Making the most of case-mother/control-mother studies

The prenatal environment plays an important role in many conditions, particularly those with onset early in life, such as childhood cancers and birth defects. Because both maternal and fetal genotypes can influence risk, investigators sometimes use a case-mother/control-mother design, with mother-offspring pairs as the unit of analysis, to study genetic factors. Risk models should account for both the maternal genotype and the correlated fetal genotype to avoid confounding. The usual logistic regression analysis, however, fails to fully exploit the fact that these are mothers and offspring. Consider an autosomal, diallelic locus, which could be related to disease susceptibility either directly or through linkage with a polymorphic causal locus. Three nested levels of assumptions are often natural and plausible. The first level simply assumes Mendelian inheritance. The second further assumes parental mating symmetry for the studied locus in the source population. The third additionally assumes parental allelic exchangeability. Those assumptions imply certain nonlinear constraints; the authors enforce those constraints by using Poisson regression together with the expectation-maximization algorithm. Calculations reveal that improvements in efficiency over the usual logistic analysis can be substantial, even if only the Mendelian assumption is honored. Benefits are even more marked if, as is typical, information on genotype is missing for some individuals.     

Rotenone, paraquat, and Parkinson's disease

Background

Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans.

Objectives

Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans.

Methods

We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case.

Results

In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7).

Conclusions

PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.     

Review of tumor markers for ovarian cancer

Forty-two substances having been described as potential tumor markers for ovarian cancer are reviewed regarding sensitivity, specificity, and correlation with clinical course of disease. At present, there is no reliable marker for the primary diagnosis of the vast majority of ovarian cancers. Tumor markers may however serve as adjunctive tools in monitoring ovarian cancer patients after treatment.     

Pesticide use and fatal injury among farmers in the Agricultural Health Study

Purpose

To assess whether pesticide use practices were associated with injury mortality among 51,035 male farmers from NC and IA enrolled in the Agricultural Health Study.

Methods

We used Cox proportional hazards models adjusted for age and state to estimate fatal injury risk associated with self-reported use of 49 specific pesticides, personal protective equipment, specific types of farm machinery, and other farm factors collected 1–15 years preceding death. Cause-specific mortality was obtained through linkage to mortality registries.

Results

We observed 338 injury fatalities over 727,543 person-years of follow-up (1993–2008). Fatal injuries increased with days/year of pesticide application, with the highest risk among those with 60+ days of pesticide application annually [hazard ratio (HR) = 1.87; 95% confidence interval (CI) = 1.10, 3.18]. Chemical-resistant glove use was associated with decreased risk (HR = 0.73; 95% CI = 0.58, 0.93), but adjusting for glove use did not substantially change estimates for individual pesticides or pesticide use overall. Herbicides were associated with fatal injury, even after adjusting for operating farm equipment, which was independently associated with fatal injury. Ever use of five of 18 herbicides (2,4,5-T, paraquat, alachlor, metribuzin, and butylate) were associated with elevated risk. In addition, 2,4-D and cyanazine were associated with fatal injury in exposure–response analyses. There was no evidence of confounding of these results by other herbicides.

Conclusion

The association between application of pesticides, particularly certain herbicides, and fatal injuries among farmers should be interpreted cautiously but deserves further evaluation, with particular focus on understanding timing of pesticide use and fatal injury.     

Pulmonal- und peripher-arterielle Embolie bei offenem Foramen ovale

Paradoxe Embolien sind in der Theorie gut bekannt, in der Praxis aber recht selten. Pathophysiologisch liegt typischerweise die Konstellation aus ven?ser Thrombose, erh?htem rechtsatrialen Druck und konsekutivem Rechts-Links-Shunt über ein offenes Foramen ovale oder einen Vorhofseptumdefekt zugrunde. Wir berichten über einen 65j?hrigen Patienten, der wegen eines akuten Schmerzereignisses mit Abblassen der Hautfarbe des linken Unterschenkels aufgenommen wurde. Zugleich hatte heftige Luftnot eingesetzt.     

Therapy of Established Postmenopausal Osteoporosis with Monofluorophosphate plus Calcium: Dose-Related Effects on Bone Density and Fracture Rate

Recent experience from different groups suggests that low fluoride doses resulting in moderate increases in bone mineral density (BMD) may be advantageous in terms of fracture-reducing potency. In a randomized prospective 3-year study we examined the therapeutic efficacy of different dosages of monofluorophosphate (MFP) plus calcium in comparison with calcium alone in 134 women with established postmenopausal osteoporosis (mean age 64.0 years, average vertebral fractures per patient 3.6). Group A received 1000 mg calcium/day and a low-dose intermittent MFP regimen (3 months on, 1 month off) corresponding to an average daily fluoride ion dose of 11.2 mg. Group B received 1000 mg calcium/day plus continuous MFP corresponding to 20 mg fluoride ions per day. Group C was treated with 1000 mg calcium alone throughout the study period. Bone density was measured with dual-energy X-ray absorptiometry at L2–4 and three proximal femur areas and with single photon absorptiometry at two radius sites. New vertebral fractures were identified from annual lateral radiographs of the spine. A significant reduction in subjective complaints as measured by a combined pain–mobility score (CPMS) was found in both fluoride groups in comparison with the calcium monotherapy group. Group A showed increases in BMD at all six measuring sites, reaching +12.6% at the spine after 3 years. In group B we found significant increases at the spine, Ward’s triangle and distal radius, but slight decreases at the femoral neck and radius shaft. For the spine the average change amounted to +19.5% after 3 years. In group C losses of BMD were observed at all six sites, with an average loss of 1.6% for the spine at the end of the study. The incidence of new vertebral fractures per 100 patient-years was 8.6, 17.0 and 31.6 in groups A, B and C, respectively. In conclusion, both calcium–MFP regimens resulted in significantly lower vertebral fracture rates than calcium monotherapy. However, the low intermittent MFP regimen, leading to a mean annual increase in spinal BMD of only 4.2%, showed a clear trend to greater effectiveness in reducing vertebral fracture than the higher fluoride dosage that was followed by an average spinal BMD increase of 6.5% per year. Furthermore the rate of fluoride-specific side effects (lower-extremity pain syndrome) was 50% lower in patients receiving the lower fluoride dosage. Received: 3 November 1997 / Accepted: 4 June 1998