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Biomedical subjects

L Carpenter

Publications and source records attributed to L Carpenter.

At least 37 records · Page 2Linked to original sources
PubMed1999

Protein kinase Ciota activity is necessary for Bcr-Abl-mediated resistance to drug-induced apoptosis.

K562 chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs, such as taxol, that induce cell death by apoptosis. This resistance is mediated by the chimeric tyrosine kinase oncogene Bcr-Abl. However, little is known about the mechanism by which Bcr-Abl protects K562 cells from apoptosis. We recently demonstrated that expression of PKCiota is necessary for the resistance of K562 cells to taxol-induced apoptosis (Murray, N. R., and Fields, A. P. (1997) J. Biol. Chem. 272, 27521-27524). We now demonstrate that treatment of K562 cells with taxol leads to sustained activation of PKCiota. In contrast, Bcr-Abl-negative HL60 myeloid leukemia cells, which are sensitive to taxol-induced apoptosis, do not exhibit sustained PKCiota activation in response to taxol. Treatment of K562 cells with tyrphostin AG957, a selective Bcr-Abl inhibitor, blocks taxol-induced PKCiota activation and sensitizes these cells to taxol-induced apoptosis, indicating that PKCiota is a relevant downstream target of Bcr-Abl-mediated resistance. Furthermore, expression of constitutively active PKCiota by adenovirus-mediated gene transfer rescues AG957-treated K562 cells from taxol-induced apoptosis. Taken together, these results demonstrate that both Bcr-Abl and PKCiota activity are necessary for apoptotic resistance in K562 cells. Furthermore, they identify PKCiota as a critical downstream target of Bcr-Abl that is sufficient to mediate the anti-apoptotic effects of Bcr-Abl.

3T3 Cells↗
PubMed1999

Limited efficacy of ketoconazole in treatment-refractory major depression.

The authors examined the efficacy of ketoconazole in 16 adults with treatment-refractory major depressive disorder. Subjects participated in a 6-week, double-blind, placebo-controlled trial. Assessments of mood were made using the Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory (BDI), and the Clinical Global Impression Scale (CGI). Results showed that none of eight patients randomly assigned to receive placebo and two of eight patients randomly assigned to receive ketoconazole met criteria for response. As a group, patients assigned to receive ketoconazole showed no significant reductions in HAM-D, BDI, or CGI scores during the 6-week trial compared with those receiving placebo. These findings suggest a limited efficacy for ketoconazole in patients with treatment-refractory major depression.

Adult↗
PubMed1999

Cancer and occupation in women: identifying associations using routinely collected national data.

Some potentially important findings from an analysis of 119,227 cancers registered in women in England over the 7-year period 1981 to 1987 are discussed. Data are presented for four cancer sites with established occupational etiologies (bladder, pleura, lung, larynx), three occupational groups in which women predominate (teachers, nurses, barstaff), and the main female cancers of the reproductive system (breast, uterus, cervix, ovary). Excesses of bladder cancer in female rubber workers (proportional registration ratio [PRR] 350, 95% confidence interval [CI] 141-723), pleural cancer in female carpenters (PRR 1596, 95% CI 329-4665) and lung cancer in female construction workers (PRR 269, 95% CI 154-437) and barstaff (PRR 138, 95%CI 124-156) are noted. It is concluded that analyses of routinely collected data on cancer and occupation in women have the potential to provide valuable pointers for further research.

Adult↗
PubMed1998

Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography.

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.

Adult↗
PubMed1997

Cloning of the monocarboxylate transporter isoform MCT2 from rat testis provides evidence that expression in tissues is species-specific and may involve post-transcriptional regulation.

The cDNA for the monocarboxylate transporter MCT2 from rat testis has been cloned and sequenced. The derived protein sequence shows 82% identity with that from hamster. Rat MCT2 has a relative insertion of five amino acids in the N-terminal sequence preceding the first predicted transmembrane segment. MCT2 appears to be less highly conserved between species than MCT1. Using Northern blotting of RNA from rat and mouse tissues, MCT2 message was demonstrated to be abundant in the testis where a smaller, less abundant MCT2 transcript was also present. Low levels of a slightly different-sized transcript were found in rat and mouse liver, and mouse kidney. In hamster, only one-size transcript was detected at relatively high abundance in all the tissues examined. Antibodies were raised against a peptide derived from the extreme C-terminus of rat MCT2, and Western blotting with these detected MCT2 in membrane fractions prepared from rat testis, liver and brain but not those from heart or skeletal muscle. In hamster, MCT2 was detected in liver, heart and testis but not in brain [Garcia, Brown, Pathak, and Goldstein (1995) J. Biol. Chem. 270, 1843-1849]. For both rat MCT1 and MCT2 there were marked differences between the relative abundance of their respective messages and the amount of protein in membrane fractions from different tissues. This suggests that expression of both of these transporters in different tissues may be species-specific and regulated post-transcriptionally. The different-sized MCT2 transcripts may arise from alternative splicing. Starvation of rats for up to 48 h did not lead to any change in MCT1 or MCT2 expression in the liver, as determined by either Northern or Western blotting.

