Publications

AIM

The Primary Medical Education (PRIME) program is an outpatient-based, internal medicine residency track nested within the University of California, San Francisco (UCSF) categorical medicine program. Primary Medical Education is based at the San Francisco Veteran's Affairs Medical Center (VAMC), 1 of 3 teaching hospitals at UCSF. The program accepts 8 UCSF medicine residents annually, who differentiate into PRIME after internship. In 2000, we implemented a novel research methods curriculum with the dual purposes of teaching basic epidemiology skills and providing mentored opportunities for clinical research projects during residency.

SETTING

Single academic internal medicine program.

PROGRAM DESCRIPTION

The PRIME curriculum utilizes didactic lecture, frequent journal clubs, work-in-progress sessions, and active mentoring to enable residents to "try out" a clinical research project during residency.

PROGRAM EVALUATION

Among 32 residents in 4 years, 22 residents have produced 20 papers in peer-reviewed journals, 1 paper under review, and 2 book chapters. Their clinical evaluations are equivalent to other UCSF medicine residents.

DISCUSSION

While learning skills in evidence-based medicine, residents can conduct high-quality research. Utilizing a collaboration of General Internal Medicine researchers and educators, our curriculum affords residents the opportunity to "try-out" clinical research as a potential future career choice.

Perchlorate (ClO4-) has been detected in groundwater sources in numerous communities in California and other parts of the United States, raising concerns about potential impacts on health. For California communities where ClO4- was tested in 1997 and 1998, we evaluated the prevalence of primary congenital hypothyroidism (PCH) and high thyroid-stimulating hormone (TSH) levels among the 342,257 California newborns screened in 1998. We compared thyroid function results among newborns from 24 communities with average ClO4- concentrations in drinking water>5 microg/L (n=50,326) to newborns from 287 communities with average concentrations5 microg/L were observed, with 20.4 expected [adjusted prevalence odds ratio (POR)=0.71; 95% confidence interval (CI), 0.40-1.19]. Although only 36% of all California newborns were screened before 24 hr of age in 1998, nearly 80% of newborns with high TSH were screened before 24 hr of age. Because of the physiologic postnatal surge of TSH, the results for newborns screened before 24 hr were uninformative for assessing an environmental impact. For newborns screened>or=24 hr, the adjusted POR for high TSH was 0.73 (95% CI, 0.40-1.23). All adjusted odds ratios (ORs) were controlled for sex, ethnicity, birth weight, and multiple birth status. Using an assessment of ClO4- in drinking water based on available data, we did not observe an association between estimated average ClO4- concentrations>5 microg/L in drinking water supplies and the prevalence of clinically diagnosed PCH or high TSH concentrations.

The nature of the stress experienced by Escherichia coli K-12 exposed to chromate, and mechanisms that may enable cells to withstand this stress, were examined. Cells that had been preadapted by overnight growth in the presence of chromate were less stressed than nonadapted controls. Within 3 h of chromate exposure, the latter ceased growth and exhibited extreme filamentous morphology; by 5 h there was partial recovery with restoration of relatively normal cell morphology. In contrast, preadapted cells were less drastically affected in their morphology and growth. Cellular oxidative stress, as monitored by use of an H2O2-responsive fluorescent dye, was most severe in the nonadapted cells at 3 h postinoculation, lower in the partially recovered cells at 5 h postinoculation, and lower still in the preadapted cells. Chromate exposure depleted cellular levels of reduced glutathione and other free thiols to a greater extent in nonadapted than preadapted cells. In both cell types, the SOS response was activated, and levels of proteins such as SodB and CysK, which can counter oxidative stress, were increased. Some mutants missing antioxidant proteins (SodB, CysK, YieF, or KatE) were more sensitive to chromate. Thus, oxidative stress plays a major role in chromate toxicity in vivo, and cellular defense against this toxicity involves activation of antioxidant mechanisms. As bacterial chromate bioremediation is limited by the toxicity of chromate, minimizing oxidative stress during bacterial chromate reduction and bolstering the capacity of these organisms to deal with this stress will improve their effectiveness in chromate bioremediation.

