Undergraduate medical education in pain medicine, end-of-life care, and palliative care.
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Journal Article↗
Biomedical subjects
R Gallagher
Publications and source records attributed to R Gallagher.
Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine.
The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50-150 mg kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect equivalent to a single 200 mg kg 1 dose of cyclophosphamide. Tirapazamine (25 mg kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect equivalent to a single 150 mg kg(-1) dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50-200 mg kg(-1)); AQ4N (50-200 mg kg(-1)) produced a more effective combination than tirapazamine (12.5-50 mg kg(-1)). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg(-1)) 6 h prior to cyclophosphamide (100 mg k(-1)) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg(-1)).
Animals↗
Childhood cancer in the offspring of male sawmill workers occupationally exposed to chlorophenate fungicides.
The objective of this study was to determine whether paternal occupational exposure to chlorophenol fungicides and their dioxin contaminants is associated with childhood cancer in the offspring of sawmill workers. We used data from 23,829 British Columbian sawmill workers employed for at least 1 continuous year between 1950 and 1985 in 11 sawmills that used chlorophenates. Probabilistic linkage of the sawmill worker cohort to the provincial marriage and birth files produced an offspring cohort of 19,674 children born at least 1 year after the initiation of employment in the period 1952-1988. We then linked the offspring cohort to the British Columbia Cancer Registry. We included all malignancies in cases younger than 20 years of age that appeared on the cancer registry between 1969 and 1993. We calculated standardized incidence ratios (SIRs) using the British Columbia population as a reference. A nested case-control analysis assessed the effects of paternal cumulative exposure and windows of exposure on the risk of developing cancer in the offspring. We identified 40 cases of cancer during 259,919 person-years of follow-up. The all-cancer SIR was 1.0 [95% confidence interval (CI), 0.7-1.4]; the SIR for leukemia was 1.0 (CI, 0.5-1.8); and the SIR for brain cancer was 1.3 (CI, 0.6-2.5). The nested case-control analysis showed slightly increased risks in the highest categories of chlorophenol exposure, although none was statistically significant. Our analyses provide little evidence to support a relationship between the risk of childhood cancer and paternal occupational exposure to chlorophenate fungicides in British Columbian sawmills.
Adolescent↗
Hypofrontality and negative symptoms in patients with dementia of Alzheimer type.
OBJECTIVE: The purpose of the current study was to examine the relation between regional cerebral blood flow (rCBF) and negative symptoms (NS) in patients with dementia of Alzheimer type (DAT). BACKGROUND: Negative symptoms in neuropsychiatric disorders were associated with altered rCBF in frontal cortex. METHODS: Twenty-five subjects with a diagnosis of DAT were administered the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale, the Hamilton Rating Scale for Depression, and the Mini-Mental State Examination. The subjects were divided into two groups by means of a median split with regard to NS severity (high NS group, N = 12; low NS group, N = 13). Each patient underwent a single photon emission tomography scan using 99mTc-HMPAO at rest. Cortical and subcortical regions of interest were symmetrically defined in each hemisphere. Cortical-to-cerebellar perfusion ratios were established quantitatively using ADAC software. RESULTS: High NS group subjects had a significantly lower rCBF than low NS group subjects in the frontal cortex and cingulate gyrus (MANOVA: p = 0.022) as a result of differences in the dorsolateral prefrontal cortex bilaterally (right: F = 12.12, p = 0.002; left: F = 6.55, p = 0.02) and in the frontal cortex, mainly in the right hemisphere (right: F = 6.33, p = 0.02; left: F = 3.26, p = 0.08). For all the subjects (N = 25), there were negative correlations between the SANS total score and rCBF, most prominently in the dorsolateral prefrontal cortex bilaterally (right: r = -0.48, p <0.01; left: r = -0.49, p = 0.01). No significant correlation was found between rCBF in any of the regions of interest and either the Mini-Mental State Examination or the Hamilton Rating Scale for Depression scores. CONCLUSIONS: This study indicates that decreased perfusion in the frontal cortex is associated with NS severity but not with measures of cognitive impairment or depressive symptoms in DAT patients. These results support the hypothesis that the frontal lobes may be involved in the cause of NS in DAT, and they underscore the importance of NS evaluation in neuroimaging studies.
Aged↗
Drug delivery by the intravaginal route.
The human vagina represents a potential, accessible space that offers a valuable route for drug delivery through the use of specifically designed carrier systems for both local and systemic applications. Intravaginal drug delivery is particularly appropriate for drugs associated with women's health issues but may also have applications in general drug delivery within the female population. A range of drug delivery platforms suitable for intravaginal administration are discussed in this review, including hydrogels, vaginal tablets, pessaries/suppositories, particulate systems, and intravaginal rings. Drug release mechanisms and absorption pathways are reviewed with respect to a range of therapeutic and prophylactic indications for intravaginal delivery.