Amino Acid Sequence↗
PubMed1997

Development of a tool to rate the quality assessment of randomized controlled trials using a Delphi technique.

The aim of this study was to develop a quality of study tool rate the methodological quality of individual primary randomized controlled trials (RCTs) to be included in a meta-analysis. A Delphi-technique using several rounds of questions to seek consensus, among trialists, on criteria important in a RCT was used. Eight trialists formed the Delphi panel. The developed quality of study tool consisted of 53 items in 15 dimensions. The tool was tested for reliability and validity. Unlike many other quality assessment tools, the developed tool may be used to rate numerically each primary study. This is important in reviews or in meta-analyses where one objective may be to ascertain whether those studies of a higher quality exhibit different results to reviewing studies of lower quality. The tool needs further testing.

Clinical Nursing Research↗
PubMed1996

Cloning and sequencing of the monocarboxylate transporter from mouse Ehrlich Lettré tumour cell confirms its identity as MCT1 and demonstrates that glycosylation is not required for MCT1 function.

Lactate transport is mediated in most tissues by H+-monocarboxylate-- cotransporters (MCTs). We have cloned and sequenced the lactate transporter from Ehrlich Lettré tumour cells by using the polymerase chain reaction (PCR) to amplify MCT1-related sequence from cDNA. The sequence is 93% and 87% identical to MCT1 from Chinese hamster and human respectively and so represents mouse MCT1. Most differences between MCT1 from Chinese hamster and mouse are conservative substitutions, located in hydrophilic parts of the molecule. Specific antipeptide antibodies confirm the presence of MCT1 protein in membranes from Ehrlich Lettré tumour cells. One difference between the mouse and Chinese hamster MCT1 is the absence of a predicted external consensus sequence for N-linked glycosylation in the mouse sequence. Using N-glycanase-F treatment and an in vitro translation system, we provide evidence that this glycosylation site is not actually utilised in Chinese hamster MCT1. These results are discussed in relation to current understanding of the roles of glycosylation of membrane proteins.

Amino Acid Sequence↗
PubMed1996

Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).

BACKGROUND: It has been suggested that the incidence of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is three or more times higher in northern than in southern Europe. The aim of this EC funded study was to investigate this apparent variation by ascertaining the incidence of IBD across Europe. METHODS: For the period 1 October 1991 to 30 September 1993 all new patients diagnosed with IBD were prospectively identified in 20 European centres according to a standard protocol for case ascertainment and definition. FINDINGS: Altogether 2201 patients aged 15 years or more were identified, of whom 1379 were diagnosed as UC (including proctitis), 706 as CD, and 116 as indeterminate. The overall incidence per 100,000 at ages 15-64 years (standardised for age and sex) of UC was 10.4 (95% confidence interval (95% CI) 7.6 to 13.1) and that of CD was 5.6 (95% CI 2.8 to 8.3). Rates of UC in northern centres were 40% higher than those in the south (rate ratio (RR) = 1.4 (95% CI 1.2 to 1.5)) and for CD they were 80% higher (RR = 1.8 (95% CI 1.5 to 2.1)). For UC the highest reported incidence was in Iceland (24.5, 95% CI 17.4 to 31.5) and for CD, Maastricht (The Netherlands; 9.2, 95% CI 6.5 to 11.8) and Amiens (north west France; 9.2, 95% CI 6.3 to 12.2). The lowest incidence of UC was in Almada (southern Portugal) (1.6, 95% CI 0.0 to 3.2) and of CD in Ioannina (north west Greece) (0.9, 95% CI 0.0 to 2.2). An unexpected finding was a difference in the age specific incidence of UC in men and women with the incidence in women but not men declining with age. INTERPRETATION: The higher overall incidence rates in northern centres did not seem to be explained by differences in tobacco consumption or education. Nevertheless, the magnitude of the observed excess for both conditions is less than expected on the basis of previous studies. This may reflect recent increases in the incidence of IBD in southern Europe whereas those in the north may have stabilised.

