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1.  Contemporary Rates of Severe Hypoglycaemia in Youth with Type 1 Diabetes: Variability by Insulin Regimen 
To determine incidence rates of severe hypoglycaemia and compare incidence rates by insulin regimen in a diverse sample of youth with type 1 diabetes from two sites.
In this observational study, 255 youth (51% female) aged 9–15 years receiving varied insulin regimens provided data prospectively for a median of 1.2 years. Reported episodes of severe hypoglycaemia, defined as episodes requiring help from another person for oral treatment or episodes resulting in seizure/coma, and current insulin regimens were collected systematically. Incidence rates were calculated and compared according to insulin regimen in bivariate and multivariate analyses.
At first encounter, participants had a median age of 12.2 years (range 9.0–15.0), median diabetes duration of 4.4 years (range 1.0–13.0) and mean A1C of 67±12 mmol/mol (8.3±1.1%). The incidence rate was 37.6/100-patient-years for all severe hypoglycaemia and 9.6/100-patient-years for seizure/coma. The incidence rate for severe hypoglycaemia was 31.8/100-patient-years on continuous subcutaneous insulin infusion (CSII), 34.4/100-patient-years on basal-bolus injections (B-B) and 46.1/100-patient-years on NPH (NPH vs. CSII: p=.04). The incidence rate for seizure/coma was 4.5/100-patient-years on CSII, 11.1/100-patient-years on B-B, and 14.4/100-patient-years on NPH (NPH vs. CSII: p=.004). In the multivariate analysis, the rate of seizure/coma was significantly higher for those on NPH vs. CSII (rate ratio 2.9, p=.03).
Rates of severe hypoglycaemia in youth with type 1 diabetes remain high. CSII was associated with lower rates of all severe hypoglycaemia and seizure/coma in comparison to NPH.
PMCID: PMC3597100  PMID: 22417321
Hypoglycaemia; type 1 diabetes; paediatrics; insulin therapy
4.  Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial 
The lancet oncology  2009;11(1):29-37.
High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide.
Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1–21 plus dexamethasone 40 mg on days 1–4, 9–12, and 17–20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with, number NCT00098475.
445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1·75, 80% CI 1·30–2·32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94–99) in the low-dose dexamethasone group compared with 87% (82–92) in the high-dose group (p=0·0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0·0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0·003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0·0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0·04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0·08), respectively.
Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma.
PMCID: PMC3042271  PMID: 19853510
5.  Cognitive activities delay onset of memory decline in persons who develop dementia 
Neurology  2009;73(5):356-361.
Persons destined to develop dementia experience an accelerated rate of decline in cognitive ability, particularly in memory. Early life education and participation in cognitively stimulating leisure activities later in life are 2 factors thought to reflect cognitive reserve, which may delay the onset of the memory decline in the preclinical stages of dementia.
We followed 488 initially cognitively intact community residing individuals with epidemiologic, clinical, and cognitive assessments every 12 to 18 months in the Bronx Aging Study. We assessed the influence of self-reported participation in cognitively stimulating leisure activities on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model.
Each additional self-reported day of cognitive activity at baseline delayed the onset of accelerated memory decline by 0.18 years. Higher baseline levels of cognitive activity were associated with more rapid memory decline after that onset. Inclusion of education did not significantly add to the fit of the model beyond the effect of cognitive activities.
Our findings show that late life cognitive activities influence cognitive reserve independently of education. The effect of early life education on cognitive reserve may be mediated by cognitive activity later in life. Alternatively, early life education may be a determinant of cognitive reserve, and individuals with more education may choose to participate in cognitive activities without influencing reserve. Future studies should examine the efficacy of increasing participation in cognitive activities to prevent or delay dementia.
= Alzheimer disease;
= baseline;
= Cognitive Activity Scale;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders;
= diagnosis;
= National Institute on Aging;
= Selective Reminding Test;
= Wechsler Adult Intelligence Scale Verbal IQ.
PMCID: PMC2725932  PMID: 19652139
6.  Increases in sexually transmitted infections and sexual risk behaviour without a concurrent increase in HIV incidence among men who have sex with men in San Francisco: a suggestion of HIV serosorting? 
Sexually Transmitted Infections  2006;82(6):461-466.
Sexually transmitted infections (STI) and unprotected anal intercourse (UAI) have been increasing among men who have sex with men (MSM) in San Francisco. However, HIV incidence has stabilised.
