Moral Distress with Obstacles to Hepatitis C Treatment: A Council of Academic Family Medicine Educational Research Alliance (CERA) Study of Family Medicine Program Directors.

BACKGROUND AND OBJECTIVE: To determine whether family medicine program directors (PDs) experienced moral distress due to obstacles to Hepatitis C virus (HCV) treatment, and to explore whether they found those obstacles to be unethical. DESIGN: An omnibus survey by the Council of Academic Family Medicine's Educational Research Alliance was administered to 452 and completed by 273 US-based PDs. The survey gauged attitudes and opinions regarding ethical dilemmas in patient access to HCV treatment. RESULTS: Most of the respondents were male. Sixty-four percent of respondents believed that treatment should be an option for all patients regardless of cost. Forty-one percent believed that it was unethical to deny treatment based on past or current substance use, and 38% believed treatment should be offered to patients who were substance abusers. Moral distress was reported by 61% (score >3) of participants when they were unable to offer treatment to patients due to the patient's failure to meet eligibility criteria. In addition, PDs reporting moderate-to-high levels of moral distress were also likely to report the following opinions: 1) treatment should be offered regardless of cost, 2) it is unethical to deny treatment based on past behavior, 3) substance abusers should be offered treatment, 4) it is unethical for medicine to be prohibitively expensive, and 5) Medicaid policy that limits treatment will worsen racial and ethnic disparities. CONCLUSIONS: Currently, important ethical dilemmas exist in the access and delivery of HCV therapy. Although a diversity of opinions is noted, a significant proportion of PDs are concerned about patients' inability to avail equitable care and experience distress. In some cases, this moral distress is in response to, and in conflict with, current guidelines.

Intent to Build Hepatitis C Treatment Capacity Within Family Medicine Residencies: A Nationwide Survey of Program Directors: A CERA Study.

BACKGROUND AND OBJECTIVES: In the current interferon-free era, family medicine is in a unique position to deliver hepatitis C (HCV) treatment with adequate training. Little is known about attitudes of family medicine program directors (PDs) toward capacity building within their residency programs. We report the results of a nationwide survey of family medicine PDs to examine these attitudes. METHODS: This study was part of a CERA (Council of Academic Family Medicine Educational Research Alliance) omnibus survey administered to family medicine PDs between February 2015 and March 2015. Attitudes were assessed using a Likert scale ranging from 1=strongly disagree to 6=strongly agree. RESULTS: We surveyed 452 physicians, with 273 responses (response rate 61%). The majority of PDs (78%) believed that chronic HCV represented a significant problem for primary care, and 61.9% believed their program should take steps to build capacity in HCV treatment. There was no effect of regional HCV prevalence, residency program context, or PD characteristics on intent to build capacity. CONCLUSIONS: This is the first report to examine PDs intent to build capacity in HCV treatment in this interferon-free, direct antiviral era. Our findings highlight a historic opportunity to train family physicians and position them on the frontline as HCV treatment providers.

Meeting Resident Scholarly Activity Requirements Through a Longitudinal Quality Improvement Curriculum.

BACKGROUND: Quality improvement (QI) skills are learned during residency, yet there are few reports of the scholarly activity outcomes of a QI curriculum in a primary care program. INTERVENTION: We examined whether scholarly activity can result from a longitudinal, experiential QI curriculum that involves residents, clinic staff, and faculty. METHODS: The University of Pittsburgh Medical Center Shadyside Family Medicine Residency implemented a required longitudinal outpatient practice improvement rotation (LOPIR) curriculum in 2005. The rotation format includes weekly multidisciplinary work group meetings alternating with resident presentations delivered to the entire program. Residents present the results of a literature review and provide 2 interim project updates to the residency. A completed individual project is required for residency graduation, with project results presented at Residency Research Day. Scholarly activity outcomes of the curriculum were analyzed using descriptive statistics. RESULTS: As of 2014, 60 residents completed 3 years of the LOPIR curriculum. All residents satisfied the 2014 Accreditation Council for Graduate Medical Education (ACGME) scholarly activity and QI requirements with a literature review presentation in postgraduate year 2, and the presentation of a completed QI project at Residency Research Day. Residents have delivered 83 local presentations, 13 state/regional presentations, and 2 national presentations. Residents received 7 awards for QI posters, as well as 3 grants totaling $21,639. The educational program required no additional curriculum time, few resources, and was acceptable to residents, faculty, and staff. CONCLUSIONS: LOPIR is an effective way to meet and exceed the 2014 ACGME scholarly activity requirements for family medicine residents.