Adolescent↗
PubMed1995

Three-rescuer CPR: the method of choice for firefighter CPR?

STUDY OBJECTIVE: To compare the quality of CPR provided by firefighters performing three-rescuer CPR with that achieved by firefighters trained to provide standard two-rescuer CPR. DESIGN: Eight months after training a large number of firefighters to perform three-rescuer CPR, we used a quasi-experimental design to compare the performance of a randomly selected subset of these companies to that achieved by a control group of engine companies that received refresher training in standard two-rescuer CPR. Both groups used bag-valve masks to provide rescue ventilations. Testing was conducted on a no-notice basis with a recording mannequin. Key actions were scored by an experienced observer using explicit pass-fail criteria. Mannequin-generated strip charts were used to calculate the rate and depth of chest compressions and the ventilatory rate, volume, and minute ventilation in a blinded manner. SETTING: Fire stations of the Memphis Fire Department. The department is the sole provider of first-responder emergency care to the citizens of Memphis, Tennessee (population, 610,000). RESULTS: Three-rescuer teams delivered a mean minute ventilation substantially greater than that produced by two-rescuer teams (7.7 +/- 5.3 L versus 4.9 +/- 4.2 L, P < .001). Intergroup differences in the mean depth of chest compressions were less marked, but they were still significant (17.2 +/- 8.3 mm of recorder-needle deflection versus 13.7 +/- 7.0 mm, P < .001). CONCLUSION: Three rescuers can produce better CPR than two when a bag-valve-mask device is used. The technique is easily learned and readily retained.

Cardiopulmonary Resuscitation↗
PubMed1995

Effects of low doses and low dose rates of external ionizing radiation: cancer mortality among nuclear industry workers in three countries.

Studies of the mortality among nuclear industry workforces have been carried out, and nationally combined analyses performed, in the U.S., the UK and Canada. This paper presents the results of internationally combined analyses of mortality data on 95,673 workers (85.4% men) monitored for external exposure to ionizing radiation and employed for 6 months or longer in the nuclear industry of one of the three countries. These analyses were undertaken to obtain a more precise direct assessment of the carcinogenic effects of protracted low-level exposure to external, predominantly gamma, radiation. The combination of the data from the various studies increases the power to study associations between radiation and specific cancers. The combined analyses covered a total of 2,124,526 person-years (PY) at risk and 15,825 deaths, 3,976 of which were due to cancer. There was no evidence of an association between radiation dose and mortality from all causes or from all cancers. Mortality from leukemia, excluding chronic lymphocytic leukemia (CLL)--the cause of death most strongly and consistently related to radiation dose in studies of atomic bomb survivors and other populations exposed at high dose rates--was significantly associated with cumulative external radiation dose (one-sided P value = 0.046; 119 deaths). Among the 31 other specific types of cancer studied, a significant association was observed only for multiple myeloma (one-sided P value = 0.037; 44 deaths), and this was attributable primarily to the associations reported previously between this disease and radiation dose in the Hanford (U.S.) and Sellafield (UK) cohorts. The excess relative risk (ERR) estimates for all cancers excluding leukemia, and leukemia excluding CLL, the two main groupings of causes of death for which risk estimates have been derived from studies of atomic bomb survivors, were -0.07 per Sv [90% confidence interval (CI): -0.4, 0.3] and 2.18 per Sv (90% CI: 0.1, 5.7), respectively. These values correspond to a relative risk of 0.99 for all cancers excluding leukemia and 1.22 for leukemia excluding CLL for a cumulative protracted dose of 100 mSv compared to 0 mSv. These estimates, which did not differ significantly across cohorts or between men and women, are the most comprehensive and precise direct estimates of cancer risk associated with low-dose protracted exposures obtained to date. Although they are lower than the linear estimates obtained from studies of atomic bomb survivors, they are compatible with a range of possibilities, from a reduction of risk at low doses, to risks twice those on which current radiation protection recommendations are based.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

The kinetics, substrate and inhibitor specificity of the lactate transporter of Ehrlich-Lettre tumour cells studied with the intracellular pH indicator BCECF.