To describe recent trends in sexual risk behaviour, STI, and HIV incidence among MSM in San Francisco and to assess whether increases in HIV serosorting (that is, selective unprotected sex with partners of the same HIV status) may contribute to preventing further expansion of the epidemic.
The study applies an ecological approach and follows the principles of second generation HIV surveillance. Temporal trends in biological and behavioural measures among MSM were assessed using multiple pre‐existing data sources: STI case reporting, prevention outreach programmatic data, and voluntary HIV counselling and testing data.
Reported STI cases among MSM rose from 1998 through 2004, although the rate of increase slowed between 2002 and 2004. Rectal gonorrhoea cases increased from 157 to 389 while early syphilis increased from nine to 492. UAI increased overall from 1998 to 2004 (p<0.001) in community based surveys; however, UAI with partners of unknown HIV serostatus decreased overall (p<0.001) among HIV negative MSM, and among HIV positive MSM it declined from 30.7% in 2001 to a low of 21.0% in 2004 (p<0.001). Any UAI, receptive UAI, and insertive UAI with a known HIV positive partner decreased overall from 1998 to 2004 (p<0.001) among MSM seeking anonymous HIV testing and at the STI clinic testing programme. HIV incidence using the serological testing algorithm for recent HIV seroconversion (STARHS) peaked in 1999 at 4.1% at the anonymous testing sites and 4.8% at the STI clinic voluntary testing programme, with rates levelling off through 2004.
HIV incidence among MSM appears to have stabilised at a plateau following several years of resurgence. Increases in the selection of sexual partners of concordant HIV serostatus may be contributing to the stabilisation of the epidemic. However, current incidence rates of STI and HIV remain high. Moreover, a strategy of risk reduction by HIV serosorting can be severely limited by imperfect knowledge of one's own and one's partners' serostatus.
PMCID: PMC2563862  PMID: 17151031
men who have sex with men; sexual risk behaviour; sexually transmitted infections; HIV
7.  Clinician–patient communication: evidence-based recommendations to guide practice in cancer 
Current Oncology  2009;16(6):42-49.
Goals of Work
To develop recommendations for effective communication between cancer health care providers and patients based on a systematic review of methods of clinician–patient communication that may affect patient outcomes associated with distress at critical points in the course of cancer care.
Materials and Methods
A systematic review of the literature was conducted, and evidence-based recommendations were formulated to guide clinician–patient communication in cancer care. A formal external review was conducted to validate the relevance of these recommendations.
Main Results
Recommendations for communication in cancer care are presented, based on
guidelines from the Australian National Breast Cancer Centre and the Australian National Cancer Control Initiative,an updated systematic review of the research evidence, anda consensus by the Clinician–Patient Communications Working Panel of the Program in Evidence-Based Care of Cancer Care Ontario.
The recommendations were sent to 110 Ontario practitioners for external review: 33 responded (30% response rate). Most of these respondents (87%) agreed with the draft recommendations and approved of their use as a practice guideline (90%). A condensed version of the recommendations, including 10 key points, was also created.
There is evidence to support general clinician–patient communication approaches, although the preferences of cancer patients regarding such communication exhibit individual and cultural variability. Recommendations are provided, based on evidence, the consensus of an expert panel, and feedback from a survey of external practitioners. Evidence evaluating the role of decision aids and strategies to facilitate better communication is inconsistent, although such tools may be of value for some patients.
PMCID: PMC2794681  PMID: 20016745
Practice guideline; systematic review; cancer; communication; relationships
8.  Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults 
Neurology  2008;70(18):1594-1600.
Characterization of the behavioral correlates of neuromorphometry and neurochemistry in older adults has important implications for an improved understanding of the aging process. The objective of this study was to test the hypothesis that a measure of hippocampal neuronal metabolism was associated with verbal memory in nondemented older adults after controlling for hippocampal volume.
4-T MRI, proton magnetic resonance spectroscopy (1H MRS), and neuropsychological assessment were conducted in 48 older adults (23 women; mean age 81 years). Average hippocampal N-acetyl aspartate/creatine ratios (NAA/Cr) and hippocampal volumes were obtained. Neuropsychological evaluation included tests of verbal memory (Buschke and Grober Free and Cued Selective Reminding Test–Immediate Recall [FCSRT-IR], Wechsler Memory Scale–Revised Logical Memory subtest) and attention and executive function (Trail Making Test Parts A and B).