Promoting patient phronesis: communication patterns in an online lifestyle program coordinated with primary care.

Phronesis, or practical wisdom developed through experience, is an Aristotelian concept that can shed light on the capacities of patients to make health-related decisions and engage in healthy behaviors. In this article, the authors develop a conceptual framework for understanding the role of phronesis in lifestyle change as well as its relationship to patient activation, which is considered to be a critical component of the Chronic Care Model and patient education in general. The authors develop the concept of phronesis by analyzing qualitatively the comments made by 35 participants working to manage chronic health issues in a weight-loss study. The authors iteratively coded transcribed passages of exit interviews for phronesis and patient activation. These passages provide experientially grounded content for evaluating the use of phronesis and its development among individuals engaging in lifestyle change. Phronesis is expressed in 31% of participant responses to questions regarding the relationship between the online lifestyle intervention, participant health, and participant readiness to engage in productive clinical encounters with health care practitioners. Of those responses, 73% express some level of patient activation. The authors conclude that phronesis may be an important new tool for understanding successful self-management support, with potential usefulness in the creation of tailored lifestyle interventions, the development of patient activation, and the ability of participants to enact health-related behaviors.

Analysis of sweet diterpene glycosides from Stevia rebaudiana: improved HPLC method.

An improved analytical method was developed which may be applied to quality control of stevioside and rebaudioside A contents in dried leaves of Stevia rebaudiana before processing; in a selective sampling program searching for plants of higher yield in diterpene glycosides content; or when a large number of samples are sent to the laboratory for analysis. The procedure developed involves two steps: solvent extraction followed by an isocratic HPLC analysis. The sample, 1 g of dried leaves of S. rebaudiana, is ground and solvent-extracted with EtOH 70% (w/w) in Erlenmeyer flasks by shaking for 30 min in a 70 degrees C water bath. After the extract was cooled, it was filtered and analyzed by HPLC using an NH(2) column (250 x 4.6 mm) and a mixture of acetonitrile/water (80:20, v/v) as mobile phase, pH 5 adjusted with acetic acid. The detection was in the UV range at 210 nm (0.04 AUFS). Quantitation was performed by means of an external standard calibration curve for each analyte which had been obtained from standard solutions of pure stevioside and rebaudioside A. Working under these conditions there were no observed interference effects. The method saves time in sample preparation, and reduces sample handling and chromatographic analysis time, while having little loss of precision [coefficient of variation (CV%) between 1.8% and 3.0%] and recovery [between 98.5% and 100.5%]. The method was applied to 30 samples of S. rebaudiana from Misiones (Northeastern Argentina), and the stevioside content found ranged between 3.78 and 9.75% (weight) whereas Rebaudioside A content ranged between 1.62 and 7.27% (weight).

Macrophage-derived heme-oxygenase-1: expression, regulation, and possible functions in skin repair.