Absorption↗
A unique carboxy-terminus truncation mutant of the retinoic acid receptor alpha gene associated with a variant marker chromosome in a retinoic acid resistant HL-60 subline.
In order to contribute to the study of the molecular basis of leukemic cellular resistance to the induction of differentiation by all-trans retinoic acid (RA) we have generated and analyzed a mutant, RA-resistant HL-60 cell line. Molecular analysis of the retinoic acid receptor alpha (RARalpha) cDNA disclosed, in one of the two alleles, a novel mutation consisting of a 7-base deletion in the ligand binding domain that includes part of a FokI restriction endonuclease site previously described. As a consequence of this deletion and translational frame-shift, a stop signal is created that truncates the protein at codon 421, disrupting an essential functional component of the receptor. Transducing an epitope tagged RARalpha into the mutant is sufficient to inhibit clonal growth in the presence of RA. Standard cytogenetic analysis, fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) analysis revealed the presence of two RARalpha loci, and showed a composite karyotype with additional abnormalities with respect to the parental line, including a chromosome 8 insertion in a chromosome previously known as marker three.
Alleles↗
Incidence of second neoplasms in patients with MALT lymphoma: no increase in risk above the background population.
BACKGROUND: Lymphomas of mucosa associated lymphoid tissue (MALT) are a special type of extranodal lymphoma, possibly related to chronic antigenic stimulation. Increased cancer susceptibility may also contribute to the development of MALT lymphoma (MALToma). It has been suggested that patients with MALToma have an increased incidence of other malignancies. PATIENTS AND METHODS: We retrospectively reviewed the histology and clinical records of 147 patients with MALToma, including 51 cases of gastric MALToma. The incidence of any second malignancy was confirmed with a provincial registry. The relative rates of cancer, excluding MALToma, were calculated relative to the background population of the same age group and secular year. RESULTS: A total of 41 tumors occurred in 32 patients (21%), including 22 solid tumors. The incidence of solid tumors in the gastric MALToma group was 15%. Seven patients had two or more second malignancies. Cancer occurred before diagnosis of MALToma in 29 cases, concurrent with MALToma in three, and after MALToma in nine. Follow-up of the surviving patients is short (median 17.6 months). The relative rate from birth of a second malignancy was 0.86 in the whole group (90% confidence interval (CI): 0.62-1.16) and 0.95 (90% CI: 0.55-1.54) in the gastric MALToma group. The rates were roughly the same if skin cancers were excluded. CONCLUSIONS: The incidence of second cancers in this series is similar to previous reports. However, when compared to an age-matched population followed for the same period of time, MALToma patients do not appear to have a statistically significant increased rate of cancers.
Adult↗
Esthesioneuroblastoma: reflections of a 21-year experience.
OBJECTIVES: To evaluate the results of standardized treatment of esthesioneuroblastoma at a single institution during a 21-year period and calculate pertinent parameters, i.e., metastatic disease (local, regional, distant), disease-free survival, and complications of treatment. STUDY DESIGN: A retrospective review was conducted of all patients treated at a single institution from September 1976 through May 1998. METHODS: Only those patients who received their complete evaluation and treatment at our institution were included in this analysis. Thirty-five patients met this criterion. In addition, results of epidemiological, pathological, and molecular analyses were evaluated to seek accurate indicators for clinical outcomes. RESULTS: Six percent of patients presented with cervical metastatic disease, but ultimately 25.7% developed at least one episode of cervical metastases; 14.3% of patients developed a local recurrence an average of 6 years after diagnosis; and 37% of the patients ultimately developed at least one episode of metastatic disease. The disease-free survival for this cohort of 35 patients was 80.4% at 8 years. CNS complications occurred in 25.7% of the patients, 22.9% had orbital complications, 20% had systemic posttreatment problems, 18.2% had chemotoxic sequelae, 8.6% had infectious complications, and 14.3% had cosmetic sequelae. No epidemiological, pathological, or molecular factors appeared to be more accurate clinical indicators than the Kadish staging system. CONCLUSIONS: This series of esthesioneuroblastoma patients (N=35) reflects an 8-year disease-free survival of 80.4%, representing a significant number of patients treated and followed at one institution for an extended period of time. No valuable pathological or molecular indicators to predict aggressive clinical behavior were found. The average time interval before recurrent disease developed was more than 6 years, far greater than that expected for other sinonasal malignancies. Therefore, extended follow-up is necessary for this patient group.
Adolescent↗
Effectiveness of an occupational and environmental medicine curriculum as indicated by evaluation of medical student performance on an objective structured clinical examination.
