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Biomedical subjects

R Rubin

Publications and source records attributed to R Rubin.

At least 19 recordsLinked to original sources
PubMed2005

Depot-specific regulation of glucose uptake and insulin sensitivity in HIV-lipodystrophy.

Altered fat distribution is associated with insulin resistance in HIV, but little is known about regional glucose metabolism in fat and muscle depots in this patient population. The aim of the present study was to quantify regional fat, muscle, and whole body glucose disposal in HIV-infected men with lipoatrophy. Whole body glucose disposal was determined by hyperinsulinemic clamp technique (80 mU x m(-2) x min(-1)) in 6 HIV-infected men and 5 age/weight-matched healthy volunteers. Regional glucose uptake in muscle and subcutaneous (SAT) and visceral adipose tissue (VAT) was quantified in fasting and insulin-stimulated states using 2-deoxy-[18F]fluoro-D-glucose positron emission tomography. HIV-infected subjects with lipoatrophy had significantly increased glucose uptake into SAT (3.8 +/- 0.4 vs. 2.3 +/- 0.5 micromol x kg tissue(-1) x min(-1), P < 0.05) in the fasted state. Glucose uptake into VAT did not differ between groups. VAT area was inversely related with whole body glucose disposal, insulin sensitivity, and muscle glucose uptake during insulin stimulation. VAT area was highly predictive of whole body glucose disposal (r2 = 0.94, P < 0.0001). This may be mediated by adiponectin, which was significantly associated with VAT area (r = -0.75, P = 0.008), and whole body glucose disposal (r = 0.80, P = 0.003). This is the first study to directly demonstrate increased glucose uptake in subcutaneous fat of lipoatrophic patients, which may partially compensate for loss of SAT. Furthermore, we demonstrate a clear relationship between VAT and glucose metabolism in multiple fat and muscle depots, suggesting the critical importance of this depot in the regulation of glucose and highlighting the significant potential role of adiponectin in this process.

Adipose Tissue↗
PubMed2004

Comparison of quality of life, work productivity and medical resource utilization of peginterferon alpha 2a vs the combination of interferon alpha 2b plus ribavirin as initial treatment in patients with chronic hepatitis C.

The on-treatment impact of interferon-based therapies on quality of life (QOL), work productivity, and medical resource utilization has not been systematically studied. We evaluated the effects of treatment with peginterferon alpha (pegIFNalpha) 2a monotherapy and the combination of interferon alpha (IFNalpha) 2b plus ribavirin (RBV) on health-related QOL, work productivity and resource utilization. A total of 412 patients with hepatitis C infection were randomized to open-label treatment with either pegIFNalpha 2a (n = 206) or IFNalpha 2b/RBV (n = 206). PegIFNalpha 2a was administered subcutaneously at a dose of 180 microg once weekly for 48 weeks; and IFNalpha 2b/RBV at doses of 3 MU thrice weekly subcutaneously and 1000-1200 mg/day orally. Outcome measures included the SF-36 Health Survey Questionnaire and additional generic and specific scales. During treatment, for all SF-36 summary and Hepatitis Quality of Life Questionnaire (HQLQ)-specific scales, the pegIFNalpha 2a group experienced less impairment than did the IFNalpha 2b/RBV patients. The between-treatment differences were significant for many of the scores particularly in the first 24 weeks of treatment. Across all measures of work functioning and productivity at each visit, patients randomized to pegIFNalpha 2a treatment showed less impairment relative to the group treated with IFNalpha 2b/RBV. Hence treatment with pegIFNalpha 2a relative to IFNalpha 2b/RBV minimizes the adverse impact of therapy on health-related QOL. Patients randomized to pegIFNalpha 2a had improved work productivity, less activity impairment, decreased need for prescription drugs to treat adverse effects, and better adherence to therapy.

Adult↗
PubMed2004

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.

Adenine↗
PubMed2002

Gene and antisense delivery in alcoholism research.

