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Background: Studies document increasing rates of hospitalization among patients with inflammatory bowel disease, but temporal trends for in-hospital mortality among patients with inflammatory bowel disease are not characterized. We sought to determine whether in-hospital mortality changed over a 13-year period among nationwide hospitalizations associated with inflammatory bowel disease. We additionally sought to identify factors correlated with mortality. Methods: We used the National Hospital Discharge Survey, a large nationally representative database, for the years 1994 through 2006. Age- and mortality-adjusted rates of in-hospital mortality and standardized mortality ratios were calculated for four time periods. Logistic regression analysis was used to assess associations between advancing time and mortality in adjusted analyses. Results: 150 (0.9%) of 17,393 hospitalizations for patients with inflammatory bowel disease ended in death. Age-adjusted in-hospital mortality decreased from 3.6 deaths per 1,000 hospital days in 1994-96 to 2.4 per 1,000 in 2003-06; standardized mortality ratio decreased from 0.33 to 0.27. Similar trends were seen for patients with ulcerative colitis, but mortality did not change over time among patients with Crohn's disease. Multivariable logistic regression analysis confirmed the significance of these changes in mortality, with 17% decreased odds of in-hospital death per three-year period (P= 0.012). Subject age (OR 1.06 per year, P<0.001), Charlson comorbidity index (OR 1.29 per 1-point increase, P<0.001), and diagnosis of ulcerative colitis (versus Crohn's disease, OR 1.41, P =.042) were also associated with in-hospital mortality. Conclusions: The odds of in-hospital mortality among hospitalized patients with inflammatory bowel disease decreased by 17% per 3-year period from 1994 to 2006 in analysis adjusted for age and comorbidity status, in this large, nationally representative database. Multiple factors likely contribute to these trends. [ABSTRACT FROM AUTHOR]

The National Center for Health Statistics (NCHS) is the principal health statistics agency for the United States. It seeks to provide accurate, relevant, and timely data on health status and utilization of health care. As such, the NCHS represents a tremendous repository of behavioral, biological, and clinical data that can be employed to identify issues and effect change in public policy related to liver health and disease. By providing an understanding of the rich, publicly available data systems within the NCHS, investigators may capitalize on an efficient means to shape current knowledge of liver disease. [ABSTRACT FROM AUTHOR]

Background: Electronic 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.Objective: We surveyed primary care providers (PCPs) to assess the impact of electronic referrals on workflow and clinical care.Design: We administered an 18-item, web-based questionnaire to all 368 PCPs who had the option of referring to SFGH.Measurements: We 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.Results: Two 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 > or =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.Conclusions: PCPs 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chemotaxis (i.e., directed migration) of hepatic stellate cells to areas of inflammation is a requisite event in the liver's response to injury. Previous studies of signaling pathways that regulate stellate cell migration suggest a key role for focal adhesions, but the exact function of these protein complexes in motility remains unclear. Focal adhesions attach a cell to its substrate and therefore must be regulated in a highly coordinated manner during migration. To test the hypothesis that focal adhesion turnover is an essential early event for chemotaxis in stellate cells, we employed a live-cell imaging technique in which chemotaxis was induced by locally stimulating the tips of rat stellate cell protrusions with platelet-derived growth factor-BB (PDGF). Focal adhesions were visualized with an antibody directed against vinculin, a structural component of the focal adhesion complex. PDGF triggered rapid disassembly of adhesions within 6.25 mm, subsequent reassembly by 12.5 mm, and continued adhesion assembly in concert with the spreading protrusion until the completion of chemotaxis. Blockade of adhesion disassembly by growing cells on fibronectin or treatment with nocodazole prevented a chemotactic response to PDGF. Augmentation of adhesion disassembly with ML-7 enhanced the chemotactic response to PDGF. These data suggest that focal adhesion disassembly is an essential early event in stellate cell chemotaxis in response to PDGF. [ABSTRACT FROM AUTHOR]

