Integrative assessment of multiple pesticides as risk factors for non-Hodgkin's lymphoma among men

Methods: During the 1980s, the National Cancer Institute conducted three case-control studies of NHL in the midwestern United States. These pooled data were used to examine pesticide exposures in farming as risk factors for NHL in men. The large sample size (n = 3417) allowed analysis of 47 pesticides simultaneously, controlling for potential confounding by other pesticides in the model, and adjusting the estimates based on a prespecified variance to make them more stable.

Results: Reported use of several individual pesticides was associated with increased NHL incidence, including organophosphate insecticides coumaphos, diazinon, and fonofos, insecticides chlordane, dieldrin, and copper acetoarsenite, and herbicides atrazine, glyphosate, and sodium chlorate. A subanalysis of these "potentially carcinogenic" pesticides suggested a positive trend of risk with exposure to increasing numbers.

Conclusion: Consideration of multiple exposures is important in accurately estimating specific effects and in evaluating realistic exposure scenarios.

     

Direct binding of C1q to apoptotic cells and cell blebs induces complement activation

Deficiency of early components of the classical pathway of complement, particularly C1q, predisposes to the development of systemic lupus erythematosus. Several studies have suggested an association between the classical complement pathway and the clearance of apoptotic cells. Mice with a targeted deletion of the C1q gene develop a lupus-like renal disease, which is associated with the presence of multiple apoptotic bodies in the kidney. In the present study we demonstrate that highly purified C1q binds to apoptotic cells and isolated blebs derived from these apoptotic cells. Binding of C1q to apoptotic cells occurs via the globular heads of C1q and induces activation of the classical complement pathway, as shown by the deposition of C4 and C3 on the surface of these cells and on cell-derived blebs. In addition, for the first time, we demonstrate that surface-bound C1q is present on a subpopulation of microparticles isolated from human plasma. Taken together, these observations demonstrate that C1q binds directly to apoptotic cells and blebs derived therefrom and support a role for C1q, possibly in concert with C4 and C3, in the clearance of apoptotic cells and blebs by the phagocytic system.     

Incidence and management of intermittent claudication in primary care in The Netherlands

OBJECTIVE: To study the incidence and management of intermittent claudication in primary care. DESIGN: In a longitudinal survey among 161 general practitioners (GPs) all incident diagnoses of intermittent claudication (IC) were selected and available information on GP management was studied. Setting: Dutch National Survey of Morbidity and Interventions in General Practice. SUBJECTS: 74153 patients aged 55 years and over. MAIN OUTCOME MEASURES: Age- and sex-specific incidence rates. RESULTS: The overall incidence rate of IC was 6.4 per 1000 person years (95% confidence interval (CI) 5.3-7.7). Incidence rate in creased from 4.0 per 1000 person years in men aged 55-59 to 12.9 per 1000 person years in men aged over 85, and for women in the same age categories from 3.3 per 1000 person years to 8.2 per 1000 person years, respectively. Of the 117 incident cases of IC, 43 (37%) were referred to a hospital specialist. In 55 cases (47%), drugs were prescribed by the GP and in 101 cases (86%) the GP gave advice, notably pertaining to exercise and cessation of smoking. CONCLUSION: The incidence rate of IC in primary care is high in both men and women, and clearly increases with age. Only a minority of patients are referred to a hospital specialist, while the vast majority receive lifestyle advice.     

Cardiac abnormalities in end stage renal failure and anaemia

Thirteen anaemic children on dialysis were assessed to determine the incidence of cardiac changes in end stage renal failure. Nine children had an increased cardiothoracic ratio on radiography. The electrocardiogram was abnormal in every case but no child had left ventricular hypertrophy as assessed by voltage criteria. However, left ventricular hypertrophy, often gross, was found on echocardiography in 12 children and affected the interventricular septum disproportionately. Cardiac index was increased in 10 patients as a result of an increased left ventricular stroke volume rather than heart rate. Left ventricular hypertrophy was significantly greater in those on treatment for hypertension and in those with the highest cardiac index. Abnormal diastolic ventricular function was found in 6/11 children. Children with end stage renal failure have significant cardiac abnormalities that are likely to contribute to the high cardiovascular mortality in this group. Anaemia and hypertension, or its treatment, probably contribute to these changes. Voltage criteria on electrocardiogram are of no value in detecting left ventricular hypertrophy. Echocardiography must be performed, with the results corrected for age and surface area, in order to detect and follow these abnormalities.     

