Hal F. Yee

Is weight reduction an effective therapy for nonalcoholic fatty liver?: A systematic review

PURPOSE To assess the evidence supporting the efficacy of weight reduction for patients with nonalcoholic fatty liver. METHODS Potentially relevant studies were identified by a computerized search of databases and a manual search of abstracts from scientific meetings. Studies were included if they reported histology, serum aminotransferase levels, or radiological imaging of the liver in obese adult patients who had undergone weight reduction. Weight reduction regimens included diet, exercise, antiobesity medications, gastric bypass, gastroplasty, or any combination of these interventions. Studies involving jejunoileal or small bowel bypass surgery were excluded. RESULTS We identified 517 potentially relevant studies, of which 15 met the inclusion criteria: one randomized controlled trial (in abstract form), two nonrandomized controlled trials, nine case series, one retrospective review, and two case reports. Three studies included more than 50 patients, whereas nine studies had 25 or fewer patients. Twelve studies used behavioral, dietary, or pharmacologic therapy for weight reduction, and three studies used surgical interventions. Although all 15 studies demonstrated overall improvement in the measurements of liver outcome after weight reduction, more than half did not report histologic results. CONCLUSION Despite general acceptance that weight reduction is an effective therapy for nonalcoholic fatty liver, this systematic review found little data to support or refute this recommendation.

Actin turnover is required to prevent axon retraction driven by endogenous actomyosin contractility

Growth cone motility and guidance depend on the dynamic reorganization of filamentous actin (F-actin). In the growth cone, F-actin undergoes turnover, which is the exchange of actin subunits from existing filaments. However, the function of F-actin turnover is not clear. We used jasplakinolide (jasp), a cell-permeable macrocyclic peptide that inhibits F-actin turnover, to study the role of F-actin turnover in axon extension. Treatment with jasp caused axon retraction, demonstrating that axon extension requires F-actin turnover. The retraction of axons in response to the inhibition of F-actin turnover was dependent on myosin activity and regulated by RhoA and myosin light chain kinase. Significantly, the endogenous myosin-based contractility was sufficient to cause axon retraction, because jasp did not alter myosin activity. Based on these observations, we asked whether guidance cues that cause axon retraction (ephrin-A2) inhibit F-actin turnover. Axon retraction in response to ephrin-A2 correlated with decreased F-actin turnover and required RhoA activity. These observations demonstrate that axon extension depends on an interaction between endogenous myosin-driven contractility and F-actin turnover, and that guidance cues that cause axon retraction inhibit F-actin turnover.

Not Perfect, but Better: Primary Care Providers’ Experiences with Electronic Referrals in a Safety Net Health System

BackgroundElectronic referrals can improve access to subspecialty care in safety net settings. In January 2007, San Francisco General Hospital (SFGH) launched an electronic referral portal that incorporated subspecialist triage, iterative communication with referring providers, and existing electronic health record data to improve access to subspecialty care.ObjectiveWe surveyed primary care providers (PCPs) to assess the impact of electronic referrals on workflow and clinical care.DesignWe administered an 18-item, web-based questionnaire to all 368 PCPs who had the option of referring to SFGH.MeasurementsWe asked participants to rate time spent submitting a referral, guidance of workup, wait times, and change in overall clinical care compared to prior referral methods using 5-point Likert scales. We used multivariate logistic regression to identify variables associated with perceived improvement in overall clinical care.ResultsTwo hundred ninety-eight PCPs (81.0%) from 24 clinics participated. Over half (55.4%) worked at hospital-based clinics, 27.9% at county-funded community clinics, and 17.1% at non-county-funded community clinics. Most (71.9%) reported that electronic referrals had improved overall clinical care. Providers from non-county-funded clinics (AOR 0.40, 95% CI 0.14-0.79) and those who spent ≥6 min submitting an electronic referral (AOR 0.33, 95%CI 0.18-0.61) were significantly less likely than other participants to report that electronic referrals had improved clinical care.ConclusionsPCPs felt electronic referrals improved health-care access and quality; those who reported a negative impact on workflow were less likely to agree. While electronic referrals hold promise as a tool to improve clinical care, their impact on workflow should be considered.

HIV Controllers with HLA-DRB1*13 and HLA-DQB1*06 Alleles Have Strong, Polyfunctional Mucosal CD4+ T-Cell Responses

ABSTRACT A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4+ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8+ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4+ T cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the rectal mucosa of 28 “controllers” (viral load [VL] of <2,000 copies/ml), 14 “noncontrollers” (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had higher-magnitude Gag-specific mucosal CD4+ T-cell responses than individuals on HAART (P < 0.05), as measured by their ability to produce gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 1β (MIP-1β). The frequency of polyfunctional mucosal CD4+ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P < 0.05). Controllers with the strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4+ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4+ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8+ T-cell response (Spearmans r = 0.43, P = 0.005), suggesting that increased CD4+ T-cell “help” may be important in maintaining strong CD8+ T-cell responses in the gut of HIV controllers.