Linear regression analysis indicated that after adjusting for age, hippocampal NAA/Cr was a significant predictor of FCSRT-IR performance (β = 0.38, p = 0.01, R 2 = 0.21). Hippocampal volume was also a significant predictor of FCSRT-IR performance after adjusting for age and midsagittal area (β = 0.47, p = 0.01, R 2 = 0.24). In a combined model, hippocampal NAA/Cr (β = 0.33, p = 0.03) and volume (β = 0.35, p = 0.03) were independent predictors of FCSRT-IR performance, accounting for 30% of the variance in memory.
These findings indicate that nondemented older adults with smaller hippocampal volumes and lower levels of hippocampal N-acetyl aspartate/creatine ratio metabolites perform more poorly on a test of verbal memory. The integrity of both the structure and metabolism of the hippocampus may underlie verbal memory function in nondemented elderly.
PMCID: PMC2735229  PMID: 18367703
9.  Treatment of depression in cancer patients 
Current Oncology  2007;14(5):180-188.
What is the efficacy of pharmacologic and non-pharmacologic treatments for major depression and other depressive disorders in cancer populations?
Depression occurs at an increased rate in medically ill populations, including patients with cancer. In the general population, depression has been shown to be responsive to structured forms of psychotherapy and to pharmacologic interventions. The Supportive Care Guidelines Group conducted a systematic review of the evidence for the effectiveness of those therapies in patients with depression and cancer and developed the present clinical practice guideline based on that review and on expert consensus.
Outcomes of interest included symptomatic response to treatment, discontinuation rate of treatment, adverse effects, and quality of life.
Clinical recommendations were developed by the Supportive Care Guidelines Group based on a systematic review of the published literature through June 2005, feedback obtained from Ontario health care providers on the draft recommendations, the Report Approval Panel (rap) of Cancer Care Ontario’s Program in Evidence-Based Care, and expert consensus.
The systematic review of the literature included eleven trials (seven of pharmacologic agents and four of non-pharmacologic interventions). Feedback received from 44 responding health care providers and the rap on the draft recommendations was addressed and documented in the guideline.
Among providers, 82% agreed with the draft recommendations as stated, 68% agreed that the report should be approved as a practice guideline, and 73% indicated that they would be likely to use the guideline in their own practice.
Practice Guideline
These recommendations apply to adult cancer patients with a diagnosis of major depression or other non-bipolar depressive disorders. They do not address the treatment of non-syndromal depressive symptoms, for which specific antidepressant treatment is not usually indicated. The guideline is intended both for oncology health professionals and for mental health professionals engaged in the treatment of cancer patients. Expert consensus was central to the development of the guideline recommendations because of limited evidence in cancer patients.
Treatment of pain and other reversible physical symptoms should be instituted before or with initiation of specific antidepressant treatment.
Antidepressant medications should be considered for the treatment of moderate-to-severe major depression in cancer patients. Current evidence does not support the relative superiority of one pharmacologic treatment over another, nor the superiority of pharmacologic treatment over psychosocial interventions. The choice of an antidepressant should be informed by individual medication and patient factors: the side effect profiles of the medication, tolerability of treatment (including the potential for interaction with other current medications), response to prior treatment, and patient preference.
Cancer patients diagnosed with major depression may benefit from a combined modality approach that includes both psychosocial and pharmacologic interventions. Psychosocial treatment approaches that may be of value include those that provide information and support and those that address any combination of emotional, cognitive, and behavioural factors.
Qualifying Statements
Referral to a mental health specialist is appropriate when the diagnosis of depression is unclear, when the syndrome is severe, when patients do not respond to treatment, or when other complicating factors that may affect the choice of treatment are present.
Although care has been taken in the preparation of the information contained in this guideline, any person seeking to apply or to consult the guideline is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician.
PMCID: PMC2002483  PMID: 17938701
Practice guideline; depression; treatment; cancer
10.  Risky Behaviors Among Ohio Appalachian Adults 
Preventing Chronic Disease  2006;3(4):A127.