This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. Drs. Yedy Israel and Fulton Crews were organizers and co-chairpersons. The presentations were (1) Introduction to the symposium, by Yedy Israel; (2) Gene delivery to the brain, by Fulton T. Crews; (3) Gene therapy in alcoholic liver injury, by Ronald Thurman; and (4) Antisense oligonucleotides and antisense-gene delivery, by Yedy Israel.

Alcoholism↗
PubMed2001

Inhibition of insulin-like growth factor-1 receptor and IRS-2 signaling by ethanol in SH-SY5Y neuroblastoma cells.

The effect of ethanol on insulin-like growth factor-1 (IGF-I)-mediated signal transduction and functional activation in neuronal cells was examined. In human SH-SY5Y neuroblastoma cells, ethanol inhibited tyrosine autophosphorylation of the IGF-I receptor. This corresponded to the inhibition of IGF-I-induced phosphorylation of p42/p44 mitogen-activated/extracellular signal-regulated protein kinase (MAPK) by ethanol. Insulin-related substrate-2 (IRS-2) and focal adhesion kinase phosphorylation were reduced in the presence of ethanol, which corresponded to the prevention of lamellipodia formation (30 min). By contrast, ethanol had no effect on Shc phosphorylation when measured up to 1 h, and did not affect the association of Grb-2 with Shc. Neurite formation at 24 h was similarly unaffected by ethanol. The data indicate that the IGF-I receptor is a target for ethanol in SH-SY5Y cells However, there is diversity in the sensitivity of signaling elements within the IGF-I receptor tyrosine kinase signaling cascades to ethanol, which can be related to the inhibition of specific functional events in neuronal activation.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by oxidant stress in cerebellar granule neurons: modulation by N-methyl-D-aspartate through calcineurin activity.

Insulin receptor-substrate-1 (IRS-1) is a docking protein for several tyrosine kinase receptors. Upon tyrosine phosphorylation, IRS-1 binds to signaling molecules that express Src homology 2 (SH-2) binding domains, including phosphatidylinositol 3-kinase (PI 3-kinase), phosphotyrosine phosphatase SHP-2 (Syp), Nck, Crk and Grb-2. Hydrogen peroxide (H(2)O(2)) induces tyrosine phosphorylation of key signaling mediators presumably by inhibition of tyrosine phosphatases. In many cell types, the activation of extracellular signal-related kinases (e.g. MAPK) and other protein kinases by H(2)O(2) leads to transcriptional activation. In the current study, we examined the effect of H(2)O(2) on IRS-1 tyrosine phosphorylation in primary cultured rat cerebellar granule neurons. H(2)O(2) stimulated the rapid tyrosine phosphorylation of IRS-1 and p42/p44 MAP kinase, and induced its association with PI 3-kinase. H(2)O(2)-induced IRS-1 phosphorylation was rapidly reversible (5 min) whereas MAPK phosphorylation persisted for up to 1 h. NMDA reversed H(2)O(2)-mediated tyrosine phosphorylation of IRS-1 and its association with PI 3-kinase. The dephosphorylation of IRS-1 by NMDA was calcium-dependent and was inhibited by the calcineurin inhibitor cyclosporine. Calmodulin-dependent tyrosine phosphatase activity of calcineurin was observed in vitro using both immunoprecipitated and recombinant tyrosine-phosphorylated IRS-1 as substrates. These data highlight the role of multiple phosphatases in the regulation of IRS-1 tyrosine phosphorylation and identify a novel functional property of calcineurin.

Animals↗
PubMed2001

The longitudinal primary care clerkship at Harvard Medical School.

