Publications

OBJECTIVE

There are few estimates of the incidence and prevalence of inflammatory bowel disease in North American communities. We sought to estimate the incidence and prevalence of inflammatory bowel disease (IBD), including Crohn's disease (CD), and ulcerative colitis (UC), among 3.2 million members of Kaiser Permanente, Northern California, for the period 1996-2002.

METHODS

All health plan members who had one or more diagnoses of CD (ICD-9 code 555) or UC (ICD-9 code 556) on computerized records during the period 1996-2002 and with at least 12 months of membership were identified as possible IBD cases (N = 12,059). We randomly sampled 24% of these for chart review to confirm the diagnosis and obtain the initial diagnosis date. Incidence rates and the point prevalence on December 31, 2002 were standardized to the 2000 U. S. Census.

RESULTS

The annual incidence rate per 100,000 persons was 6.3 for CD (95% confidence interval [CI], 5.6-7.0) and 12.0 for UC (CI, 11.0-13.0). The point prevalence per 100,000 on December 31, 2002 was 96.3 for CD (95% CI, 89.6-103.0) and 155.8 for UC (95% CI, 146.6-164.9), increasing to 100.3 and 205.8 per 100,000, respectively, when hospital discharge data from 1985 to 1995 were included. The age-specific incidence of CD was bimodal, while UC incidence rose in early adulthood and remained elevated with advancing age.

CONCLUSIONS

The incidence we estimated for CD was similar to the previous U. S. estimate. Our incidence estimate for UC was much higher than the previous U.S. estimate, but similar to that of recent Canadian and European studies. The prevalence we estimated for CD was somewhat lower than previous estimates.

Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity-related insulin resistance; it also plays an important role in obesity-related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity-related liver disease. This review summarizes how innate immune processes, occurring both within and outside the liver, cause not only insulin resistance but also end-organ damage in the form of nonalcoholic fatty liver disease.

OBJECTIVE

To report on the effect of the Breast and Cervical Cancer Intervention Study (BACCIS), a multicomponent intervention conducted in the San Francisco Bay Area between 1992 and 1997.

METHODS

BACCIS targeted approximately 25,000 multiethnic, underserved women in eight neighborhoods and the public health clinics that served them. An outreach intervention using lay health worker peers and clinic provider inreach intervention to improve breast and cervical cancer screening were evaluated in a quasi-experimental, controlled trial with pretest and posttest household surveys of 1,599 and 1,616 women, respectively. Surveys were conducted in English, Spanish, Mandarin, and Cantonese.

RESULTS

Analyses of community survey results showed no significant improvement in reported screening behaviors. Reports of mammography in the intervention areas in the previous 2 years, or for Pap smear in the previous 3 years, did not differ significantly (73-71% and 84-87%, respectively, for pretest and posttest surveys).

CONCLUSION

High baseline screening rates, lack of sensitive measures of change at the population level, contamination of the control group, and an imbalance of predictive factors at baseline contributed to the difficulty of assessing the value of the intervention. Lessons learned from this inconclusive study may be of value to future community intervention studies of cancer screening and other health behaviors in multiethnic underserved urban populations.

Sex differences in thrombosis are well described, but their underlying mechanism(s) are not completely understood. Coagulation proteins are synthesized in the liver, and liver gene expression is sex specific and depends on sex differences in growth hormone (GH) secretion--males secrete GH in a pulsatile fashion, while females secrete GH continuously. Accordingly, we tested the hypothesis that sex-specific GH secretion patterns cause sex differences in thrombosis. Male mice were more susceptible to thrombosis than females in the thromboplastin-induced pulmonary embolism model and showed shorter clotting times ex vivo. GH-deficient little (lit) mice were protected from thrombosis, and pulsatile GH given to lit mice restored the male clotting phenotype. Moreover, pulsatile GH administration resulted in a male clotting phenotype in control female mice, while continuous GH caused a female clotting phenotype in control male mice. Expression of the coagulation inhibitors Proc, Serpinc1, Serpind1, and Serpina5 were strongly modulated by sex-specific GH patterns, and GH modulated resistance to activated protein C. These results reveal what we believe to be a novel mechanism whereby sex-specific GH patterns mediate sex differences in thrombosis through coordinated changes in the expression of coagulation inhibitor genes in the liver.

BACKGROUND

Malaria risk may be heterogeneous in urban areas of Africa. Identifying those at highest risk for malaria may lead to more targeted approaches to malaria control.

METHODS

A representative sample of 558 children aged 1-10 years were recruited from a census population in a single parish of Kampala and followed up for 2 years. Malaria was diagnosed when a child presented with a new episode of fever and a thick blood smear positive for parasites. Multivariate analysis was used to identify independent predictors of malaria incidence.

RESULTS

A total of 695 episodes of uncomplicated malaria were diagnosed after 901 person years of follow-up. Sickle cell trait (relative risk [RR], 0.68 [95% confidence interval {CI}, 0.52-0.90]), glucose-6-phosphate dehydrogenase deficiency in female children (RR, 0.48 [95% CI, 0.31-0.75]), and use of an insecticide-treated bed net (RR, 0.52 [95% CI, 0.32-0.83]) were associated with a lower risk of malaria. The distance of the subject's residence from a swamp bordering the parish showed a strong "dose-response" relationship; living in the swamp was the strongest predictor of malaria risk (RR, 3.94 [95% CI, 2.61-5.97]).