This article describes the prevalence of risky behaviors known to be associated with increased cancer morbidity and mortality among Ohio Appalachian adults. These behaviors, or risk factors, include: 1) tobacco use; 2) energy imbalance (involving poor diet, obesity, and physical inactivity); and 3) sexual behaviors. We report current estimates of the prevalence of these behaviors among Ohio Appalachian adult residents and review social, psychological, and biological variables associated with these risky behaviors. We also present recent empirical studies that have been completed or are in progress in Ohio Appalachia. Finally, we discuss how these studies help bridge well-documented gaps in the literature.
PMCID: PMC1779290  PMID: 16978502
11.  Perceptions of public health. 
Public Health Reports  1998;113(4):324-329.
PMCID: PMC1308389  PMID: 9672570
12.  The relationship between low-level benzene exposure and leukemia in Canadian petroleum distribution workers. 
Environmental Health Perspectives  1996;104(Suppl 6):1375-1379.
This study was conducted to evaluate the relationship between leukemia occurrence and long-term, low-level benzene exposures in petroleum distribution workers. Fourteen cases were identified among a previously studied cohort [Schnatter et al., Environ Health Perspect 101 (Suppl 6):85-89 (1993)]. Four controls per case were selected from the same cohort, controlling for birth year and time at risk. Industrial hygienists estimated workplace exposures for benzene, without knowledge of case-control status. Average benzene concentrations ranged from 0.01 to 6.2 ppm. Company medical records were used to abstract information on other potential confounders such as cigarette smoking. Odds ratios were calculated for several exposure metrics. Conditional logistic regression modeling was used to control for potential confounders. The risk of leukemia was not associated with increasing cumulative exposure to benzene for these exposure levels. Duration of benzene exposure was more closely associated with leukemia risk than other exposure metrics, although results were not statistically significant. A family history of cancer and cigarette smoking were the two strongest risk factors for leukemia, with cumulative benzene exposure showing no additional risk when considered in the same models. This study is consistent with other data in that it was unable to demonstrate a relationship between leukemia and long-term, low-level benzene exposures. The power of the study was limited. Thus, further study on benzene exposures in this concentration range are warranted.
PMCID: PMC1469742  PMID: 9118923
13.  Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers. 
OBJECTIVE: To evaluate the relation between mortality from lymphohaematopoietic cancer and long term, low level exposures to benzene among male petroleum distribution workers. METHODS: This nested case control study identified all fatal cases of lymphohaematopoietic cancer among a previously studied cohort. Of the 29 cases, 14 had leukaemia, seven multiple myeloma, and eight non-Hodgkin's lymphoma. A four to one matching ratio was used to select a stratified sample of controls from the same cohort, controlling for year of birth and time at risk. Industrial hygienists estimated workplace exposures for benzene and total hydrocarbons, without knowledge of case or control status, for combinations of job, location, and era represented in all work histories. Average daily benzene concentrations ranged from 0.01 to 6.2 parts per million (ppm) for all jobs. Company medical records were used to abstract information on other potential confounders such as cigarette smoking, although the data were incomplete. Odds ratios (ORs) were calculated with conditional logistic regression techniques for several exposure variables. RESULTS: Risks of leukaemia, non-Hodgkin's lymphoma, and multiple myeloma were not associated with increasing cumulative exposure to benzene or total hydrocarbons. For leukaemia, the logistic regression model predicted an OR of 1.002 (P < 0.77) for each ppm-y of exposure to benzene. Duration of exposure to benzene was more closely associated with risk of leukaemia than other exposure variables. It was not possible to completely control for other risk factors, although there was suggestive evidence that smoking and a family history of cancer may have played a part in the risk of leukaemia. CONCLUSION: This study did not show a relation between lymphohaematopoietic cancer and long term, low level exposures to benzene. The power of the study to detect low-such as twofold-risks was limited. Thus, further study on exposures to benzene in this concentration range are warranted.
PMCID: PMC1128597  PMID: 9038803
14.  Circumcision without tears. 
PMCID: PMC1335016  PMID: 8804252
15.  Pharmacokinetics of sex steroids in patients with beta thalassaemia major. 
Journal of Clinical Pathology  1993;46(7):660-664.
