Biomedical subjects
J Berry
Publications and source records attributed to J Berry.
Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1.
A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previously mapped to chromosome 17q12-q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT.
Isolation of murine cementoblasts: unique cells or uniquely-positioned osteoblasts?
While cementoblasts express a number of mineral-related proteins, including bone sialoprotein (BSP), osteopontin (OPN) and osteocalcin (OC), these proteins do not appear to be expressed by cells of the intermediate dental follicle/periodontal ligament (PDL). This information was utilized in an experimental strategy to isolate presumptive cementoblasts from the root surface of day 24 murine mandibular first molars. Using microscopic dissection techniques, molars were carefully extracted from their alveolar crypts and subjected to trypsin-collagenase digestion to remove adherent cells. Primary cultures were established and assayed for expression of proteins known to be expressed by cementoblasts at this timepoint in vivo (i.e. BSP, OPN, OC) and also an odontoblast-specific protein (i.e. DSP) to rule out contamination by pulpal cells. A subgroup of cells were found to express Type I collagen (89% of cells), BSP (46%), OPN (23%) and OC (30%); DSP was not detected within these cultures. We propose that cells within this heterogeneous population, which express this profile of osteogenic proteins, represent cementoblasts. The availability of a cementoblast cell line will make possible rigorous and controlled in vitro analysis of these cells and allow for determination of the unique characteristics of these cells not shared with other cells, particularly osteoblasts.
Understanding your Mexican patient.
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Reliability and validity of the functional performance inventory in patients with moderate to severe chronic obstructive pulmonary disease.
The Functional Performance inventory (FPI) is a new instrument designed to measure functional status in terms of activities that people perform on a daily basis. Psychometric characteristics were examined by a survey of 45 men and 27 women with chronic obstructive pulmonary disease (COPD). Internal consistency reliability was high and no ceiling and floor effects were observed for the Total FPI. Concurrent validity was demonstrated by correlations with the Total Sickness Impact Profile (r = -.59). Construct validity was supported by correlations with the Medical Outcomes Study Short Form-36, Physical Functioning (r = .69), the Physical Activity Scale for the Elderly (r = .62) and American Thoracic Society-Division of Lung Disease Breathlessness scale (r = -.62). The Total FPI is a reliable and valid measure of functional performance in persons with COPD.
Can a laboratory diagnosis of bacterial vaginosis be made from a transported high vaginal swab using anaerobic culture and microscopy of a wet preparation?
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Outpatient general anesthesia: a comparison of a combination of midazolam plus propofol and propofol alone.
STUDY OBJECTIVE: To compare the hemodynamics, efficacy, safety, and postoperative recovery of patients following the use of either midazolam plus propofol or placebo plus propofol for induction and maintenance of general anesthesia for outpatient surgical procedures of less than two hours' duration. DESIGN: Prospective, parallel, randomized, double-blind, placebo-controlled, multicenter study. SETTING: Ten outpatient surgery centers. PATIENTS: 203 ASA physical status I, II, and III patients undergoing various outpatient surgical procedures. INTERVENTIONS: Patients were randomly assigned to one of the two treatment groups. For induction of anesthesia, Group 1 received midazolam (0.077 +/- 0.0021 mg/kg) via slow intravenous (IV) push plus continuous infusion propofol (provided in a concentration of 5 mg/ml), and Group 2 received placebo plus full-concentration (10 mg/ml) propofol. Thereafter, Group 1 received half-concentration propofol and Group 2 received full-concentration propofol via continuous infusion for maintenance of anesthesia. Investigators administered doses of study medication in a blinded fashion as required to achieve the desired clinical effect. Drugs used to maintain anesthesia were restricted to study drug, short-acting opioids, and nitrous oxide. Succinylcholine chloride or vecuronium were used to facilitate intubation of study patients. MEASUREMENTS AND MAIN RESULTS: There were no statistically significant differences between the midazolam/propofol and placebo/propofol groups with respect to the mean (SE) decrease in mean arterial pressure from pre-dose to time of intubation or from time of intubation to initiation of surgery; the mean (SE) time required from initiation of study medication to completion of intubation [6.7 (0.23) minutes vs. 7.0 (0.26) minutes, respectively]; or the mean (SE) amount of propofol required to induce and maintain anesthesia [6.03 (0.329) mg/kg vs. 9.71 (0.489) mg/kg, respectively]. There was no significant difference between the two treatment groups in the time to recovery following the completion of surgery (as assessed by Aldrete Post Anesthesia Recovery Score). Most patients (approximately 79%) in both groups rated the quality of the anesthetic regimen as excellent; however, as assessed by patient questionnaires, fewer patients in the midazolam/ propofol group were able to recall the events surrounding their surgical procedure as compared with patients in the placebo/ propofol group (89.2% vs. 77.9%; p = 0.022). There were no differences between the two groups with respect to the frequency or severity of adverse events. CONCLUSIONS: Concomitantly administered midazolam and reduction-concentration propofol did not exacerbate the well-described hypotensive effects of full-strength propofol during induction of anesthesia. The time to intubation was equivalent with the combination of midazolam/propofol as compared with propofol alone. Recovery from the two regimens was not significantly different. However, reduced recall of perioperative events was observed more often in the midazolam/propofol regimen compared with propofol alone.