CONCLUSION

Malaria incidence was highly heterogeneous in this urban cohort of children. Malaria control interventions in urban areas should target populations living in pockets of high malaria risk.

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.

STUDY DESIGN

Randomized controlled trial.

OBJECTIVE

To characterize the increase in gelatinase A (MMP2) activity after spinal cord injury (SCI) in the mouse model, and the effects of MMP2/MMP9 inhibition on apoptotic cells.

SUMMARY OF BACKGROUND DATA

Clinical consequences of SCI are due to a series of secondary injury cascades. Matrix metalloproteinases are thought play a key role in this, leading to apoptotic cell death.

METHODS

SCI via a drop tower in mice was used. MMP2 beta-gal reporter mice were used to quantify the level of MMP2 after SCI. In a follow-up experiment, mice which underwent SCI were randomized to daily SQ injections of MMP2/MMP9 inhibitor versus placebo. MMP2 levels were quantified and histology was performed with TUNEL and Luxol fast blue staining.

RESULTS

MMP2 transcription was significantly upregulated after SCI, by the beta-gal assay. Inhibition of MMP2/MMP9 activity after SCI led to statistically significant decreases in apoptosis within the zone of injury. There was a trend towards preservation of myelin by preserved luxol fast blue staining.

CONCLUSION

After SCI, MMP2 is upregulated along with neuron and glial cells apoptosis. The level of apoptosis could be reduced with MMP2/MMP9 inhibition. This supports MMP2 as cause for apoptosis after SCI with the potential for therapeutic intervention as apoptosis can be reduced with MMP2 inhibition.

OBJECTIVES

Although discussing a prognosis is a duty of physicians caring for critically ill patients, little is known about surrogate decision-makers' beliefs about physicians' ability to prognosticate. We sought to determine: 1) surrogates' beliefs about whether physicians can accurately prognosticate for critically ill patients; and 2) how individuals use prognostic information in their role as surrogate decision-makers.

DESIGN, SETTING, AND PATIENTS

Multicenter study in intensive care units of a public hospital, a tertiary care hospital, and a veterans' hospital. We conducted semistructured interviews with 50 surrogate decision-makers of critically ill patients. We analyzed the interview transcripts using grounded theory methods to inductively develop a framework to describe surrogates' beliefs about physicians' ability to prognosticate. Validation methods included triangulation by multidisciplinary analysis and member checking.

MEASUREMENTS AND MAIN RESULTS

Overall, 88% (44 of 50) of surrogates expressed doubt about physicians' ability to prognosticate for critically ill patients. Four distinct themes emerged that explained surrogates' doubts about prognostic accuracy: a belief that God could alter the course of the illness, a belief that predicting the future is inherently uncertain, prior experiences where physicians' prognostications were inaccurate, and experiences with prognostication during the patient's intensive care unit stay. Participants also identified several factors that led to belief in physicians' prognostications, such as receiving similar prognostic estimates from multiple physicians and prior experiences with accurate prognostication. Surrogates' doubts about prognostic accuracy did not prevent them from wanting prognostic information. Instead, most surrogate decision-makers view physicians' prognostications as rough estimates that are valuable in informing decisions, but are not determinative. Surrogates identified the act of prognostic disclosure as a key step in preparing emotionally and practically for the possibility that a patient may not survive.

CONCLUSIONS

Although many surrogate decision-makers harbor some doubt about the accuracy of physicians' prognostications, they highly value discussions about prognosis and use the information for multiple purposes.

BACKGROUND

Mortality risk in adult asthma is poorly understood, especially the interplay among race, disease severity, and health care access.

OBJECTIVE

To examine mortality risk factors in adult asthma.

METHODS

In a prospective cohort study of 865 adults with severe asthma in a closed-panel managed care organization, we used structured interviews to evaluate baseline sociodemographics, asthma history, and health status. Patients were followed up until death or the end of the study (mean, 2 years). We used Cox proportional hazards regression to evaluate the impact of sociodemographics, cigarette smoking, and validated measures of perceived asthma control, physical health status, and severity of asthma on the risk of death.

RESULTS

We confirmed 123 deaths (mortality rate, 6.7 per 100 person-years). In an analysis adjusted for sociodemographics and tobacco history, higher severity-of-asthma scores (hazard ratio [HR], 1.11 per 0.5-SD increase in severity-of-asthma score; 95% confidence interval [CI], 1.01-1.23) and lower perceived asthma control scores (HR, 0.91 per 0.5-SD increase in perceived asthma control score; 95% CI, 0.83-0.99) were each associated with risk of all-cause mortality. In the same adjusted analysis, African American race was not associated with increased mortality risk relative to white race (HR, 0.64; 95% CI, 0.36-1.14).

CONCLUSIONS

In a large managed care organization in which access to care is unlikely to vary widely, greater severity-of-asthma scores and poorer perceived asthma control scores are each associated with increased mortality risk in adults with severe asthma, but African American patients are not at increased risk for death relative to white patients.