Publications

Growth cones are highly polarized and dynamic structures confined to the tips of axons. The polarity of growth cones is in part maintained by suppression of protrusive activity from the distal axon shaft, a process termed axon consolidation. The mechanistic basis of axon consolidation that contributes to the maintenance of growth cone polarity is not clear. We report that inhibition of RhoA-kinase (ROCK) or myosin II resulted in unstable consolidation of the distal axon as evidenced by increased filopodial and lamellipodial extension. Furthermore, when ROCK or myosin II was inhibited lamellipodia formed at the growth cone migrated onto the axon shaft. Analysis of EYFP-actin dynamics in the distal axon revealed that ROCK negatively regulates actin polymerization and initiation of protrusive structures from spontaneously formed axonal F-actin patches, the latter being an effect attributable to ROCK-mediated regulation of myosin II. Inhibition of ROCK or myosin II blocked growth cone turning toward NGF by preventing suppression of protrusive activity away from the source of NGF, resulting in aborted turning responses. These data elucidate the mechanism of growth cone polarity, provide evidence that consolidation of the distal axon is a component of guidance, and identify ROCK as a negative regulator of F-actin polymerization underlying protrusive activity in the distal axon.

Progressive familial intrahepatic cholestasis type 1 (PFIC1, Byler disease, OMIM 211600) is a severe inherited liver disease caused by mutations in ATP8B1. ATP8B1 is a member of the type 4 subfamily of P-type ATPases, which are phospholipid flippases. PFIC1 patients generally develop end-stage liver disease before the second decade of life. The disease is characterized by impaired biliary bile salt excretion, but the mechanism whereby impaired ATP8B1 function results in cholestasis is unclear. In a mouse model for PFIC1, we observed decreased resistance of the hepatocanalicular membrane to hydrophobic bile salts as evidenced by enhanced biliary recovery of phosphatidylserine, cholesterol, and ectoenzymes. In liver specimens from PFIC1 patients, but not in those from control subjects, ectoenzyme expression at the canalicular membrane was markedly deficient. In isolated mouse livers Atp8b1 deficiency impaired the transport of hydrophobic bile salts into bile. In conclusion, our study shows that Atp8b1 deficiency causes loss of canalicular phospholipid membrane asymmetry that in turn renders the canalicular membrane less resistant toward hydrophobic bile salts. The loss of phospholipid asymmetry may subsequently impair bile salt transport and cause cholestasis.

BACKGROUND

Homelessness is associated with high rates of health and substance use problems.

OBJECTIVE

To examine trends in the age, housing, health status, health service utilization, and drug use of the homeless population over a 14-year period.

DESIGN

Serial cross-sectional.

PARTICIPANTS

We studied 3,534 literally homeless adults recruited at service providers in San Francisco in 4 waves: 1990-1994, 1996-1998, 1999-2000, and 2003.

MEASUREMENTS

Age, time homeless, self-reported chronic conditions, hospital and emergency department utilization, and drug and alcohol use.

RESULTS

The median age of the homeless increased from 37 to 46 over the study waves, at a rate of 0.66 years per calendar year (P<.01). The median total time homeless increased from 12 to 39.5 months (P<.01). Emergency department visits, hospital admissions, and chronic health conditions increased.

CONCLUSIONS

The homeless population is aging by about two thirds of a year every calendar year, consistent with trends in several other cities. It is likely that the homeless are static, aging population cohort. The aging trends suggest that chronic conditions will become increasingly prominent for homeless health services. This will present challenges to traditional approaches to screening, prevention, and treatment of chronic diseases in an aging homeless population.

BACKGROUND

The Botswana government recently implemented a policy of routine or "opt-out" HIV testing in response to the high prevalence of HIV infection, estimated at 37% of adults.

METHODS AND FINDINGS

We conducted a cross-sectional, population-based study of 1,268 adults from five districts in Botswana to assess knowledge of and attitudes toward routine testing, correlates of HIV testing, and barriers and facilitators to testing, 11 months after the introduction of this policy. Most participants (81%) reported being extremely or very much in favor of routine testing. The majority believed that this policy would decrease barriers to testing (89%), HIV-related stigma (60%), and violence toward women (55%), and would increase access to antiretroviral treatment (93%). At the same time, 43% of participants believed that routine testing would lead people to avoid going to the doctor for fear of testing, and 14% believed that this policy could increase gender-based violence related to testing. The prevalence of self-reported HIV testing was 48%. Adjusted correlates of testing included female gender (AOR = 1.5, 95% CI = 1.1-1.9), higher education (AOR = 2.0, 95% CI = 1.5-2.7), more frequent healthcare visits (AOR = 1.9, 95% CI = 1.3-2.7), perceived access to HIV testing (AOR = 1.6, 95% CI = 1.1-2.5), and inconsistent condom use (AOR = 1.6, 95% CI = 1.2-2.1). Individuals with stigmatizing attitudes toward people living with HIV and AIDS were less likely to have been tested for HIV/AIDS (AOR = 0.7, 95% CI = 0.5-0.9) or to have heard of routine testing (AOR = 0.59, 95% CI = 0.45-0.76). While experiences with voluntary and routine testing overall were positive, 68% felt that they could not refuse the HIV test. Key barriers to testing included fear of learning one's status (49%), lack of perceived HIV risk (43%), and fear of having to change sexual practices with a positive HIV test (33%).

CONCLUSIONS

Routine testing appears to be widely supported and may reduce barriers to testing in Botswana. As routine testing is adopted elsewhere, measures should be implemented to assure true informed consent and human rights safeguards, including protection from HIV-related discrimination and protection of women against partner violence related to testing.