Expression of bone associated markers by tooth root lining cells, in situ and in vitro.
Periodontal disease is marked by inflammation and subsequent loss and/or damage to tooth-supporting tissues including bone, cementum, and periodontal ligament. A key tissue in the initial process of periodontal development as well as regeneration following periodontal disease is cementum. Research efforts aimed toward understanding mechanisms involved in periodontal development and regeneration, and in particular the formation of root cementum, have been hampered by an inability to isolate and culture cells involved in cementum production (i.e., cementoblasts). Much has been learned regarding the processes and mechanisms involved in bone formation and function from experiments using bone cell cultures. Therefore, the purpose of this study was to develop a strategy whereby cementoblasts could be isolated, cultured, and characterized. As a first step, using in situ hybridization, we determined the timed and spatial expression of mineral-associated proteins during first molar root development in CD-1 mice. These proteins included dentin sialoprotein (DSP), osteopontin (OPN), bone sialoprotein (BSP), osteocalcin (OCN), and type I collagen. During root development in mice BSP, OPN, and OCN mRNAs were expressed selectively by cells lining the tooth root surface--cementoblasts--with high levels of expression at day 41. Importantly, at this time point BSP, OPN, and OCN mRNAs were not expressed throughout the periodontal ligament. These findings provided us with markers selective to root-lining cells, or cementoblasts, in situ, and established the time (day 41) for isolating cells for in vitro studies. To isolate cells from tissues adherent to the root surface, enzymatic digestion was used, similar to what are now considered classical techniques for isolation of osteoblasts. To determine whether cells in vitro contained root-lining cells and cementoblasts, cultured cells were analyzed for expression of mineral-associated proteins. Cells within this heterogeneous primary population expressed type I collagen, BSP, OPN, and OCN as determined by in situ hybridization. In contrast, cells within this population did not express dentin sialoprotein, an odontoblast-specific protein. These procedures have provided a means to obtain root-lining cells in vitro that can now be cloned and used for studies directed at determining the properties of root-lining cells, or cementoblasts, in vitro.
A phase II trial of circadian-timed paclitaxel and cisplatin therapy in metastatic breast cancer.
PURPOSE: In a phase II study with combination paclitaxel and cisplatin in metastatic breast cancer using circadian timing, we attempted to maximise response and minimise toxicity. MATERIALS AND METHODS: Forty-one patients with histologically-proven metastatic breast cancer with or without previous chemotherapy were treated with Paclitaxel 135 mg/m2 administered as a three-hour infusion at 06.00 hours followed by cisplatin 75 mg/m2 as a one-hour infusion at 18.00 hours utilising circadian timing. Six cycles were planned once every 21 days. Response assessment was performed every two cycles, and toxicity was measured using WHO criteria. RESULTS: All patients were evaluable for response and toxicity. There were nine (22%) complete responses (CR), and 24 (59%) partial responses (PR), for an overall response rate of 80% (95% confidence interval (CI) 69-92). Responses were seen in patients previously treated with anthracyclines (75%) (95% CI 57-92), and in patients who had had no prior chemotherapy (90%) (95% CI 71-100). Responses were seen in all metastatic sites: liver 80%, lung 76%, bone 69%, and soft tissues 71%. The overall median response duration was seven months (range 3-26, 95% CI 5.0-9.8), and 14 of the responses (42%), (95% CI 28-62) were durable. A total of 212 cycles of chemotherapy were given. There were 15 episodes (7%) of grade 3-4 neutropenia, seven (3.2%) of grade 3-4 neurologic toxicity, and three (1.4%) of grade 3-4 nephrotoxicity. There were no toxic deaths. CONCLUSION: The combination of paclitaxel and cisplatin is very effective in metastatic breast cancer, and with application of circadian timing, toxicity has been acceptable. This combination is being tested as primary therapy in locally-advanced breast cancer at our institution.
DNA vaccination with the major outer-membrane protein gene induces acquired immunity to Chlamydia trachomatis (mouse pneumonitis) infection.