BACKGROUND: Expression and enzymatic activity of heme oxygenase (HO) has been implicated in the development, as well as in the resolution, of inflammatory conditions. Because inflammation is central to tissue repair, we investigated the presence and potential functions of HO in an excisional model of normal and diabetes-impaired wound repair in mice. MATERIALS AND METHODS: Expression of HO-1 during cutaneous healing was analyzed by RNase protection assay, Western blot, and immunohistochemical techniques in a murine model of excisional repair. Furthermore, we determined HO-1-dependent release of proinflammatory cytokines from RAW 264.7 macrophages by enzyme-linked immunosorbent assay (ELISA). RESULTS: Upon injury, we observed a rapid and strong increase in HO-1 mRNA and protein levels at the wound site. By contrast to normal repair, late stages of diabetes-impaired repair were associated with elevated HO-1 expression. Besides a few keratinocytes of the hyperproliferative epithelium, immunohistochemistry revealed infiltrating macrophages as the predominant and major source of HO-1 at the wound site. In vitro studies demonstrated the potency of exogenous and also endogenous nitric oxide (NO) to strongly induce HO-1 expression in RAW 264.7 macrophages. However, L-NIL-mediated enzymatic inhibition of inducible NO-synthase (iNOS) at the wound site in vivo was not paralleled by decreased HO-1 levels. In vitro inhibition of HO-1 enzymatic activity by tin protoporphyrin IX (SnPPIX) in RAW 264.7 macrophages markedly attenuated tumor necrosis factor-alpha (TNF-alpha), but strongly increased interleukin-1beta (IL-1beta) release in RAW 264.7 macrophages in vitro. CONCLUSIONS: The observed injury-mediated increase in HO-1 mRNA and protein at the wound site was due to infiltrating HO-1 expressing monocytic cells. Macrophage-derived HO-1 expression was not under regulatory control by NO in skin repair. We provide evidence that HO-1 might exert a regulatory role in macrophage-derived cytokine release.

Leptin enhances wound re-epithelialization and constitutes a direct function of leptin in skin repair.

Wound-healing disorders are a therapeutic problem of extensive clinical importance. Leptin-deficient ob/ob mice are characterized by a severely delayed wound healing that has been explained by the mild diabetic phenotype of these animals. Here we demonstrate that systemically and topically supplemented leptin improved re-epithelialization of wounds in ob/ob mice. Leptin completely reversed the atrophied morphology of the migrating epithelial tongue observed at the wound margins of leptin-deficient animals into a well-organized hyperproliferative epithelium. Moreover, topically supplemented leptin accelerated normal wound-healing conditions in wild-type mice. As assessed by immunohistochemistry, proliferating keratinocytes located at the wound margins specifically expressed the leptin-receptor subtype ObRb during repair. Additionally, leptin mediated a mitogenic stimulus to the human keratinocyte cell line HaCaT and human primary keratinocytes in vitro. Therefore, leptin might represent an effective novel therapeutic factor to improve impaired wound-healing conditions.

Somatizing patients: Part I. Practical diagnosis.

The phenomenon of somatization, which results in unexplained physical complaints, is ubiquitous in primary care settings although it often goes unrecognized. Medical training emphasizes the identification and treatment of organic problems and may leave physicians unprepared to recognize and address somatoform complaints. As a process, somatization ranges from mild stress-related symptoms to severe debilitation. Patients at the low end of the spectrum often respond to simple reassurance, but patients who are more impaired require interventions specifically designed to avoid unnecessary exposure to dangerous, costly and frustrating diagnostic procedures and treatments.

The function of nitric oxide in wound repair: inhibition of inducible nitric oxide-synthase severely impairs wound reepithelialization.

Recently, we demonstrated a large induction of inducible nitric oxide synthase (iNOS) during cutaneous wound repair. In this study, we established an in vivo model in mice to investigate the role of NO during the wound healing process. During excisional repair, mice were treated with L-N6-(1-iminoethyl)lysine (L-NIL), a selective inhibitor of iNOS enzymatic activity. Compared with control mice, L-NIL-treated animals were characterized by a severely impaired reepithelialization process, as the hyperproliferative epithelia at the wound edges appeared to be delayed and characterized by an atrophied morphology. Immunohistochemical labeling for detection of proliferating cells (BrdU-, Ki67-staining) revealed a strong reduction in proliferating keratinocyte cell numbers during the process of re-epithelialization after inhibition of iNOS activity during repair. Western blot analysis of total wound lysates from PBS- and L-NIL-treated mice clearly demonstrated a reduction in proliferating cell nuclear antigen, representing a marker for cell proliferation, in lysates isolated from L-NIL-treated mice. The dependency between keratinocyte proliferation and NO availability observed during wound repair in vivo is further supported by the observation that proliferation of the keratinocyte cell line (HaCaT) is stimulated by low concentrations of NO-donors also in vitro. In summary, our data demonstrate that the presence of a functionally active iNOS is a crucial prerequisite for normal wound reepithelialization.

