicians rated disease activity (using the revised Systemic Lupus Activity Measure; SLAM-R) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). Mental and physical health composite scores were derived from the Medical Outcomes Study Short Form 36. Patients were subdivided into more active (SLAM-R > or = 10; n = 38) or less active disease states (n = 91). RESULTS: Better mental health was predicted by more education and less emotion-oriented coping in the patients in a more active disease state (P = 0.0001; R2 = 0.46). Better mental health was predicted by less stress, less emotion-oriented coping and more task-oriented coping in patients during a less active disease state (P = 0.0001; R2 = 0.45). Better physical health was predicted by more emotion-oriented coping in patients in a more active disease state (P = 0.04; R2 = 0.11). Better physical health was predicted by less stress and younger age in patients during a less active disease state (P = 0.0001; R2 = 0.20). CONCLUSION: The positive association between emotion-oriented coping and better physical health in patients during a more active disease state suggests that this style of coping may be more adaptive in situations that are considered uncontrollable (e.g., SLE flare). Predictors of mental health were similar to those found in the literature, especially for SLE patients in a less active disease state.

Acute Disease↗

Refolding and characterization of recombinant human soluble CTLA-4 expressed in Escherichia coli.

CD28 and CTLA-4 are homologous cell surface proteins expressed by T cells. CD28 is constitutively expressed by most T cells, whereas CTLA-4 is expressed by activated T cells. Both proteins are ligands for the costimulatory molecules CD80 and CD86 expressed by activated B cells, macrophages, and dendritic cells. A fusion protein comprising the CTLA-4 extracellular domain joined to a human immunoglobulin heavy chain constant region (CTLA4Ig) binds CD80 and CD-86 with high affinity and inhibits CD80/CD86-dependent immune responses in vitro and in vivo. Attempts at producing the CTLA-4 extracellular domain as an unfused protein have met with limited success. Here we describe the expression and purification of the CTLA-4 extracellular domain as a nonfused protein in Escherichia coli. The 12.5-kDa CTLA-4 extracellular domain was insoluble when expressed in E. coli and required denaturation, reduction, and refolding steps to become soluble and assume its proper conformation. The protein refolded into a mixture of monomers, disulfide-linked dimers, and higher order disulfide-linked aggregates. sCTLA-4 dimers were the predominant refold form when air was used as the oxidizing agent during the refold procedure. Purified sCTLA-4 dimers were 10- to 50-fold more potent than sCTLA-4 monomers at inhibiting T cell activation using a CD80-dependent in vitro bioassay.

Abatacept↗

The geographical distribution of suicides in farmers in England and Wales.

Farmers in England and Wales have an elevated risk of suicide. The aim of this study was to investigate the geographical distribution of suicides in farmers. Rates of suicide (including suicide and open verdicts) of farmers in England and Wales between 1981 and 1993 were calculated on a county basis. Trends in rates and differences in rates between counties, regions and England and Wales were then analysed. There were 719 suicides (634 suicide verdicts and 85 open verdicts). There was evidence of a decline in annual rates of suicide in farmers during the study period in England but not Wales. There was no evidence of geographical heterogeneity of farming suicides according to counties, but a relatively high rate for Devon (N = 62 suicides). County farming suicide rates did not appear to be related to local general population suicide rates, density of farmers or type of farm holding. While identification of counties with relatively large numbers of farming suicides should assist targeting of local preventive programmes, it is clear that any significant prevention strategies should be implemented on a national basis.

Adolescent↗

The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination.

A case is reported of a woman who was exposed to human immunodeficiency virus through self-insemination. She was artificially inseminated with fresh semen obtained from a gay man in whom HIV seroconversion was taking place. Postexposure prophylaxis with antiretrovirals was initiated 10 days later, and despite successful conception, HIV infection was not established. A healthy male infant was subsequently delivered with no obvious toxicity related to medication.

Adult↗

Recurrence of gynecologic malignancy at the vaginal vault after hysterectomy.

OBJECTIVE: Vaginal vault recurrences of genital tract malignancy are not uncommon, and may be the first sign of recurrent disease. This paper reviews the experience at Columbia Presbyterian Medical Center. METHODS: The tumor lists from 1993 to 1996 of the Division of Ob/Gyn Pathology at Columbia Presbyterian Medical Center were reviewed, and correlated with retrospective chart review. RESULTS: Of 36 cases, 13 were from uterine primaries, seven were cervical in origin, eight were ovarian primaries, and in eight cases, the exact primary was not known at the time of biopsy. For the cases where the primary diagnosis and disease free interval were known, the time interval from hysterectomy to vault recurrence ranged from 1.5 months to 84 months, with a mean of 25.6 months. CONCLUSION: Vaginal vault recurrences are often the site of recurrent female genital tract malignancies. Patients treated for gynecological cancer must have regular pelvic examinations including cytologic examination as part of their oncologic surveillance.

Adult↗

Criteria for assessing cutaneous anergy in women with or at risk for HIV infection. HIV Epidemiologic Research Study Group.

BACKGROUND: Controversy exists about both the clinical utility of anergy testing and the optimal criteria for defining anergy. OBJECTIVE: We sought to assess various definitions of cutaneous anergy for ability to distinguish HIV status, level of immunodeficiency, and ability to mount a tuberculin reaction among women with or at risk for HIV infection. METHODS: HIV-seropositive (n = 721) and HIV-seronegative (n = 358) at-risk women at academic medical centers in Baltimore, Detroit, New York, and Providence had cutaneous testing with mumps, Candida, tetanus toxoid, and tuberculin antigens. Associations with HIV status and CD4+ lymphocyte levels were analyzed. RESULTS: Candida, mumps, and tetanus antigens alone or in combination elicited reactions significantly less often in HIV-seropositive than in HIV-seronegative women and less often in seropositive women with lower CD4+ counts, regardless of induration cutpoint chosen to define a positive reaction. The best antigen combinations for distinguishing groups included tetanus and mumps. Some women nonreactive to the 3 antigens ("anergic") had positive tuberculin reactions among both seropositive subjects (range, 1.1% to 2.9% depending on induration cutpoint for defining anergy) and seronegative subjects (range, 8.9% to 14%). CONCLUSION: Absence of reactions to Candida, mumps, and tetanus antigens alone or in combination and at any induration cutpoint is associated with HIV status and with CD4+ level. Combinations, including tetanus and mumps antigens with an induration cutpoint of less than 2 mm, may be the best for defining anergy.

Antigens, Fungal↗