The efficacy of DNA vaccination for prevention of Chlamydia trachomatis infection was studied using the murine model of pneumonia induced by the mouse pneumonitis (MoPn) isolate of C. trachomatis. Intramuscular DNA immunization with two chlamydial genes, one that encodes the major outer-membrane protein (MOMP) and one that encodes a cytoplasmic enzyme (cytosine triphosphate [CTP] synthetase) were tested. The MOMP DNA vaccine but not the CTP synthetase DNA vaccine generated significant delayed-type hypersensitivity and serum antibodies to MoPn elementary bodies and reduced the peak growth of MoPn by >100-fold following lung challenge infection. MOMP DNA immunization suggests a new approach to vaccine development for prevention of human chlamydial infection.
A prospective study of VEC-POB and POCE chemotherapy in aggressive non-Hodgkin's lymphoma.
The optimal combination and scheduling of chemotherapy for aggressive non-Hodgkin's lymphoma is unclear, and the elderly have a poor tolerance to treatment. A Phase II prospective study was undertaken using outpatient weekly combination chemotherapy: the VEC-POB (etoposide, epirubicin, cyclophosphamide, cisplatin, Oncovin, bleomycin, and prednisone) regimen in patients < 60 years and less intensive POCE (etoposide, Oncovin, cyclophosphamide, and epirubicin) in patients > or = 60 years. All patients with intermediate and high-grade lymphoma (International Working Formulation) with bulky disease and/or advanced stages (III, IV) seen between January 1991 and June 1992 were entered. Of 29 patients treated with VEC-POB, 23 patients (79%) achieved complete remission (CR), with one (3%) toxic death. Overall survival at 29 months is 67%, and disease-free survival at 60 months is 60%. Of 29 patients treated with POCE, 14 achieved CR, with three (10%) toxic deaths. Overall survival is 58% at 18 months, and disease-free survival at 10 months is 50%. Adverse prognostic factors were analyzed. The results are comparable to the best results achieved with other regimens, and toxicity is acceptable.
Effect of tamoxifen on the pharmacokinetics of doxorubicin in patients with non-Hodgkin's lymphoma.
The authors examined the effect of tamoxifen (TAM), a multiple-drug resistance modulator, on the pharmacokinetics of doxorubicin (DOX) in patients with non-Hodgkin's lymphoma treated according to the CHOP-protocol which included DOX, cyclophosphamide, vincristine, and prednisone. The dose of DOX was 50 mg/m2, but was reduced 25% if the patient was older than 60 years. Of these, 10 randomly-selected patients received a daily dose of 480 mg of TAM (Group-1) and 10 others did not (Group-2). Blood samples were collected at different time intervals, and DOX was measured in plasma by liquid chromatography. The concentration-time data of DOX exhibited the characteristics of the two-compartment open model well. The mean (SEM) values of alpha, beta, k12, k21, k10, Vc, Vss, AUC, total clearance, and mean residence time observed in Group-1 were 4.06 (0.96) hr(-1), 0.0395 (0.0068) hr(-1), 3.13 (0.79) hr(-1), 0.264 (0.052) hr(-1), 0.708 (0.19) hr(-1), 525 (156) l/m2, 1060 (163) l/m2, 1145 (234) microg x hr/l, 49.3 (8.5) l/hr x m2, and 26.8 (6.6) hours, respectively. Those in Group-2 were 4.99 (1.13) hr(-1), 0.0432 (0.0073) hr(-1), 2.46 (0.63) hr(-1), 0.111 (0.026) hr(-1), 2.46 (0.86) hr(-1), 231 (53) l/m2, 812 (149) l/m2, 1690 (276) microg x hr/l, 30.3 (4.1) l/hr x m2, and 29.7 (5.1) hours, respectively. Of these parameters, the difference between the two groups was significant (p < or = 0.0169) only in k21. Thus, the coadministration of TAM at the earlier-mentioned dose appears generally to have no significant influence on the pharmacokinetics of doxorubicin when used in the CHOP-protocol.
Local Research Ethics Committees can audit ethical standards in research.
OBJECTIVES: To show that a Local Research Ethics Committee (LREC) can carry out an audit of ethical standards in research. To find out if a researcher met certain ethical standards in recruiting subjects for clinical trials and in obtaining their consent. DESIGN: Postal questionnaire. SETTING: Clinical research by one doctor during one year. SUBJECTS: Eleven patients entered in clinical trials. MAIN OUTCOME MEASURES: Success in ethics committee obtaining data. Achievement of ethical standards in recruitment of subjects and in obtaining consent. RESULTS: The audit was successfully carried out and standards were partly met. CONCLUSIONS: Local Research Ethics Committees can carry out audits of the conduct of research projects which they have approved. Provision for possible audits can be made at the time of application to the committee. Our committee thought the ethical standards in the research which we audited were acceptable.
Hormonal factors and the laboratory detection of Chlamydia trachomatis in women: implications for screening?