Nitric oxide triggers enhanced induction of vascular endothelial growth factor expression in cultured keratinocytes (HaCaT) and during cutaneous wound repair.

Recently, we demonstrated a large induction of inducible nitric oxide synthase (iNOS) during cutaneous wound repair. In this study, we investigated the role of nitric oxide (NO) for the expression of vascular endothelial growth factor (VEGF), which represents the most important angiogenic factor during the proliferative phase of skin repair. Since keratinocytes are the major source of VEGF production during this process, we used cultured keratinocytes (HaCaT cell line) as an in vitro model to investigate NO action on growth factor- and cytokine-stimulated VEGF expression. Exogenously added NO enhanced transforming growth factor-beta1-, keratinocyte growth factor-, interleukin-1beta-, tumor necrosis factor-alpha-, and interferon-gamma-induced VEGF mRNA and protein synthesis in keratinocytes. We could demonstrate that high-level expression of cytokine-induced VEGF mRNA in keratinocytes is dependent on endogenously produced NO, as inhibition of the coinduced iNOS by N(G)-monomethyl-L-arginine (L-NMMA) markedly decreased cytokine-triggered VEGF mRNA levels in the cells. We also established an in vivo model in mice to investigate the role of NO during wound healing. During excisional wound repair, mice were treated with L-N(6)-(1-iminoethyl)lysine (L-NIL), a selective inhibitor of iNOS enzymatic activity. Compared to control mice, L-NIL-treated animals were characterized by markedly reduced VEGF mRNA levels during the inflammatory phase of repair. Immunohistochemistry demonstrated reduced VEGF protein expression and a completely disorganized pattern of VEGF-expressing keratinocytes within the hyperproliferative epithelium at the wound edge in L-NIL-treated mice. We demonstrate that triggering of VEGF expression is a crucial molecular mechanism underlying NO function during wound healing.

Coordinated induction of inducible nitric oxide synthase and GTP-cyclohydrolase I is dependent on inflammatory cytokines and interferon-gamma in HaCaT keratinocytes: implications for the model of cutaneous wound repair.

Recently we demonstrated a strong expression of inducible nitric oxide synthase (iNOS) and GTP-cyclohydrolase I (GTP-CH I) in the basal keratinocytes of the epidermis adjacent to the wound and of the hyperproliferative epithelium during wound healing. To identify possible mediators of iNOS and GTP-CH I expression during this process, we analyzed the regulation of iNOS and GTP-CH I expression in cultured human keratinocytes. We found a large and long lasting coinduction of iNOS and GTP-CH I expression upon simultaneous treatment of quiescent cells with inflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma, but not with serum growth factors. The stimulatory effect of interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma is strongly synergistic on iNOS and GTP-CH I expression, because these factors alone stimulated GTP-CH I expression, although to a much lesser extent. Furthermore, iNOS mRNA levels are not influenced at all by stimulation with IL-1beta and revealed only a weak induction after treatment with tumor necrosis factor-alpha and interferon-gamma. Induction of iNOS and GTP-CH I gene expression upon cytokine and interferon-gamma exposure is independent of de novo protein synthesis. Because these cytokines are present at the wound site, they might be responsible for iNOS and GTP-CH I induction during cutaneous repair. Serum, which is released upon hemorrhage, is likely to play no stimulatory role in iNOS and GTP-CH I induction during wound healing.