AIMS--To assess the pharmacokinetics of oral, intramuscular, or transdermal hormone replacement in patients with beta thalassaemia major. METHODS--Oral (testosterone undecanoate 40 mg) and intramuscular (testosterone propionate 15 mg, phenylpropionate 30 mg, isocaproate 30 mg and decanoate 50 mg) testosterone and transdermal (17 beta oestradiol 25 micrograms and 50 micrograms) oestradiol were evaluated in 21 male (16-29 years) and 11 female (19-26 years) patients with beta thalassaemia major and various forms of hypogonadism. RESULTS--In male patients given oral testosterone, peak testosterone concentrations were observed either two to four hours or seven hours after administration; intramuscular testosterone produced peak values seven days after injection. Transdermal 17 beta oestradiol given to female patients produced a biphasic pattern with an initial peak concentration occurring at 36 hours and a secondary rise at 84 hours. CONCLUSIONS--The results indicate that oral androgens should be given twice daily in cases of hypogonadism, and where growth is incomplete, lower than recommended doses. If intramuscular testosterone is used, smaller doses of 10-25 mg should be given every one to two weeks. Transdermal administration of 25-50 micrograms 17 beta oestradiol generally produces a plasma E2 value in the early to mid-follicular phase range (100-300 pmol/l). This is appropriate in adults but excessive for prepubertal girls. Diffuse iron infiltration of tissues does not seem to interfere with the absorption of androgens and oestrogens from the gut, muscle, or skin.
PMCID: PMC501398  PMID: 8157756
16.  Downregulation of calcitonin receptor mRNA expression by calcitonin during human osteoclast-like cell differentiation. 
Journal of Clinical Investigation  1995;95(1):167-171.
Calcitonin inhibits both osteoclast formation and bone resorption, and is a primary treatment for patients with hypercalcemia and increased bone turnover. However, the clinical utility of calcitonin is limited because patients become refractory to calcitonin after several days (the calcitonin "escape phenomenon"). The molecular basis for calcitonin "escape" is unclear. To determine the regulatory mechanisms controlling calcitonin receptor (CTR) expression in osteoclasts and their precursors, we treated immature mononuclear precursors for human osteoclast-like multinucleated cells (MNC) formed in vitro with 1,25-(OH)2D3, to induce their differentiation to committed mononuclear precursors, and mature multinucleated osteoclasts, and used reverse transcriptase (RT)-PCR to assess expression of CTR mRNA in both committed mononuclear precursors and MNC. The PCR fragment produced was cloned and sequenced to confirm that it was derived from CTR mRNA. CTR mRNA expression was detected in mononuclear MNC precursors after 7 d of 1,25-(OH)2D3 treatment. It was also present in osteoclast-like MNC and highly purified giant cells from osteoclastomas, but not in monocytes or macrophage polykaryons formed in vitro. Calcitonin markedly decreased CTR but not actin mRNA expression in giant cells and MNC after 12 h, and removal of calcitonin restored CTR mRNA expression. Similarly, calcitonin decreased calcitonin-induced adenylate cyclase activity. These data suggest: (a) downregulation of CTR gene expression by calcitonin may in part explain the calcitonin "escape phenomenon"; and (b) expression of CTR mRNA occurs in mononuclear osteoclast precursors within 7 d after exposure to 1,25-(OH)2D3.
PMCID: PMC295397  PMID: 7814611
17.  Assessing prevention effectiveness using data to drive program decisions. 
Public Health Reports  1994;109(2):187-194.
The measure of the effectiveness of health promotion and disease prevention activities is the impact of prevention policies, programs, and practices on public health and clinical medicine. Assessing prevention effectiveness involves continuing quantitative analysis of health outcomes resulting from prevention practices. Additionally, assessment involves evaluation of disease- and injury-prevention activities, including their medical, legal, ethical, and economic impacts. Although assessing the effectiveness of prevention activities involves measuring efficacy, safety, and cost, the primary criterion is to improve health at a reasonable cost, not merely to contain costs. Policy makers can use the results of assessments to set priorities in public health. The authors use case studies to illustrate various approaches to evaluating prevention programs, including programs for preventing measles, breast cancer, and diabetic retinopathy. Rigorous evaluation of the effectiveness of prevention activities is essential to the wide acceptance of preventive interventions and the willingness to pay for them.
PMCID: PMC1403474  PMID: 8153269
18.  Genetic organization of the duplicated vap region of the Dichelobacter nodosus genome. 
Journal of Bacteriology  1994;176(9):2663-2669.