1. Suspensions of cultured Ehrlich-Lettre tumour cells were loaded with the pH-sensitive fluorescent indicator 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), and changes in intracellular pH upon addition of L-lactate and other monocarboxylates were continuously monitored by fluorimetry using dual-wavelength excitation (450/500 nm) and single-wavelength emission (> 520 nm). 2. The rapid fluorescence changes were analysed by first-order regression analysis, and with suitable calibration procedures this enabled calculation of initial rates of proton uptake associated with monocarboxylate transport. 3. The stoichiometry was shown to be one proton per lactate molecule transported. 4. The kinetics of carrier-mediated transport of a wide range of monocarboxylates were determined at 25 degrees C. The Km values for L-lactate, pyruvate and D-lactate were found to be 4.54, 0.72 and 27.5 mM respectively, similar to values found previously for rat erythrocytes. This similarity was shared with a wide range of variously substituted C2, C3 and C4 monocarboxylates, all of which were transported with similar Vmax. No stereoselectivity was found in the Km values for D- and L-2-chloropropionate (0.75 mM) or D- and L-3-hydroxybutyrate (11 mM), but in the latter case the Vmax. of the D-isomer was twice that of the L-isomer. 5. The temperature-dependence of L-lactate transport demonstrated a transition point, with activation energies of 60 and 109 kJ.mol-1 above and below 19 degrees C respectively The Km for L-lactate below the transition temperature was about half that above it. 6. Inhibition of lactate transport into tumour cells by a wide range of compounds known to inhibit the erythrocyte monocarboxylate carrier was analysed. Patterns of inhibition were similar to those seen in the erythrocyte, but the Ki values were 2-4-fold higher in the tumour cells. 7. It is concluded that tumour cells contain an isoform of the monocarboxylate carrier with functional properties almost identical with that found in erythrocytes. This is probably identical with MCT1, which was recently cloned and sequenced from Chinese Hamster Ovary cells [Kim Garcia, Goldstein, Pathak, Anderson and Brown (1994) Cell 76, 865-873].

Animals↗
PubMed1994

Efficacy of Haemophilus influenzae type b conjugate vaccine PRP-T.

Efficacy of the Haemophilus influenzae type b (Hib) conjugate vaccine PRP-T (Pasteur-Merieux) was evaluated in a controlled community intervention study in the Oxford region, UK. PRP-T was offered to infants from May 1, 1991 in three of the region's eight districts and from July 1, 1991, in a fourth district. It was given by separate injection in addition to the standard diphtheria, tetanus, and pertussis vaccine according to an accelerated 2, 3, and 4 month schedule without a booster dose in the second year of life. By October 1, 1992, more than 90% of infants in vaccine districts had received at least one dose of PRP-T. None of the infants given three doses had developed Hib infection, whereas 11 infections occurred in the control population (vaccine efficacy 100%, 95% CI 80-100%). Intention-to-treat analysis also showed a high estimate of efficacy for the vaccine (90%, 50-99%). Follow-up of study children until November 1, 1993, has shown only 1 vaccine failure in an infant, and no invasive infections in those older than 1 year (average age 22 months). PRP-T vaccine had high protective efficacy with an accelerated immunisation schedule. Furthermore, the vaccine appears to remain protective through the second year of life without a booster dose. These findings provide encouragement for use of PRP-T in the Expanded Programme of Immunisation.

Child, Preschool↗
PubMed1994

Heterotopic ossification following uncemented total hip arthroplasty. Effect of the operative approach.

A consecutive series of 112 primary uncemented total hip arthroplasties using the same type of prosthesis was reviewed for the incidence and severity of heterotopic ossification (HO). Sixty-three of these patients underwent a posterior approach (group 1) and 49 underwent an anterolateral approach (group 2). The two groups were virtually identical when risk factors, such as age, sex, estimated blood loss, length of surgery, and diagnosis were compared. Patients in group 1 had a significantly lower incidence and severity of HO than those in group 2. The overall incidence of class III or IV HO was very low (8%), indicating that uncemented total hip arthroplasty in itself is not predisposed to moderate or severe degrees of HO. Patients undergoing uncemented total hip arthroplasty through an anterolateral approach had a higher incidence of HO than those undergoing a posterior approach in this series.

Adult↗
PubMed1994

Modelling different strategies to prevent coronary heart disease in primary care.