Substrate specificity of human aldose reductase: identification of 4-hydroxynonenal as an endogenous substrate.

Aldose reductase, which catalyzes the reduction of glucose to sorbitol as part of the polyol pathway, has been implicated in the development of diabetic complications and is a prime target for drug development. However, aldose reductase exhibits broad specificity for both hydrophilic and hydrophobic aldehydes, which suggests that aldose reductase may also be a detoxification enzyme. Several series of structurally related aldehydes were compared as substrates in order to deduce the structural features that result in low Michaelis constants. Aldehydes that contain an aromatic ring are generally excellent substrates, consistent with crystallographic data which suggest that aldose reductase possesses a large hydrophobic substrate binding site. However, there is little discrimination among different aromatic aldehydes. In addition, small hydrophilic aldehydes exhibit low Km values if the alpha-carbon is oxidized. Analysis of the binding of NADPH by fluorescence quenching techniques indicates that aldose reductase exhibits higher affinity for NADPH than NADP, suggesting that this enzyme is normally primed for reductive metabolism. Thus aldose reductase appears to have evolved to catalyze the reduction of a very broad range of aldehydes. Structural features of substrates that bind to aldose reductase with low Km values were used to identify potential endogenous substrates. 4-Hydroxynonenal, a reactive alpha-beta unsaturated aldehyde produced during oxidative stress, is an excellent substrate (Km = 22 microM, kcat/Km = 4.6 x 10(6) M-1 min-1). Reductive metabolism of endogenous aldehydes in addition to glucose, catalyzed by aldose reductase, may play an important role in the development of diabetic complications.

Nutritive value of marine algae Laminaria japonica and Undaria pinnatifida.

The chemical composition, that is crude proteins, fats, carbohydrates, cellulose, ashes, minerals and nucleic acids were determined in two commercially available marine algae: Laminaria japonica and Undaria pinnatifida. The energetic value and energetic share of proteins, fats and carbohydrates were calculated. The results were discussed in terms of importance of marine algae in human diet.

Aldose reductase-catalyzed reduction of acrolein: implications in cyclophosphamide toxicity.

Acrolein, a highly cytotoxic aldehyde, is a metabolic by-product of the antineoplastic agent cyclophosphamide and is responsible for the development of hemorrhagic cystitis, a serious side effect of cyclophosphamide therapy. Aldose reductase (EC 1.1.1.21), a member of the aldo-keto reductase superfamily, catalyzes the NADPH-dependent reduction of acrolein to allyl alcohol (Km = 80 microM, kcat = 87 min-1). Aldose reductase is expressed at different levels in individuals. This suggests that individual differences in the reductive metabolism of acrolein may be a determinant of acrolein toxicity. In addition to being a substrate, acrolein also produces a time-dependent 7-20-fold increase in the activity of aldose reductase toward a variety of substrates. This involves initial binding of acrolein to a second site (Ks = 58 microM). Acrolein activation of aldose reductase results not only in higher kcat values for all substrates but also in higher Km values and decreased catalytic efficiencies. Acrolein activation of aldose reductase reduces its affinity for aldose reductase inhibitors.

Adenine and pyridine nucleotides during rabbit reticulocyte maturation and cell aging.

In this paper we have used a new method which allows the simultaneous extraction and HPLC determination of ATP, ADP, AMP, NADP, NADPH, NAD and NADH to evaluate the changes in concentration of these compounds during maturation of rabbit reticulocytes and cell aging. The results show a significant increase of ATP concentration, higher ATP/ADP, ATP/AMP ratios and lower NADP+/NADPH, NAD+/NADH ratios in rabbit reticulocytes when compared to mature cells. Similar results were also obtained when the whole red blood cell population was separated into fractions of increasing mean age on discontinuous gradients of Percoll-BSA. These metabolic modifications are discussed in relation to the age-dependent metabolic decline of the erythrocyte.