Medical students must learn to recognize occupational and environmental-related illness. An occupational and environmental medicine curriculum can achieve this goal. The curriculum must be evaluated to ensure that medical students are learning to recognize exposure-related health conditions and to evaluate if this ability correlates with medical interviewing skills. A case, formatted for an Objective Structured Clinical Examination (OSCE), was developed to evaluate student performance on an exposure-related clinical problem. The OSCE results were analyzed to identify the areas that differentiated the students who recognized an exposure-related medical condition from those who did not. We conclude that an OSCE is an effective curriculum evaluation tool to assess whether a core occupational and environmental-related curriculum is contributing to student learning in exposure history-taking and associated clinical reasoning skills.
Clinical Competence↗
Perceived benefits and barriers of prenatal care in low income women.
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Adolescent↗
Exposures of children in Canada to 60-Hz magnetic and electric fields.
OBJECTIVES: This study sought to characterize personal exposures of Canadian children to 60-Hz magnetic and electric fields and explain the variability. METHODS: Altogether 382 Canadian children up to 15 years of age wore meters recording 60-Hz electric and magnetic fields over 2 days. Meter location was noted. Thereafter, meters measured fields in the center of the children's bedrooms for 24 hours. Personal exposures were calculated for home, school or day care, outside the home, bedroom at night, and all categories combined (total). RESULTS: The arithmetic mean (AM) was 0.121 microT [geometric mean (GM): 0.085 microT), range 0.01-0.8 microT] for total magnetic fields. Fifteen percent of the total exposures exceeded 0.2 microT. The AM of the total electric fields was 14.4 (GM 12.3, range 0.82-64.7) V/m. By location category, the highest and lowest magnetic fields occurred at home during the day (0.142 microT) and during the night (0.112 microT), respectively. Measurements during sleep provided the highest correlation with total magnetic field exposure. Province of measurement explained 14.7% of the variation in the logarithms of total magnetic fields, and season accounted for an additional 1.5%. CONCLUSIONS: This study has identified differences in children's magnetic field exposures between provinces. Measurements at night provided the best surrogate for predicting total magnetic field exposure, followed by at-home exposure and 24-hour bedroom measurements. Electrical heating and air conditioning, wiring type, and type of housing appear to be promising indicators of magnetic field levels.
Canada↗
Antitumour prodrug development using cytochrome P450 (CYP) mediated activation.
An ideal cancer chemotherapeutic prodrug is completely inactive until metabolized by a tumour-specific enzyme, or by an enzyme that is only metabolically competent towards the prodrug under physiological conditions unique to the tumour. Human cancers, including colon, breast, lung, liver, kidney and prostate, are known to express cytochrome P450 (CYP) isoforms including 3A and 1A subfamily members. This raises the possibility that tumour CYP isoforms could be a focus for tumour-specific prodrug activation. Several approaches are reviewed, including identification of prodrugs activated by tumour-specific polymorphic CYPs, use of CYP-gene directed enzyme prodrug therapy and CYPs acting as reductases in hypoxic tumour regions. The last approach is best exemplified by AQ4N, a chemotherapeutic prodrug that is bioreductively activated by CYP3A. This study shows that freshly isolated murine T50/80 mammary carcinoma and RIF-1 fibrosarcoma 4-electron reduces AQ4N to its cytotoxic metabolite, AQ4 (T50/80 Km = 26.7 microM, Vmax = 0.43 microM/mg protein/min; RIF-1 Km = 33.5 microM, Vmax = 0.42 microM/mg protein/min) via AQM, a mono-N-oxide intermediate (T50/80 Km = 37.5 microM; Vmax = 1.4 microM/mg protein/min; RIF-1 Km = 37.5 microM; Vmax = 1.2 microM/mg protein/ min). The prodrug conversion was dependent on NADPH and inhibited by air or carbon monoxide. Cyp3A mRNA and protein were both present in T50/80 carcinoma grown in vivo (RIF-1 not measured). Exposure of isolated tumour cells to anoxia (2 h) immediately after tumour excision increased cyp3A protein 2-3-fold over a 12 h period, after which time the cyp protein levels returned to the level found under aerobic conditions. Conversely, cyp3A mRNA expression showed an initial 3-fold decrease under both oxic and anoxic conditions; this returned to near basal levels after 8-24 h. These results suggest that cyp3A protein is stabilized in the absence of air, despite a decrease in cyp3A mRNA. Such a 'stabilization factor' may decrease cyp3A protein turnover without affecting the translation efficiency of cyp3A mRNA. Confirmation of the CYP activation of AQ4N bioreduction was shown with human lymphoblastoid cell microsomes transfected with CYP3A4, but not those transfected with CYP2B6 or cytochrome P450 reductase. AQ4N is also reduced to AQ4 in NADPH-fortified human renal cell carcinoma (Km = 4 microM, Vmax = 3.5 pmol/mg protein/min) and normal kidney (Km = 4 microM, Vmax = 4.0 pmol/mg protein/min), both previously shown to express CYP3A. Germane to the clinical potential of AQ4N is that although both normal and tumour cells are capable of reducing AQ4N to its cytotoxic species, the process requires low oxygen conditions. Hence, AQ4N metabolism should be restricted to hypoxic tumour cells. The isoform selectivity of AQ4N reduction, in addition to its air sensitivity, indicates that AQ4N haem coordination and subsequent oxygen atom transfer from the active-site-bound AQ4N is the likely mechanism of N-oxide reduction. The apparent increase in CYP3A expression under hypoxia makes this a particularly interesting application of CYPs for tumour-specific prodrug activation.