The contractile force generated by hepatic stellate cells in response to endothelin-1 contributes to sinusoidal blood flow regulation and hepatic fibrosis. This study's aim was to directly test the widely held view that changes in cytosolic Ca2+ concentration ([Ca2+]i) mediate stellate cell force generation. Contractile force generation by primary cultures of rat hepatic stellate cells grown in three-dimensional collagen gels was directly and quantitatively measured using a force transducer. Stellate cell [Ca2+]i, myosin activation, and migration were quantified using standard techniques. [Ca2+]i was modulated using ionomycin, BAPTA, KCl, and removal of extracellular Ca2+ Removal of extracellular Ca2+ did not alter endothelin-1-stimulated force development or [Ca2+]i. lonomycin, a Ca2+ ionophore, triggered an increase in [Ca2+]i that was three times greater than that stimulated by endothelin-1, but only induced 16% of the force and 38% of the myosin regulatory light chain (MLC) phosphorylation induced by endothelin-1. Physiological increases in [Ca2+]i induced by hyperkalemia had no effect on contractile force. Loading BAPTA, a Ca2+ chelator, in stellate cells completely blocked endothelin-1-induced increases in [Ca2+]i but had no effect on endothelin-1-stimulated force generation or MLC phosphorylation. In contrast, Y-27632, a selective rho-associated kinase inhibitor, inhibited endothelin-1-stimulated force generation by at least 70% and MLC phosphorylation by at least 80%. Taken together, these observations indicate that changes in [Ca2+]i are neither necessary nor sufficient for contractile force generation by rat stellate cells. Our results challenge the current model of contractile regulation in hepatic stellate cells and have important implications for our understanding of hepatic pathophysiology. [ABSTRACT FROM AUTHOR]

Intestinal response to injury requires coordinated regulation of the tension exerted by subepithelial myofibroblasts (SEM). However, the signals governing relaxation of intestinal SEM have not been investigated. Our aim was to test the hypothesis that signal transduction pathways initiated by C-type natriuretic peptide (CNP) induce intestinal SEM relaxation. We directly quantified the effects of CNP on isometric tension exerted by cultured human colonic SEM. We also measured the effects of CNP on cGMP content, myosin regulatory light chain (MLC) phosphorylation, and cytosolic Ca[sup 2+] concentration. CNP induced relaxation of SEM within 10 s. By 10 min, relaxation reached a plateau that was sustained for 2 h. CNP-induced relaxation was saturable, with a maximal decrease in tension (51.7 ± 3.8 dyn) observed at 250 nM. SEM relaxation in response to CNP constituted ∼23% of total basal tension. CNP increased intracellular cGMP content and reduced MLC phosphorylation. Effects of CNP on cGMP and MLC exhibited the same dose dependence as CNP-induced relaxation. MLC phosphorylation decreased within 2 min of CNP exposure and was sustained for at least 45 min. CNP also stimulated a large transient increase in cytosolic Ca[sup 2+] concentration that occurred within 30 s and was nearly complete by 1 min. We also observed that calyculin-A, a potent inhibitor of MLC phosphatase, completely abolished the reduction in MLC phosphorylation induced by CNP. These results suggest that CNP induces intestinal SEM relaxation through cGMP-associated reductions in MLC phosphorylation. Moreover, these findings raise the possibility that CNP plays a role in intestinal wound healing. guanosine 3',5'-cyclic monophosphate; contraction; myosin; subepithelial myofibroblast; intestine [ABSTRACT FROM AUTHOR]

Although hepatic myofibroblast migration plays a key role in the liver's injury response, the signal transduction pathways mediating the migration of this cell type are uncertain. Recently, we reported that lysophosphatidic acid (LPA) stimulates the migration of hepatic myofibroblasts. The goal of this study was to test the hypothesis that rho and p38 MAP kinase signaling pathways mediate LPA-stimulated hepatic myofibroblast migration. We measured migration, myosin regulatory light chain and p38 MAP kinase phosphorylation, and contractile force generation by human hepatic myofibroblasts. LPA stimulated migration in a dose-dependent and saturable manner that was partially blocked by Y-27632, a rho-associated kinase inhibitor, as well as by SB-202190, a p38 MAP kinase inhibitor. LPA also induced myosin regulatory light chain phosphorylation and contractile force generation in a Y-27632 dependent, and SB-202190 independent fashion. Moreover, LPA stimulated a dose-dependent and saturable phosphorylation of p38 MAP kinase, which was not altered by Y-27632 or C3 transferase, a rho inactivator. These novel results suggest that LPA stimulates hepatic myofibroblast migration via distinct pathways that signal through rho and p38 MAP kinase. [ABSTRACT FROM AUTHOR]

