Quality of life outcomes in adults with moderate-to-severe plaque psoriasis treated with dimethylfumarate (DMF): a post hoc analysis of the BRIDGE study.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease associated with quality of life (QoL) impairment. BRIDGE was a randomized, double-blind, phase III study comparing the efficacy and safety of dimethylfumarate (DMF) with a fixed combination of fumaric acid esters (FAE) or placebo for the treatment of moderate-to-severe psoriasis. OBJECTIVES: This post hoc analysis investigated treatment effect on QoL overall and by patient subgroups categorized by disease severity. Week 8 efficacy responses were also investigated as possible predictors of Week 16 Dermatology Life Quality Index (DLQI) outcomes. METHODS: Patients were randomized to receive a maximum daily dose of 720 mg of DMF, FAE (gradual up-titration) or placebo for 16 weeks. Psoriasis Area Severity Index, Body Surface Area, Physician's Global Assessment and DLQI were assessed at baseline, Weeks 8 and 16. DLQI 0-1 indicated 'no effect on patient life'. Associations between baseline severity, Week 16 DLQI and Week 8 efficacy (as observed cases) were also examined. RESULTS: At baseline, 671 patients were included in the full analysis set (267 randomized to DMF, 273 to FAE and 131 to placebo). DMF was superior to placebo (P < 0.001) and not significantly different to FAE regarding Week 16 DLQI outcomes (P > 0.05). Baseline disease severity did not impact DLQI outcomes at Week 16. In DMF- and FAE-treated patients, Week 8 PASI 50/75 responders reported better DLQI responses at Week 16 vs non-responders (P < 0.05). Week 8 PASI ≤ 3 and/or PGA 0-1 responders were also more likely to report DLQI 0-1 at Week 16 vs non-responders (P < 0.05). CONCLUSION: Dimethylfumarate significantly improved DLQI outcomes vs. placebo and was not affected by baseline disease severity. Efficacy responses (PASI 50/75, PASI ≤3 and PGA 0-1) as early as Week 8 were predictive of QoL outcomes at Week 16 in DMF- and FAE-treated patients.

Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm® - and placebo-controlled trial (BRIDGE).

BACKGROUND: Fumaric acid esters (FAEs) are recommended in international guidelines for induction and long-term treatment of adults with moderate-to-severe chronic plaque psoriasis. The fixed combination Fumaderm® is approved in Germany, with dimethyl fumarate (DMF) being the main active ingredient. OBJECTIVES: To assess the efficacy and safety of a new formulation of DMF (LAS41008), compared with placebo and Fumaderm® , in adults with moderate-to-severe chronic plaque psoriasis. METHODS: In this phase III, double-blind, placebo-controlled, noninferiority trial (BRIDGE, NCT01726933, EudraCT 2012-000055-13), patients were randomized to receive LAS41008, Fumaderm® or placebo (2 : 2 : 1) for 16 weeks, uptitrating to a maximum daily DMF dose of 720 mg, depending upon individual response. The coprimary end points were the percentage of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and the percentage achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment (PGA) at week 16. RESULTS: In total, 671 patients were randomized and included in the full analysis set (n = 267, LAS41008; n = 273, Fumaderm® ; n = 131, placebo). At week 16, 37·5% of patients treated with LAS41008 achieved PASI 75, compared with 15·3% receiving placebo (superiority for LAS41008 vs. placebo: P < 0·001) and 40·3% receiving Fumaderm® (noninferiority for LAS41008 vs. Fumaderm® : P < 0·001). Overall, 33% of patients treated with LAS41008 were 'clear' or 'almost clear' in the PGA at week 16, compared with 13·0% receiving placebo (P < 0·0001; LAS41008 superiority vs. placebo) and 37·4% receiving Fumaderm® . Most treatment-related adverse events were classed as 'mild' in severity. CONCLUSIONS: LAS41008 (DMF) is effective in the treatment of adults with moderate-to-severe chronic plaque psoriasis.

Modulation of Wnt and Hedgehog signaling pathways is linked to retinoic acid-induced amelioration of chronic allograft dysfunction.