One thousand and fifty-six new and re-registered consecutive women attending a genitourinary medicine clinic requiring speculum examination were screened for Chlamydia trachomatis by enzyme immunoassay (IDEIA, Dako Diagnostics Ltd). Of 1022 women who had results available for both cervix and urethra C. trachomatis was detected in 8.8% (89/1022) in any site, 2.3% (23/1022) in both sites, 4.9% (51/1022) at the cervix alone and 1.5% (15/1022) at the urethra alone. Thus sampling at the urethra increased detection by 17% (15/89). Analysis of 808 women with a regular menstrual cycle showed a significant association of combined oral contraceptive use, age and ectropion with the detection of C. trachomatis. The detection of C. trachomatis showed a significant variation with the menstrual cycle (P = 0.023) (relative risk (rr) 1.7 (95% confidence intervals (CI) 1.0-2.8)). It was detected significantly more often in the latter part. Stepwise logistic regression analysis revealed that ectropion and age were the stronger determinants of C. trachomatis detection and not oral contraceptive use or menstrual cycle. The variation in detection of C. trachomatis with the menstrual cycle was independently associated with combined oral contraceptive use and the lack of a cervical ectropion. The increased detection at the cervix was present after the second week in combined oral contraceptive users (P = 0.008) (rr = 2.3 (1.2-4.5)) but only after the 3rd week in women without an ectropion (P = 0.004) (rr = 2.7 (1.3-5.5)). Combined oral contraceptives, ectropion and youth, are markers for the carriage of C. trachomatis in the lower genital tract of women. It is also detected significantly more often in the latter part of the menstrual cycle in women who are oral contraceptive users.
Preventing falls in high-risk patients.
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Environment of infants during sleep and risk of the sudden infant death syndrome: results of 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers.
OBJECTIVE: To investigate the role of sleeping arrangements as risk factors for the sudden infant death syndrome after a national risk reduction campaign. DESIGN: Two year population based case-control study. Parental interviews were conducted for each infant who died and for four controls matched for age and date of interview. SETTING: Three regions in England with a total population of 17 million people. SUBJECTS: 195 babies who died and 780 matched controls. RESULTS: Prone and side sleeping positions both carried increased risks of death compared with supine when adjusted for maternal age, parity, gestation, birth weight, exposure to smoke, and other relevant factors in the sleeping environment (multivariate odds ratio = 9.00 (95% confidence interval 2.84 to 28.47) and 1.84 (1.02 to 3.31), respectively). The higher incidence of side rather than prone sleeping led to a higher population attributable risk (side 18.4%, prone 14.2%). More of the infants who died were found with bed covers over their heads (21.58; 6.21 to 74.99). The use of a dummy had an apparent protective effect (0.38; 0.21 to 0.70). Bed sharing for the whole night was a significant risk factor for infants whose mothers smoked (9.25; 2.31 to 34.02). No protective effect of breast feeding could be identified on multivariate analysis. CONCLUSIONS: This study confirms the importance of certain risk factors for the sudden infant death syndrome and identifies others-for example, covers over the head, side sleeping position-which may be amenable to change by educating and informing parents and health care professionals.
Smoking and the sudden infant death syndrome: results from 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers.
OBJECTIVE: To investigate the effects of exposure to tobacco smoke and of parental consumption of alcohol and illegal drugs as risk factors for the sudden infant death syndrome after a national risk reduction campaign which included advice on prenatal and postnatal avoidance of tobacco smoke. DESIGN: Two year population based case-control study. Parental interviews were conducted for each infant who died and four controls matched for age and date of interview. SETTING: Three regions in England with a total population of 17 million people. SUBJECTS: 195 babies who died and 780 matched controls. RESULTS: More index than control mothers (62.6% v 25.1%) smoked during pregnancy (multivariate odds ratio = 2.10; 95% confidence interval 1.24 to 3.54). Paternal smoking had an additional independent effect when other factors were controlled for (2.50; 1.48 to 4.22). The risk of death rose with increasing postnatal exposure to tobacco smoke, which had an additive effect among those also exposed to maternal smoking during pregnancy (2.93; 1.56 to 5.48). The population attributable risk was over 61%, which implies that the numbers of deaths from the syndrome could be reduced by almost two third if parents did not smoke. Alcohol use was higher among index than control mothers but was strongly correlated with smoking and on multivariate analysis was not found to have any additional independent effect. Illegal drug use was more common among the index parents, and paternal use of illegal drugs remained significant in the multivariate model (4.68; 1.56 to 14.05). CONCLUSIONS: This study confirms the increased risk of the sudden infant death syndrome associated with maternal smoking during pregnancy and shows evidence that household exposure to tobacco smoke has an independent additive effect. Parental drug misuse has an additional small but significant effect.