Risk Factors for Chronic Liver Disease in Blacks, Mexican Americans, and Whites in the United States: Results From NHANES IV, 1999–2004

OBJECTIVES:Morbidity and mortality due to liver disease and cirrhosis vary significantly by race/ethnicity in the United States. We examined the prevalence of liver disease risk factors among blacks, Mexican Americans, and whites, including elevated aspartate aminotransferase and alanine aminotransferase activity, infection with viral hepatitis B or hepatitis C, alcohol intake, obesity, diabetes, and metabolic syndrome.METHODS:Data were obtained from the Fourth National Health and Nutrition Examination Survey (NHANES IV). A logistic regression was used to examine the association of race/ethnicity to liver disease risk factors, controlling for the demographic and socioeconomic variables.RESULTS:Mexican-American men and women are the most likely to have elevated aminotransferase activity. Among men, Mexican Americans are more likely than whites to be heavy/binge drinkers, and blacks are more likely to have hepatitis B or hepatitis C. Among women, Mexican Americans are more likely than whites to be obese and diabetic, and less likely to be heavy/binge drinkers; blacks are more likely than whites to have hepatitis B or hepatitis C, be obese or diabetic, and less likely to be heavy/binge drinkers.CONCLUSIONS:In this national sample, the prevalence of risk factors for liver disease varies by race/ethnicity. Mexican Americans and blacks have a greater risk of developing liver disease than their white counterparts. These findings are consistent with the observed racial/ethnic disparities in morbidity and mortality due to chronic liver disease and contribute to the efforts to identify the causes of these disparities. This information can be used by health professionals to tailor screening and intervention programs.

eReferral — A New Model for Integrated Care

In facing the challenge of taking better care of more patients at lower cost, health care organizations can learn from safety-net systems: one innovation prompted by clinical exigencies, eReferral, offers a new model for integrating primary and specialty care.

Evaluating Electronic Referrals for Specialty Care at a Public Hospital

BACKGROUNDPoor communication between referring clinicians and specialists may lead to inefficient use of specialist services. San Francisco General Hospital implemented an electronic referral system (eReferral) that facilitates iterative pre-visit communication between referring and specialty clinicians to improve the referral process.OBJECTIVEThe purpose of the study was to determine the impact of eReferral (compared with paper-based referrals) on specialty referrals.DESIGNThe study was based on a visit-based questionnaire appended to new patient charts at randomly selected specialist clinic sessions before and after the implementation of eReferral.PARTICIPANTSSpecialty clinicians.MAIN MEASURESThe questionnaire focused on the self-reported difficulty in identifying referral question, referral appropriateness, need for and avoidability of follow-up visits.KEY RESULTSWe collected 505 questionnaires from speciality clinicians. It was difficult to identify the reason for referral in 19.8% of medical and 38.0% of surgical visits using paper-based methods vs. 11.0% and 9.5% of those using eReferral (p-value 0.03 and <0.001). Of those using eReferral, 6.4% and 9.8% of medical and surgical referrals using paper methods vs. 2.6% and 2.1% were deemed not completely appropriate (p-value 0.21 and 0.03). Follow-up was requested for 82.4% and 76.2% of medical and surgical patients with paper-based referrals vs. 90.1% and 58.1% of eReferrals (p-value 0.06 and 0.01). Follow-up was considered avoidable for 32.4% and 44.7% of medical and surgical follow-ups with paper-based methods vs. 27.5% and 13.5% with eReferral (0.41 and <0.001).CONCLUSIONUse of technology to promote standardized referral processes and iterative communication between referring clinicians and specialists has the potential to improve communication between primary care providers and specialists and to increase the effectiveness of specialty referrals.

A Safety-Net System Gains Efficiencies Through ‘eReferrals’ To Specialists

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A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice

We have developed a novel model for depleting mouse hepatic stellate cells (HSCs) that has allowed us to clarify their contributions to hepatic injury and fibrosis. Transgenic (Tg) mice expressing the herpes simplex virus thymidine kinase gene (HSV‐Tk) driven by the mouse GFAP promoter were used to render proliferating HSCs susceptible to killing in response to ganciclovir (GCV). Effects of GCV were explored in primary HSCs and in vivo. Panlobular damage was provoked to maximize HSC depletion by combining CCl4 (centrilobular injury) with allyl alcohol (AA) (periportal injury), as well as in a bile duct ligation (BDL) model. Cell depletion in situ was quantified using dual immunofluorescence (IF) for desmin and GFAP. In primary HSCs isolated from both untreated wild‐type (WT) and Tg mice, GCV induced cell death in ∼50% of HSCs from Tg, but not WT, mice. In TG mice treated with CCl4+AA+GCV, there was a significant decrease in GFAP and desmin‐positive cells, compared to WT mice (∼65% reduction; P < 0.01), which was accompanied by a decrease in the expression of HSC‐activation markers (alpha smooth muscle actin, beta platelet‐derived growth factor receptor, and collagen I). Similar results were observed after BDL. Associated with HSC depletion in both fibrosis models, there was marked attenuation of fibrosis and liver injury, as indicated by Sirius Red/Fast Green, hematoxylin and eosin quantification, and serum alanine/aspartate aminotransferase. Hepatic expression of interleukin‐10 and interferon‐gamma was increased after HSC depletion. No toxicity of GCV in either WT or Tg mice accounted for the differences in injury. Conclusion: Activated HSCs significantly amplify the response to liver injury, further expanding this cell types repertoire in orchestrating hepatic injury and repair. (HEPATOLOGY 2013)

Quantitation of rat hepatic stellate cell contraction: stellate cells' contribution to sinusoidal resistance

Although it has been hypothesized that contraction of hepatic stellate cells (HSC) regulates blood flow by modulating sinusoidal resistance, neither HSC contraction nor relaxation has been directly quantitated. To test this hypothesis, a force transducer was employed to directly measure the magnitude and rate of contraction and relaxation by primary rat HSC (4.7 × 105 ± 0.2 × 105 cells) cultured within a collagen gel. Serial exposures to 10% fetal bovine serum stimulated 81 ± 14 and 82 ± 10 dyn of contractile force, respectively. Subsequent stimulation with 2 nM endothelin-1 (ET-1) resulted in the development of 185 ± 25 dyn of force. Contractions began within 10 s of ET-1 stimulation, and the half time of maximal force development was <5 min. Removal of agonist resulted in complete or nearly complete relaxation within 45 min. These results suggest that the magnitude and rate of HSC contraction and relaxation are capable of modulating blood flow via sinusoidal constriction.