Animals↗
Second malignancies in patients with hairy cell leukemia in british columbia: a 20-year experience.
The purpose of this study was to compare the relative risk of second malignancies in a cohort of patients with hairy cell leukemia (HCL) against the normal population. Potential effects of type of treatment and duration of follow-up and the site distribution of cancer were also examined. Between 1976 and 1996, 117 patients were diagnosed with HCL in British Columbia who were referred to the British Columbia Cancer Agency (BCCA) for treatment. All additional malignancies were traced using a provincial population-based cancer registry and follow-up records from the BCCA. There were 90 men and 27 women. Median age at diagnosis was 53 years. The median follow-up time was 68 months. Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine (2-chlorodeoxyadenosine). Thirty-six patients had an additional malignancy (30.7%) with a total of 44 tumors. Six patients (5.1%) had two or more malignancies. Twenty-five patients had malignancies diagnosed after HCL (21.3%), three concurrent with HCL (2.6%), and 12 preceding HCL (10.2%). Second tumors (n = 28 tumors) occurred at a median of 40 months after HCL (range, 3 to 167). The relative rate (RR) of second malignancy among men and women was 2.91 (P < .001) and 1.65 (P = .23), respectively, compared with age and secular trend-matched controls. There were eight prostate cancers, nine nonmelanoma skin cancers, two lung cancers, and four gastrointestinal adenocarcinomas. The RR (90% confidence interval [CI]) in the various treatment groups were: splenectomy (RR = 0.21 to 3.81), purine analogues (RR = 0.60 to 5.69), interferon then purine analogues (RR = 1.60 to 4.31), interferon alone (RR = 1. 57 to 8.40). Cancer risk peaked at 2 years after HCL (RR = 4.13) and fell steadily afterwards, reaching a RR of 1.82 at 6 years. Twenty patients died, six due to HCL, 10 due to second malignancies, and four of unrelated causes. HCL patients appear to be inherently prone to malignancies. This appears to be more related to HCL tumor burden than to genetic predisposition or treatment effect. RR tends to fall with time after effective treatment. However, close monitoring for and vigorous prevention of cancer in HCL patients is advisable.
Adult↗
The effects of social support and education on health care costs after three years.
OBJECTIVE: To determine whether experimentally developed social support, education about appropriate use of the health care system, and their combination are effective in reducing health care costs for people with osteoarthritis at a 3-year followup assessment. METHOD: Three hundred sixty-three health maintenance organization members with osteoarthritis were randomly assigned to 1 of 3 intervention groups or to a control group. Two hundred fifty-six participants completed the 3-year assessment. Health status and health care use were assessed upon entering the study, and after 1, 2, and 3 years. RESULTS: Health care costs in the combined experimental groups were lower than those in the control group by $1,279/participant/year in year 3. There were no significant changes in health status between participants' entry into the study and the year 3 assessment. The 3 interventions had nearly equal effects on health status and health care costs. Implementation costs were least for the social support intervention, but the group that combined education and social support had less attrition and greater persistence. CONCLUSION: Interventions that target appropriate use of the health care system can be highly cost-effective without adversely affecting health status.
Aged↗
Sunscreens. Use and misuse.
Although sunscreens are widely available and in common use, surveys show that an average of only half of the people on a beach on a given day wear sunscreens. Many people go to the beach to get or maintain a suntan, but many people also leave their skin unprotected. This article discusses the proper use of sunscreens, common misunderstandings, and how unprotected long-term exposure to the sun can effect your skin.
Adolescent↗
Nicotine withdrawal as an etiologic factor in delirium.
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Aged↗
Global initiative takes shape slowly.
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Africa↗
All-trans retinoic acid and interferon-alpha-2a in patients with metastatic or recurrent carcinoma of the uterine cervix: clinical and pharmacokinetic studies. New York Gynecologic Oncology Group.
BACKGROUND: Recent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS: Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS: Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS: The combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.
Adult↗