The primary care clerkship (PCC) at Harvard Medical School was established in 1997. The goals are to provide students with longitudinal experiences with patients and to include modern themes in the curriculum: managing illness and clinical relationships over time; finding the best available answers to clinical questions; preventing illness and promoting health; dealing with clinical uncertainty; getting the best outcomes with available resources; working in a health care team; and sharing decision making with patients. The PCC, a required course in the clinical years, meets one afternoon a week for nine months. Students spend three afternoons per month in primary care practices, where they see three to five patients per session and follow at least one patient ("longitudinal patient") over time. Classroom sessions, in both large- and small-group formats, promote a common educational philosophy and experience, and reinforce habits of problem-based learning established in the preclinical years. The students rated 74% of their preceptors excellent, especially praising their ability to facilitate and support good interpersonal relationships with patients, their ability to encourage students' independent evaluation of patients (as opposed to shadowing), and their enthusiasm for teaching. Students saw their longitudinal patients a mean of 4.8 times; 83% saw their patients at least three times. The PCC complements the curriculum of block clerkships in hospitals, and because the two are offered concurrently, students are required to come to terms with two substantially different cultures within medicine. Other medical schools are beginning to develop longitudinal clerkships to ensure that students have essential educational experiences that are difficult to achieve in block, hospital-based clerkships.

Attitude of Health Personnel↗
PubMed2001

Diffuse desmoplastic breast carcinoma metastases to the liver simulating cirrhosis at MR imaging: report of two cases.

Two patients with breast carcinoma, without a prior diagnosis of liver lesions, had proved desmoplastic hepatic metastases that resembled cirrhosis at magnetic resonance (MR) imaging. The cirrhotic appearance of the livers may have resulted from the hepatotoxic effects of chemotherapy and/or hepatic infiltration by the metastatic tumor itself. Despite its high soft-tissue contrast, MR imaging may fail to depict extensive metastases from breast carcinoma, especially when they simulate other diseases (eg, cirrhosis). Correlation of MR imaging findings with clinical history is mandatory.

Adenocarcinoma↗
PubMed2001

Psychosocial therapies in diabetes: report of the Psychosocial Therapies Working Group.

OBJECTIVE: To review key advances in the behavioral science literature related to psychosocial issues and therapies for persons with diabetes, to discuss barriers to research progress, and to make recommendations for future research. RESEARCH DESIGN AND METHODS: Key findings from the literature on psychosocial research in diabetes are reviewed separately for children and adults. Specific issues covered include psychosocial adjustment and psychiatric disorders, neurocognitive functioning, quality of life, and psychosocial therapies. Barriers that must be addressed to allow research in this area to progress are discussed. Recommendations are then made concerning high-priority areas for advancing research in the field. CONCLUSIONS: A substantial amount of behavioral science research has demonstrated that psychosocial factors play an integral role in the management of diabetes in both children and adults. Research has also shown the efficacy of a number of psychosocial therapies that can improve regimen adherence, glycemic control, psychosocial functioning, and quality of life. More research in this area is needed to develop psychosocial intervention programs for specific patient populations and to demonstrate the cost-effectiveness of these approaches.

Adolescent↗
PubMed2001

Liver disease and diabetes mellitus.

The liver plays an important role in the pathogenesis of NIDDM. More importantly to the clinician is the myriad of situations in which the care of the patient with diabetes is affected by or causes an effect to the liver. Patients with underlying diabetes can present with abnormal liver chemistries, which can represent findings as benign as hepatic steatosis or as severe as cirrhosis of the liver. The medications used to treat diabetes can be potent hepatotoxins. Several primary liver diseases are associated with increased risk of the development of diabetes. Epidemiologically, there seems to be a correlation between diabetes mellitus, the most common endocrinologic disease, and hepatitis C, the leading cause of chronic liver disease in the United States. In the management of end-stage liver disease, both cirrhosis and orthotopic liver transplantation promote glucose intolerance and diabetes in a number of patients through various mechanisms including insulin resistance and impaired insulin secretion. These relationships highlight both the importance of the liver as an endocrine organ and the multisystem aspects of the patient with diabetes mellitus.