Cirrhosis, a pathological condition defined by deranged hepatic architecture resulting from progressive fibrosis, is the final common pathway through which nearly all chronic diseases of the liver produce morbidity and mortality. Historically, treatments for hepatic fibrosis have been directed against specific causes of chronic liver injury, and include corticosteroids for autoimmune hepatitis, interferon for hepatitis B and C, and iron depletion for haemochromatosis. However, there is no effective treatment for most causes of chronic liver disease. Fortunately, the past decade has witnessed great advances in our understanding of the fundamental pathophysiological mechanisms underlying fibrosis of the liver. It is now recognised that hepatic stellate cells (myofibroblast-like cells that encircle the sinusoids) are primarily responsible for hepatic fibrosis and subsequent progression to cirrhosis. In response to liver injury stellate cells undergo a phenotypic transformation that is termed activation, and characterised by chemotaxis, proliferation, contraction, fibrogenesis, and extracellular matrix degradation. Under conditions of persistent injury the behavioural responses of these stellate cells act in concert to bring about fibrosis of the liver. Recent investigations elucidating the signal transduction pathways that link hepatic injury to stellate cell function suggest novel targets at which treatment for fibrosis may be directed. For example, antagonism of TGF-β receptor signaling has been shown to modulate fibrosis in animal models. This work, as well as other studies in both humans and animals, indicates that hepatic fibrosis may be slowed or reversed. These results suggest that a rational approach to treatment can be developed based on our detailed understanding of the molecular and cellular mechanisms underlying cirrhosis, which will have a major impact on the clinical management of patients with chronic liver disease. [ABSTRACT FROM AUTHOR]

Although endothelin-1-stimulated contractile force generation by stellate cells is believed to play an important role in hepatic pathophysiology, the molecular signals that mediate this process are incompletely understood. The aim of this study was to test the hypothesis that myosin mediates the contractile force generated by stellate cells in response to endothelin-1. Contractile force generation by primary and immortalized stellate cells was directly and quantitatively measured. Myosin phosphorylation and reorganization, and actin stress fiber formation were investigated in immortalized stellate cells. Endothelin-1 stimulated a rapid and robust generation of contractile force by primary and immortalized stellate cells with a similar dose dependence. Myosin phosphorylation, actin stress fiber assembly, and reorganization of myosin to stress fibers were induced by concentrations of endothelin-1 that also stimulated stellate cell contraction. BQ-123, a selective endothelin receptor antagonist, inhibited myosin phosphorylation and contractile force generation. Y-27632, which selectively inhibits rho-associated kinase, also blocked endothelin-1-stimulated myosin phosphorylation and contractile force generation with a similar dose dependence. These results suggest that endothelin-1-stimulated contractile force generation by stellate cells is mediated by myosin.Copyright © 2002 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The role of G protein-coupled receptors and their ligands in intestinal epithelial cell signaling and proliferation is poorly understood. Here, we demonstrate that arginine vasopressin (AVP) induces multiple intracellular signal transduction pathways in rat intestinal epithelial IEC-18 cells via a V1A receptor. Addition of AVP to these cells induces a rapid and transient increase in cytosolic Ca2+ concentration and promotes protein kinase D (PKD) activation through a protein kinase C (PKC)-dependent pathway, as revealed by in vitro kinase assays and immunoblotting with an antibody that recognizes autophosphorylated PKD at Ser916. AVP also stimulates the tyrosine phosphorylation of the nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) and promotes Src family kinase phosphorylation at Tyr418, indicative of Src activation. AVP induces extracellular signal-related kinase (ERK)-1 (p44mapk) and ERK-2 (p42mapk) activation, a response prevented by treatment with mitogen-activated protein kinase kinase (MEK) inhibitors (PD-98059 and U-0126), specific PKC inhibitors (GF-I and Ro-31-8220), depletion of Ca2+ (EGTA and thapsigargin), selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (tyrphostin AG-1478, compound 56), or the selective Src family kinase inhibitor PP-2. Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca2+-, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways. [ABSTRACT FROM AUTHOR]

OBJECTIVE:Hemodialysis patients with hepatitis B surface antigen (HBsAg) are considered to have the hepatitis B virus (HBV) and are segregated to limit transmission. However, transient de novo HBsAg has been identified in hemodialysis patients shortly after vaccination. Our hypothesis is that immunization rather than actual HBV infection is the most common cause of de novo HBsAg among hemodialysis patients.METHODS:We performed a prospective study between January, 1998 and June, 2000 of de novo HBV infection in over 2400 hemodialysis patients who were screened monthly for HBsAg using a standard enzyme immunoassay. Positive results were confirmed with a neutralization assay. If the confirmatory test was positive, anti-hepatitis B core antibody IgM testing was performed.RESULTS:We identified nine patients with de novo HBsAg confirmed with the neutralization assay. In eight of the nine patients with de novo HBsAg (89%), HBsAg was temporally related to HBV immunization. In none of these eight patients was there a detectable anti-hepatitis B core antibody IgM, an elevated ALT level, or clinical history suggestive of recent hepatitis. The mean age (± SD) of the four men and four women was 56.4 ± 18.8 yr. HBsAg was detectable within 3 days of immunization in most patients.CONCLUSION:Our results suggest that HBV immunization is the most common cause of detectable HBsAg in hemodialysis patients. Hemodialysis patients should not be screened for HBV within a week of immunization, and caution should be exercised when interpreting HBsAg seropositivity within 4 wk of HBV immunization. [Copyright &y& Elsevier]