We followed parasite genotypes of 75 patients for 42 days after treatment of uncomplicated malaria with chloroquine + sulfadoxine-pyrimethamine in Kampala, Uganda. Infections were complex (mean, 2.88 strains) and followed three patterns: 27% of patients eliminated all strains and remained parasite-free, 48% had a long aparasitemic interval followed by reappearance of original strains after 3-33 days (mean, 9.2 days), and 25% failed to clear original strains and required therapy after 3-35 days (mean, 17 days). These results highlight the complexity of malaria in Africa and have implications for efficacy trials, because missing late reappearances of strains could lead to misclassification of outcomes.

Polymorphisms in the Plasmodium falciparum pfmdr1 gene were assayed in pretreatment samples and in samples from patients reinfected following therapy with artemether-lumefantrine. The pfmdr1 alleles 86N, 184F, and 1246D significantly increased in prevalence after treatment. All samples had a single pfmdr1 copy. Treatment with artemether-lumefantrine selects for polymorphisms that may alter antimalarial drug response.

Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected. Moreover, loss of FATP1 function altered regulation of postprandial serum LCFA, causing a redistribution of lipids from adipocyte tissue and muscle to the liver, and led to a complete protection from diet-induced obesity and insulin desensitization. This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids. The strong protection against diet-induced obesity and insulin desensitization observed in FATP1-null animals suggests FATP1 as a novel antidiabetic target.

BACKGROUND

Given the strong relation between sexually transmitted diseases (STDs) and the spread of HIV infection, recent outbreaks of syphilis in the United States could lead to increased rates of new HIV infection. STD clinics serving persons at risk for syphilis would be logical sites to monitor rates of acute HIV infection. The detection of acute HIV infection, however, is not routine and requires the use of HIV RNA testing in combination with HIV antibody testing.

METHODS

To determine the rate of acute HIV infection, we performed HIV RNA testing on pooled HIV antibody-negative specimens from persons seeking care at San Francisco City Clinic (SFCC) and from men seeking care at 3 STD clinics in Los Angeles. We compared prevalence of acute HIV infection among those groups.

RESULTS

From October 2003 to July 2004, we tested 3075 specimens from persons at the SFCC, of which 105 (3%) were HIV antibody-positive and 11 were HIV RNA-positive/HIV antibody-negative, resulting in a prevalence of acute HIV infection of 36 per 10,000 (95% confidence interval [CI]: 26 to 50 per 10,000) and increasing by 10.5% the diagnostic yield of HIV RNA testing compared with standard testing. From February 2004 to April 2004, 1712 specimens were tested from men at 3 Los Angeles STD clinics, of which 14 (0.82%) were HIV-positive by enzyme immunoassay testing and 1 was HIV RNA-positive/HIV antibody-negative, resulting in a prevalence of 6 per 10,000 (95% CI: 3 to 13 per 10,000) and increasing the diagnostic yield for HIV infection by 7.1%.

CONCLUSIONS

In our study, the addition of HIV RNA screening to routine HIV antibody testing in STD clinics identified a substantial increased proportion of HIV-infected persons at high risk for further HIV transmission, who would have been missed by routine HIV counseling and testing protocols. Further evaluation of the addition of HIV RNA screening to routine HIV antibody testing is warranted.

CONTEXT

Biomass serves as a major fuel source for >50% of the world's population. The global burden of disease attributed to indoor air pollution from biomass combustion accounts for approximately 3% of worldwide disability-adjusted life-years lost. This is due to pneumonia in children and chronic obstructive pulmonary disease and lung cancer in women.

CASE PRESENTATION

A 53-year-old man from Mexico was referred to the pulmonary clinic for evaluation of chronic productive cough and pulmonary nodules. In his youth, he worked at a charcoal plant in Mexico, where he burned wood and was exposed to massive amounts of smoke. His evaluation revealed thickened bronchovascular bundles with nodules on thoracic computed tomography, dark black plaques in large airways on bronchoscopy, and carbon-laden macrophages and fibrotic scars on lung biopsy.

DISCUSSION

The patient was diagnosed with "hut lung," a term that refers to the noninfectious, nonmalignant respiratory manifestations of chronic, high-level exposures to biomass smoke. This is the first reported case of hut lung associated with charcoal production. This case highlights that histopathologic abnormalities of the lung parenchyma may be present in patients with only mild symptoms and that clinical progression is likely a function of both the duration and intensity of exposure.

RELEVANCE TO CLINICAL PRACTICE

As residents of lesser developed countries continue to be exposed to high levels of biomass smoke at work or at home and continue to immigrate to developed countries, it is important that health care providers in developed countries be aware of biomass-smoke-related pulmonary disease.