Simultaneous immunoglobulin/T-cell receptor gene rearrangements and multiclonality in childhood acute lymphoblastic leukemia

Twenty-five children less than 16 years of age with acute lymphoblastic leukemia (ALL) were investigated with immunologic, cytogenetic and molecular genetic techniques at diagnosis. All pre-B-cell ALL showed clonal rearrangements in the immunoglobulin heavy chain gene (J_H and/or Cμ). A very high proportion of the pre-B-cell leukemias (17 of 23 cases) also snowed clonal rearrangements in T-cell receptor genes (Tγ and/or Tβ). The two T-cell leukemias exhibited clonal T-cell receptor gene rearrangements and in one Jh and kappa light chain rearrangments also. The T-cell receptor gene rearrangements found in pre-B-cell leukemias appeared to occur randomly with respect to the Tβ and Tγ genes. A significant proportion of the leukemias (at least 24%) seemed to harbor more than one malignant (sub)clone at diagnosis. Cytogenetic studies revealed a clonal abnormality in 10 cases. Only 2 showed hyperdiploidy (> 50 chromosomes). The only correlation between cytogenetic findings and rearrangement patterns was extra bands corresponding to a possible trisomy of chromosome 14. Our data indicate, in line with previous studies, that childhood ALL has complex rearrangement patterns not useful for lineage sub-classification. For this purpose immunophenotyping appears to be superior. However, molecular analysis can reveal the presence of more than one clone not detected by immunophenotyping or karyotyping, and distribution of clones in different compartments. In this study no correlation with clinical outcome was observed.     

Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden

To estimate the prevalence of chronic granulomatous disease (CGD) in Sweden, an inquiry asking for known and possible CGD cases was mailed to paediatric, internal medicine and infectious disease departments all over Sweden. The detected patients were characterized as to genetics and the clinical presentation. Twenty–one patients (belonging to 16 different families) were found, corresponding to a prevalence of ∼ 1/450 000 individuals. The patients with X–linked disease, lacking a functional gp91^phox protein ( n = 12), comprised 57% and 43% of the patients had an autosomal recessive (AR) disease lacking p47^phox ( n = 7) or p67^phox ( n =1), respectively. All unrelated patients with X–linked disease displayed different gene abnormalities such as point mutations predicting nonsense ( n = 3), missense ( n = 1) or splice site mutations ( n = 2), but also a total deletion and a unique 40 base pair duplicature insertion. The patients with p47^phox–deficiency showed a GT deletion at a GTGT tandem repeat, and the p67^phox–deficient patient displayed a heterozygous in–frame deletion of AAG combined with a large deletion in the other allele. Three patients died during the study period, two from Pseudomonas cepacia infections. Patients with X–linked disease had more frequent infections (mean of 1.7 per year), than the patients with AR inheritance (0.5 infections per year). The most common infections were dermal abscesses ( n =111), followed by lymphadenitis ( n =82) and pneumonias ( n =73). Inflammatory bowel disease–like symptoms, mimicking Crohn's disease of the colon, was seen in three CGD patients.     

Severe pulmonary vascular occlusive disease following bone marrow transplantation in Omenn syndrome

A 5-month-old infant presented with severe combined immunodeficiency disease, reticuloendotheliosis, and hypereosinophilia (Omenn syndrome) resulting in recurrent infections and endomyocardial disease. Bone marrow transplantation from an HLA-identical donor after chemotherapeutic conditioning led to both immunological and clinical recovery. Bone marrow transplantation, however, was followed by severe pulmonary occlusive disease. The patient gradually recovered while on increased inspiratory oxygen and the calcium channel blocker nifedipine.     

Cooperative actions of hepatocyte growth factor and 1,25-dihydroxyvitamin D3 in osteoblastic differentiation of human vertebral bone marrow stromal cells

Bone formation and remodeling require continuous generation of osteoprogenitor cells from bone marrow stromal cells (MSC), which generate and respond to a variety of growth factors with putative roles in hematopoiesis and mesenchymal differentiation. In this study we examine the interaction of two such factors on the maturation of skeletal components. We previously reported that these factors, hepatocyte growth factor (HGF) and 1,25-dihydroxyvitamin D(3) (vitD(3)), act together to increase alkaline phosphatase in chondroblasts. We now describe the cooperative effect of these agents on MSC isolated and cultured from human vertebral bone marrow. MSC (passages 3-9) isolated from bone marrow cells of human vertebrae (T1-L5) from 22-36-year-old normal donors were first expanded in vitro and then plated in the presence or absence of 10 ng/mL HGF and/or 10 nmol/L vitD(3), for 7-18 days. HGF treatment increased cell proliferation 2.5-fold, with no effect on alkaline phosphatase activity. Whereas vitD(3) treatment inhibited cell growth by 50%, alkaline phosphatase activity was stimulated eightfold, although no mineralization was observed. HGF together with vitD(3) increased cell proliferation 1.5-fold and alkaline phosphatase activity 13-fold over untreated control. Moreover, mineralization was detected only with this combination. Our findings provide evidence that HGF in concert with vitamin D may promote growth and differentiation of human MSC into osteogenic cells.     

Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case-control study using spontaneous reports

The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 1985-99 (n = 24,263). The study population comprised all patients using an antidepressant drug at the time the ADR occurred. We calculated ADR-reporting odds ratios (ADR-OR) to estimate the association between SSRI-use and EPS, relative to other antidepressants. We identified 61 patients with EPS. SSRI-use was associated with spontaneous reporting of EPS compared to other antidepressants (adjusted ADR-OR 2.2; 95% confidence interval 1.2-3.9). This risk estimate appeared to be higher in patients concurrently using antipsychotic medication (6.9, 0.7-68.0), although the confidence interval was very wide. In conclusion, SSRI-use seems only to be moderately associated with EPS compared to other antidepressants. However, those concurrently using antipsychotic drugs or presenting with other risk factors may be more susceptible and should be closely monitored.