Chemical and Drug Induced Liver Injury↗
PubMed2001

Inhibition of insulin-like growth factor-I signaling by ethanol in neuronal cells.

BACKGROUND: Ethanol inhibits insulin-like growth factor-I receptor (IGF-IR) activation. However, the potency of ethanol for inhibition of the IGF-IR and other receptor tyrosine kinases varies considerably among different cell types. We investigated the effect of ethanol on IGF-I signaling in several neuronal cell types. METHODS: IGF-I signaling was examined in SH-SY5Y neuroblastoma cells, primary cultured rat cerebellar granule neurons, and rat NG-108 neuroblastoma x glioma hybrids. The tyrosine phosphorylation of IGF-IR, IRS-2, Shc, and p42/p44 MAP kinase (MAPK), and the association of Grb-2 with Shc, were examined by immunoprecipitations and Western blotting. RESULTS: IGF-I-mediated tyrosine phosphorylation of MAPK was inhibited by ethanol in all cell lines. IGF-IR autophosphorylation was markedly inhibited by ethanol in SH-SY5Y cells, was only mildly inhibited in cerebellar granule neurons, and was unaffected in rat NG-108 cells. In vitro tyrosine autophosphorylation of immunopurified IGF-IR obtained from all cell lines was inhibited by ethanol. There was also differential ethanol sensitivity of IRS-2 and Shc phosphorylation, and the association of Shc with IRS-2, among the different cell types. CONCLUSIONS: The findings demonstrate that IGF-I-mediated MAPK activation is a sensitive target of ethanol in diverse neuronal cell types. The data are consistent with ethanol-induced inhibition of IGF-IR activity, although the extent of IGF-IR tyrosine autophosphorylation per se is a poor marker of the inhibitory action of ethanol on this receptor. Furthermore, despite uniform inhibition of MAPK in the different neuronal cell types, tyrosine phosphorylation of proximal mediators of the IGF-IR are differentially inhibited by ethanol.

Blotting, Western↗
PubMed2000

Association of heterotrimeric G(i) with the insulin-like growth factor-I receptor. Release of G(betagamma) subunits upon receptor activation.

The insulin-like growth factor-I receptor (IGF-IR) is a key regulator of cell proliferation and survival. Activation of the IGF-IR induces tyrosine autophosphorylation and the binding of a series of adaptor molecules, thereby leading to the activation of MAPK. It has been demonstrated that pertussis toxin, which inactivates the G(i) class of GTP-binding proteins, inhibits IGF-I-mediated activation of MAPK, and a specific role for G(betagamma) subunits in IGF-I signaling was shown. In the present study, we have investigated the role of heterotrimeric G(i) in IGF-IR signaling in neuronal cells. Pertussis toxin inhibited IGF-I-induced activation of MAPK in rat cerebellar granule neurons and NG-108 neuronal cells. G(alphai) and G(beta) subunits were associated with IGF-IR immunoprecipitates. Similarly, in IGF-IR-null mouse embryo fibroblasts transfected with the human IGF-IR, G(i) was complexed with the IGF-IR. G(alphas) was not associated with the IGF-IR in any cell type. IGF-I induced the release of the G(beta) subunits from the IGF-IR but had no effect on the association of G(alphai). These results demonstrate an association of heterotrimeric G(i) with the IGF-IR and identify a discrete pool of G(betagamma) subunits available for downstream signaling following stimulation with IGF-I.

3T3 Cells↗
PubMed2000

Selected topics related to occupational exposures.

The auditory and nonauditory effects of noise can be quite profound, affecting approximately 15 to 20 million Americans. As with most occupational toxins, recognition and careful assessment of noise exposure are the foundation on which preventive measures and treatment are based. Dosimeters can measure noise exposure over specific time periods. Pure tone air conduction audiometric monitoring should be performed on an annual basis in workers at risk for significant noise exposure. Occupational infectious disease involves far more than hepatitis and tuberculosis. Periodic fever, dermatologic manifestations and other symptoms peculiar to a specific disease may be important clues to an occupationally related exposure. Whereas strict attention to hand washing and isolation are cornerstones of prevention, use of protective gear is mandated in certain situations. Zoonotic disease, agriculture exposure, water transmission, and biologic contaminants in buildings can be important but subtle exposures sources. Recognition of these infections often depends on the alertness of the primary care giver.