The recombinant plasmid pJIR318 contains a fragment of the Dichelobacter nodosus genome which is associated with virulence. Sequence analysis of the pJIR318 insert has shown that it contains four vap (virulence-associated protein) genes which are homologous to open reading frames found on the Escherichia coli F plasmid and the Neisseria gonorrhoeae cryptic plasmid (M. E. Katz, R. A. Strugnell, and J. I. Rood, Infect. and Immun. 60:4586-4592, 1992). The plasmid pJIR318 hybridizes to three regions of the D. nodosus genome, each of which has now been isolated. Regions 1 and 3 were found to be adjacent in the genome of D. nodosus A198, and the order of the vap genes in vap regions 1 and 2 were shown to be identical. Partial sequence analysis and Southern blot analysis of the vap regions showed that the three regions probably arose by a duplication event(s) followed by insertions and/or deletions. A recombinant plasmid, pJIR749, was isolated from a library of a benign D. nodosus strain, 305. This plasmid contained sequences from both ends of vap region 2. Analysis of pJIR749 showed that the sequences on either side of vap region 2 were separated by 324 bp in the genome of benign strain 305 and that the orientations of the sequences were different. It is clear that a simple insertion or deletion event did not generate the benign and virulent strains studied. A model which describes the evolution of the duplicated vap regions in D. nodosus A198 is presented.
PMCID: PMC205406  PMID: 8169216
19.  A retrospective mortality study among Canadian petroleum marketing and distribution workers. 
Environmental Health Perspectives  1993;101(Suppl 6):85-99.
We conducted a retrospective mortality study among 6672 petroleum marketing and distribution workers from 226 locations throughout Canada. These employees worked for at least 1 year in the marketing distribution segment from 1964 through 1983 or were annuitants as of 1964. Industrial hygienists assigned hydrocarbon (HC) exposure frequency scores for several jobs, departments, and job functions. We computed standardized mortality ratios for the total cohort, HC exposure frequency groups, and tank truck drivers, and we also used Poisson regression techniques to model mortality for selected causes of death according to HC exposure frequency. Results indicate overall mortality below that of the general Canadian population for all marketing distribution workers [Standardized mortality ratio (SMR) = 0.88]. Mortality from aortic aneurysms was significantly elevated in all marketing/distribution workers (SMR = 1.79) but was due to raised mortality in nonexposed workers (SMR = 2.80). Tank truck drivers showed significantly elevated mortality due to leukemia (SMR = 3.35) based on five deaths. The leukemia findings were not evident in the larger group of marketing distribution workers classified as exposed to hydrocarbons (SMR = 1.01). No other cause of death was elevated in truck drivers. The leukemia findings are suggestive of a possible influence due to exposure to HCs in tank truck drivers, although other explanations cannot be ruled out. Other findings of elevated mortality in the marketing distribution group are generally not statistically significant. These included moderately increased mortality due to multiple myeloma, malignant melanoma, and kidney cancer. Small numbers of observed and expected deaths limit concise interpretations for these diseases.
PMCID: PMC1519999  PMID: 8020452
20.  ABC of sleep disorder. Dreams and medical illness. 
BMJ : British Medical Journal  1993;306(6883):993-995.
PMCID: PMC1677442  PMID: 8490484
21.  Independently derived murine glomerular immune deposit-forming anti-DNA antibodies are encoded by near-identical VH gene sequences. 
Journal of Clinical Investigation  1993;91(2):402-408.
To examine the influence of variable region sequences on the capacity of individual lupus autoantibodies (autoAb) to form glomerular immune deposits, the complete VH and VL region sequences of three anti-DNA mAb that produced morphologically similar immune deposits after administration to normal mice were determined. The Ig were independently derived from 1-mo-old (H238, IgM), 3-mo-old (H8, IgG2a), and 6-mo-old (H161, IgG3) MRL-lpr/lpr mice, and they all produced subendothelial and mesangial immune deposits after passive transfer to normal mice. In addition, H238 and H161 produced granular deposits in small extraglomerular vessels. The mAb had nearly identical VH gene sequences; H8 differed from H238 and H161 by a single nucleotide in FR1 that resulted in a histidine for glutamine substitution. This VH gene sequence was also > 99% homologous to another anti-DNA Ab (termed H241), that we previously reported to produce glomerular immune deposits in a similar morphologic pattern. H161 and H238 were encoded by DFL16 and JH2 genes, whereas H8 was encoded by a JH4 gene. Different Vk family genes were used to encode the three mAb, however H161 and H238 both used a Jk5 gene. The results indicate that an identical or highly related VH gene is used to encode a subgroup of murine lupus autoAb that share immune deposit forming properties. Furthermore, they raise the possibility that amino acid residues independent from those encoded by VH genes may be influential in immune deposit formation at extraglomerular sites.