OBJECTIVE

Sex exchange is a well-established risk factor for HIV infection. Little is known about how correlates of sex trade differ by biologic sex and whether length of homelessness is associated with sex trade. We conducted a cross-sectional study among a sample of 1,148 homeless and marginally housed individuals in San Francisco to assess correlates of exchanging sex for money or drugs. Key independent variables included length of homelessness; use of crack, heroin or methamphetamine; HIV status; and sexual orientation. Analyses were restricted by biologic sex. In total, 39% of women and 30% of men reported a lifetime history of sex exchange. Methamphetamine use and greater length of homelessness were positively associated with a history of sex trade among women, while heroin use, recent mental health treatment, and homosexual or bisexual orientation were significantly associated with sex trade for men. Crack use was correlated with sex trade for both genders. Correlates of sex trade differ significantly according to biologic sex, and these differences should be considered in the design of effective HIV prevention programs. Our findings highlight the critical need to develop long-term services to improve housing status for homeless women, mental health services for homeless men, and drug treatment services for homeless adults involved in sex work.

We evaluated associations between key polymorphisms in target genes and responses to treatment with sulfadoxine-pyrimethamine (SP) or amodiaquine (AQ) for uncomplicated Plasmodium falciparum malaria in Bobo-Dioulasso, Burkina Faso. Presence of the dihydrofolate reductase (dhfr) 108N or 59R mutations (but not dhfr 51I or dihydropteroate synthetase [dhps] 437G) and P. falciparum chloroquine resistance transporter (pfcrt) 76T or P. falciparum multidrug resistance 1 (pfmdr1) 86Y or 1246Y mutations (but not pfmdr1 184F) predicted recrudescence after treatment with SP and AQ, respectively. Treatment led to significant increases in the prevalence of the same mutations (except 1246Y) in new infections that presented after therapy. The dhfr 164L and dhps 540E mutations were not seen in any isolates. These results clarify the key roles of a small number of mutations in P. falciparum resistance to SP and AQ in west Africa.

Permeability barrier function is measured with instruments that assess transepidermal water loss (TEWL), either with closed- or open-loop systems. Yet, the validity of TEWL as a measure of barrier status has been questioned recently. Hence, we tested the validity of this measure by comparing TEWL across a wide range of perturbations, with a variety of methods, and in a variety of models. TEWL rates with two closed-chamber systems (VapoMeter and H4300) and one closed-loop system (MEECO) under different experimental in vivo conditions were compared with data from four open-loop instruments, i.e. TM 210, TM 300, DermaLab and EP 1. The instruments were compared in vivo both in humans and hairless mice skin subjected to different degrees of acute barrier disruption. The values obtained with bioengineering systems were correlated with absolute water loss rates, determined gravimetrically. Measurements with both closed and open systems correlated not only with each other, but each method detected different degrees of barrier dysfunction. Although all instruments differentiated among gradations in TEWL in the mid-range of barrier disruption in vivo, differences in very low and very high levels of disruption were less accurately measured with the H4300 and DermaLab systems. Nevertheless, a high Pearson correlation coefficient (r) was calculated for data from all instruments vs. gravimetrically assessed TEWL. Together, these results verify the utility of TEWL as a measure of permeability barrier status. Moreover, all tested instruments are reliable tools for the assessment of variations in permeability barrier function.

BACKGROUND

Federal law obligates health care providers receiving federal funding to ensure language access to limited English-proficient (LEP) individuals who cannot communicate with their provider.

OBJECTIVE

To determine whether LEP individual awareness of this law improved language access through interpreter utilization.

DESIGN, SETTING, AND PARTICIPANTS

In June 2003, a telephone survey of 1,200 Californians was conducted in 11 non-English languages.

MEASUREMENTS

The survey included items on English proficiency, awareness of language law, health care utilization, and communication methods. Language access was defined as having a provider who speaks the individual's language (language-concordant) or utilizing an interpreter.

RESULTS

There were 1,000 LEP participants, of whom 371 (37%) were aware of the language law. Four hundred and ninety-one (49%) of LEP participants had a language-concordant provider. Of the remaining 509 LEP participants without a language-concordant provider, 111 (22%) reported interpreter utilization in the health care setting. After controlling for age, gender, education, income, insurance status, years in the United States, health care utilization, and level of English proficiency, awareness of law was not associated with interpreter utilization (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.38, 1.17; P=.16), but was associated with having a language-concordant provider (OR 1.64; 95% CI 1.19, 2.26; P=.003).

CONCLUSION

Awareness of language law is not sufficient to resolve language barriers for LEP individuals. Provider and organization level barriers to language access must be addressed.

Musicians are exposed to high-risk musculoskeletal activities such as repetition, hours of exposure, and awkward postures when playing instruments. These activities may result in playing-related musculoskeletal disorders. Musicians often work part-time or seasonally or are self-employed. Thus, they may be uninsured or underinsured and may delay seeking care for these painful and potentially disabling conditions. Prevention of playing-related musculoskeletal disorders includes identification of both intrinsic (e.g., musician strength and flexibility) and extrinsic (e.g., musician posture while playing an instrument) factors involved in the interface between musicians and their instruments and the playing environment (e.g., rest breaks or hours of practice). Student occupational health nurse practitioners in this pilot project performed outreach and comprehensive screening and treatment for a small group of musicians diagnosed as having playing-related musculoskeletal disorders. Tendon and nerve gliding exercises were a key component of the treatment plan.