Cardiovascular Diseases↗
PubMed2000

Selected topics related to occupational exposures. Part III. Occupational dermatology

Occupational skin disorders are very common and are a surprisingly frequent cause of lost work time. Failure to suspect an occupational cause can lead to repeated treatment failure and needlessly prolong patient misery and frustration. Primary care providers play a key role in recognizing possible occupational causes and arranging appropriate education, preventive measures, and treatment. Occupational skin conditions often occur in nonindustrial settings in workers such as hairdressers, health care personnel, and food handlers. Irritant contact dermatitis is by far the most prevalent occupational skin condition and is emphasized in this article. Allergic contact dermatitis, infections, skin cancers, and acneform eruptions may also have significant occupational associations. We will present criteria that suggest on occupational exposure, list common offending agents, and review the clinical presentations and relevant pathophysiology. We provide guidance on a directed history and physical examination and suggest when diagnostic testing is most likely to have value. Finally we outline preventive measures such as contact avoidance, barrier creams, and protective gloves and address therapy and indications for referral.

Journal Article↗
PubMed2000

Selected topics related to occupational exposures. Part IV. Occupational liver disease

Occupational and environmental substances associated with liver injury include industrial chemicals, drugs, certain bacterial and viral infections, and other physical agents. Hepatotoxic chemical agents can be classified as direct hepatotoxins, indirect hepatotoxins, or agents that cause liver injury as a result of host idiosyncrasy. More than 100 industrial chemicals have been shown to be acutely hepatotoxic. Occupations with hepatotoxin exposures are numerous and include farm workers, chemists, dry cleaners, electroplaters, garage workers, health care workers, nurses, painters, printers, rayon makers, and others. Clinical presentation of occupational liver disease may be acute/subacute or chronic but is often insidious. Some hepatotoxins are capable of causing malignancy. The key to diagnosis of occupational liver disease is exposure history. The occupational and environmental history should include a brief description of the patient's current and recent jobs to the extent necessary to assess their potential for workplace hepatotoxic exposures. Confounders such as obesity, alcohol, and viral hepatitis are common, and a careful history and examination are essential. A variety of tests are used to evaluate liver disease and may include serum markers, tests of synthetic liver function, clearance tests, and anatomic tests. A key responsibility of the primary care provider is to prevent further liver injury from preventable occupational exposures; not only the patient but also coworkers may be at risk. Efforts should be made to ensure that patients with potential hepatotoxic exposures are working or living in safe conditions. Collaboration with an occupational specialist may be especially useful in this regard.

Journal Article↗
PubMed2000

Selected topics related to occupational exposures. Part V. Occupational cardiovascular disease

Cardiovascular disease is common in the United States. Several occupational exposures, such as carbon disulfide and organic nitrates, are believed to cause occupational cardiovascular disease. In addition some other agents, such as lead and cadmium, may indirectly cause cardiovascular disease through their effects on blood pressure. For other agents (ie, carbon monoxide, solvents, and chlorofluorocarbons), acute exposure and high levels may cause cardiovascular disease but may not cause cardiovascular disease through long-term or low levels. A primary care physician who has a patient with a new or unstable cardiovascular disease should obtain an occupational history to assess whether occupational exposures may be playing a role. An occupational history may indicate potential cardiovascular risks. Such risks can include exposure to certain chemicals and metals, physical factors, exertion, or psychological stress. The primary care physician should be able to assess the situation and advise the patient, as well as the employer, about restrictions or accommodations that may need to be made.

Journal Article↗