Strategies for prevention of coronary heart disease (CHD) in primary care need to take into account the number of people who require screening, further assessment, intervention and follow-up (i.e. the patient workload generated for the general practitioner) as well as the anticipated reductions in morbidity and mortality. Risks of CHD for various risk profiles were estimated from equations produced by the Framingham study. This enabled an estimate of the number of avertable CHD events to be compared against the patient workload implications for the general practitioner when different screening and intervention strategies were used. The Framingham equations were applied to a population of 5727 men and women aged 35-64 years of age registered with general practices in the south of England. Adopting an unselective approach to screening resulted in 14.1% (n = 73) of the 517 CHD events predicted over a 10 year period being averted. A limited screening strategy, involving 25% (n = 1436) of the patients would avert 5.6% (n = 29) of the predicted CHD events, whilst more extended strategies involving between 37% (n = 2131) and 46% (n = 2660) of the practice population respectively would result in between 6.9% (n = 36) and 9.3% (n = 48) of events being averted. The marginal benefit in averting CHD events decreased as more screening criteria were included. Almost all (99%) of the people identified by the selective screening strategies would require some form of intervention, predominantly lifestyle advice. Lowering the systolic blood pressure by 15 mmHg instead of 10 mmHg was equally effective as a 5% improvement in the overall rate of smoking cessation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Efficacy of part- and full-time early intervention.

The effectiveness of an early intervention program to remediate developmental delays in children age birth to 3 years was examined in part- and full-time groups (Study 1). Significant improvements on age-appropriate measures of developmental standing were observed for both groups, with the greatest gains observed for the full-time group. In Study 2, the stress of parents with developmentally delayed children was measured on the Parental Stress Inventory. Reductions in stress related to children's characteristics and dysfunctional parenting skills were observed on some subscales, supporting prior research which indicated extension of the outcomes of early intervention beyond the child was desirable.

Child, Preschool↗
PubMed1994

Combined analysis of mortality in three United Kingdom nuclear industry workforces, 1946-1988.

Mortality during 1946-1988 has been analyzed in 75,006 employees of the United Kingdom Atomic Energy Authority, the Atomic Weapons Establishment and the Sellafield plant of British Nuclear Fuels. All-cause mortality was 19% lower than national rates among workers monitored for external radiation exposure and 18% lower among nonmonitored workers. Cancer mortality was also lower than national rates and was similar in the two groups of workers [rate ratio (RR) = 0.96]. Of 29 specific cancer sites examined, only for cancers of the pleura and uterus were there statistically significant excesses of mortality in monitored workers relative to nonmonitored workers [RR = 7.08, two-sided P (2P) = 0.008 and RR = 3.02, 2P = 0.003, respectively]. There was little association between cumulative external radiation and risk of death from all cancers combined 10 or more years after exposure [z for trend = +0.11, one-sided P (1P) = 0.5]. A positive association was observed for leukemia (assuming a 2-year lag between external radiation and increasing risk of death) (1P = 0.009) but not for other cancers associated with external radiation in previous analyses (lung, uterus, prostate and multiple myeloma, all 1P > or = 0.1). Positive associations (1P < or = 0.05) were also observed for melanoma and other skin cancers (1P = 0.03) and ill-defined and secondary cancers (1P = 0.04), but these results are difficult to interpret and, given the number of associations examined, may be chance findings. Estimates of excess relative risk per sievert were -0.02 (95% CI = -0.5-+0.6) for all cancers except leukemia and +4.18 for leukemia (95% CI = +0.4-+13.4). The positive estimates for leukemia contrast with negative values found for workers in the United States, although the confidence intervals obtained in the two studies overlap. While our estimates of risk are compatible with those derived from studies of A-bomb survivors, the statistical uncertainty associated with them is such that the data are consistent with risks ranging from no additional risk to twice the risk for cancers other than leukemia and, for leukemia, from one-fifth to three times the risk in A-bomb survivors.

Cause of Death↗
PubMed1993

Cancer mortality and morbidity in employees of the United Kingdom Atomic Energy Authority, 1946-86.

In further analyses of a cohort of 39,718 United Kingdom Atomic Energy Authority employees after 7 more years follow-up, cancer mortality, based on 1,506 deaths in 1946-86, was 20% below the national average. Prostatic cancer mortality showed a statistically significant association with external radiation exposure, largely confined to men who were also monitored for internal contamination by radionuclides other than plutonium. Prostatic cancer mortality was highest in radiation workers at Winfrith. In women monitored for radiation exposure, mortality from cancer of the uterus (including the cervix uteri) was increased relative to other employees, and, showed a statistically significant association with external radiation exposure. While there were some other statistically significant results, as would be expected by chance alone when multiple comparisons are made, there were no other cancer sites with consistently exceptional findings. Point estimates for risk associated with increasing exposure to radiation suggest a decrease of four deaths per 10(4) person-years per Sv for leukaemia and an increase of 20 deaths for all cancers except leukaemia, but confidence intervals indicate that a wide range of values are compatible with the data. Cancer morbidity based on 1,699 registrations in 1971-84 was 12% below the national average. Findings from site-specific analyses largely replicated those of the mortality analyses.

Cause of Death↗