PMCID: PMC287938  PMID: 8432848
22.  Molecular characterization of a genomic region associated with virulence in Dichelobacter nodosus. 
Infection and Immunity  1992;60(11):4586-4592.
The major pathogen implicated in footrot, a highly contagious disease of sheep, is the strict anaerobe Dichelobacter nodosus (formerly Bacteroides nodosus). Sequence analysis of a 2,262-bp segment of the D. nodosus genome which is more prevalent in virulent isolates than in other isolates showed the presence of four open reading frames which appeared to have consensus transcriptional and translational start signals. These virulence-associated genes have been designated vapABCD. Two of the three copies of the vap region in the genome of the reference strain D. nodosus A198 were shown to carry all of the vap genes, whereas one copy contained only the vapD gene. The VapD protein was gel purified, shown to contain the predicted amino-terminal sequence, and used to raise rabbit antibodies. Western blots (immunoblots) showed that all of the D. nodosus strains tested that contained the vap region produced the VapD protein. The VapD protein had significant amino acid sequence identity with open reading frame 5 from the cryptic plasmid of Neisseria gonorrhoeae, and the vapBC operon had sequence similarity with the trbH region of the Escherichia coli F plasmid. It is proposed that these gene regions evolved from the integration of a conjugative plasmid from another bacterial species into the D. nodosus chromosome.
PMCID: PMC258206  PMID: 1398971
24.  Intracellular proteolysis of pancreatic zymogens. 
Activation of pancreatic digestive zymogens within the pancreatic acinar cell may be an early event in the development of pancreatitis. To detect such activation, an immunoblot assay has been developed that measures the relative amounts of inactive zymogens and their respective active enzyme forms. Using this assay, high doses of cholecystokinin or carbachol were found to stimulate the intracellular conversion of at least three zymogens (procarboxypeptidase A1, procarboxypeptidase B, and chymotrypsinogen 2) to their active forms. Thus, this conversion may be a generalized phenomenon of pancreatic zymogens. The conversion is detected within ten minutes of treatment and is not associated with changes in acinar cell morphology; it has been predicted that the lysosomal thiol protease, cathepsin B, may initiate this conversion. Small amounts of cathepsin B are found in the secretory pathway, and cathepsin B can activate trypsinogen in vitro; however, exposure of acini to a thiol protease inhibitor (E64) did not block this conversion. Conversion was inhibited by the serine protease inhibitor, benzamidine, and by raising the intracellular pH, using chloroquine or monensin. This limited proteolytic conversion appears to require a low pH compartment and a serine protease activity. After long periods of treatment (60 minutes), the amounts of the active enzyme forms began to decrease; this observation suggested that the active enzyme forms were being degraded. Treatment of acini with E64 reduced this late decrease in active enzyme forms, suggesting that thiol proteases, including lysosomal hydrolases, may be involved in the degradation of the active enzyme forms. These findings indicate that pathways for zymogen activation as well as degradation of active enzyme forms are present within the pancreatic acinar cell.
PMCID: PMC2589730  PMID: 1340058
25.  Mycobacterium avium complex and Mycobacterium tuberculosis in patients infected with the human immunodeficiency virus. 
Western Journal of Medicine  1992;157(2):144-148.
Primary care physicians play an important role in identifying and treating bacterial infections in adults infected with the human immunodeficiency virus (HIV). Mycobacterium avium complex and Mycobacterium tuberculosis are pathogens that can cause systemic or local infection in these patients. We review the epidemiology, pathogenesis, clinical presentation, and principles of treatment for these two mycobacterial pathogens. Because M tuberculosis disease is preventable and curable and yet communicable, physicians should maintain a high degree of suspicion for tuberculosis in HIV-infected adults. In comparison, the goal of treating M avium complex in patients with advanced HIV disease is to reduce constitutional symptoms and improve survival.
PMCID: PMC1011232  PMID: 1441463

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