Presents information on a study which examined whether hepatic stellate cell contraction and relaxation around the sinusoid may control hepatic blood flow by modulating sinusoidal resistance. Materials and methods; Results; Discussion.

The objective of this study was to analyze a series of patients with Enterococcus faecium infection following transjugular intrahepatic portosystemic shunts (TIPS) in order to define the risk factors, outcome, and role of treatment including hepatic transplantation. This study is a case series from a tertiary referral center for liver transplantation. The medical records of four patients referred to one teaching hospital in San Francisco between 1990 and 1995 for evaluation or management of Enterococcal infection following TIPS were reviewed. A review of the microbiology records of all 314 patients who underwent TIPS at that institution and a MEDLINE search were performed to assess whether any other cases existed. The effect of therapy on survival was assessed, in particular, the repeated use of TIPS and prolonged courses of antibiotics. All four patients had thrombosis of their TIPS at the time of diagnosis of enterococcal bacteremia. All were treated with prolonged courses of intravenous antibiotics. One patient had echocardiographic evidence of subacute bacterial endocarditis with chronic aortic insufficiency. In all cases, liver transplantation was contraindicated in the acute setting because of uncontrolled endovascular infection. Two of four patients survived; these were the only two patients who had had a successful repeat TIPS. Enterococcal bacteremia is a rare complication following TIPS but carries a high mortality. It usually occurs in the setting of technically difficult TIPS with shunt thrombosis. Management should be focused on long term antibiotics and attempts at reestablishment of portal decompression with another TIPS. Liver transplantation should not be considered until the infection is cleared. Prophylaxis for Enterococcus species should be considered in technically difficult or unsuccessful TIPS. [ABSTRACT FROM AUTHOR]

The author discusses the importance of communication between primary care specialists (PCPs) and specialists. The author says that the interaction of the health care providers is the key to provide quality health care to the patient. He cites three practice traits that are related to the communication of both physicians such as adequate time during patient visit or consultation, the receipt of efficient reports particularly in patients with chronic conditions and nurses' monitoring of chronic patients.

To achieve the benefits of the patient-centered medical home (PCMH) model, the American College of Physicians has issued a policy paper addressing the relationship between specialist and subspecialist physicians and PCMH practices. This paper represents a significant step toward improving care coordination and quality by demonstrating that this model is supported by numerous specialties and subspecialties, recognizing the importance of building a strong medical neighborhood, and providing a framework that will foster improvements in care at the interface of PCMHs and PCMH neighbors (PCMH-Ns). Construction of a well-functioning medical neighborhood will, however, require some refinements. First, the proposed interaction typology between PCMHs and PCMH-Ns must be expanded to include innovative forms of interaction that do not depend on traditional office visits, but for which there are clear incentives. Second, the recommended care coordination agreements must be better standardized for the sake of practicality. Finally, genuine dialogue between PCMH and PCMH-N practices needs to be realized. [ABSTRACT FROM AUTHOR]

The authors reflect on the improvement of primary and specialty care. They argue that indications for referral and integrated decision support are exceptions to the health care system rules. A study on referral process was conducted at a university medical center and has resulted to communication inefficiency. They note that C. B. Forrest's proposal on typology can establish mutual duties for medical practitioners and will improve the quality of communication between physicians.

The article presents the authors' comments on whether an ideal biomarker exists for the progression of nonalcoholic fatty liver disease (NAFLD) in humans. They state that an ideal biomarker should have the characteristics including, it should be minimally invasive, it should allow repetitive measurements and should be able to identify early stages of the disease. They suggest that biomarkers for NAFLD require a combination of advanced techniques like genomics with polymorphism.

The authors discuss a clinician- and health care organization-informed approach to reduce clinical practice variation across the Los Angeles Department of Health Services (LADHS) by developing and implementing expected practices (EPs). They enumerate several steps involved in the approach to reducing variation in clinical practice, such as the establishment of Specialty-Primary Care work groups. They also elaborate on the use of EPs.