Chronic renal allograft damage (CAD) is manifested by a smoldering inflammatory process that leads to transplant glomerulopathy, diffuse interstitial fibrosis and tubular atrophy with loss of tubular structures. Using a Fischer 344 (RT1lvl) to Lewis (RT1l) rat renal allograft model, transcriptomic profiling and pathway mapping, we have previously shown that dynamic dysregulation of the Wnt signaling pathways may underlie progressive CAD. Retinoic acid, an important regulator of differentiation during vertebrate embryogenesis, can moderate the damage observed in this experimental model of CAD. We show here that subsets of the Hedgehog (Hh) and canonical Wnt signaling pathways are linked to the pathophysiology of progressive fibrosis, loss of cilia in epithelia and chronic dysfunction. Oral treatment with 13cis retinoic acid (13cRA) was found to selectively ameliorate the dysregulation of the Hh and canonical Wnt pathways associated with CAD, and lead to a general preservation of cilial structures. Interplay between these pathways helps explain the therapeutic effects of retinoic acid treatment in CAD, and suggests future targets for moderating chronic fibrosing organ damage.

The chemokine receptor Cxcr3 is not essential for acute cardiac allograft rejection in mice and rats.

Chemokine receptors have gained attention as potential targets for novel therapeutic strategies. We investigated the mechanisms of allograft rejection in chemokine receptor Cxcr3-deficient mice using a model of acute heart allograft rejection in the strain combination BALB/c to C57BL/6. Allograft survival was minimally prolonged in Cxcr3-deficient mice compared to wild-type (wt) animals (8 vs. 7 days) and treatment with a subtherapeutic dose of cyclosporine A (CsA) led to similar survival in Cxcr3-deficient and wt recipients (13 vs. 12 days). At rejection grafts were histologically indistinguishable. Microarray analysis revealed that besides Cxcr3 only few genes were differentially expressed in grafts or in spleens from transplanted or untransplanted animals. Transcript analysis by quantitative RT-PCR of selected cytokines, chemokines, or chemokine receptors or serum levels of selected cytokines and chemokines showed similar levels between the two groups. Furthermore, in a rat heart allograft transplantation model treatment with a small molecule CXCR3 antagonist did not prolong survival despite full blockade of Cxcr3 in vivo. In summary, Cxcr3 deficiency or pharmacologic blockade does not diminish graft infiltration, tempo and severity of rejection. Thus, Cxcr3 does not appear to play a pivotal role in the allograft rejection models described here.

Degos disease with an inconspicuous clinical course.

BACKGROUND: Degos disease is a rare systemic disorder with involvement of the skin and visceral organs, leading to death in about 50% of cases within 1 or 2 years. In recent years, several cases with cutaneous lesions only have been recognized. METHODS: We report on a young male patient presenting with single inconspicuous papules with bluish/black centres on the trunk and the upper limbs that, upon healing turn white. These lesions recurred on different locations over the past 6 years, and were never more than two to three at one time. RESULTS: Histopathological examinations revealed archetypal features for Degos disease. The patient had no other complaints, neither visceral organs nor the central nerve system were involved. Laboratory examinations were within normal range. CONCLUSIONS: This case increases the number of reports on a benign course of Degos disease. It raises the question if the 'malignant' and the 'benign' course of the disease represent two distinct diseases or variants of a systemic vasculitis with unknown cause.

[Apomorphine hyperpigmentation]. / Apomorphin-Pigmentierung.

A 72 year old bedridden, disoriented man presented with a continuously increasing number of blue nodules on his abdomen and both thighs. In addition, he had a melanoma on his left forearm (SSM, Clark level III, Breslow 0.75 mm), which lead to the clinical diagnosis of melanoma metastases. Biopsy of one of the blue nodules showed CD68 positive histiocytic cells loaded with brownish pigment granules and a lymphocytic infiltrate within the deep dermis and upper subcutis. The pigment reacted histochemically similarly to melanin. Melanocytes were absent at these sites. Because of the unexplained clinical and histopathological picture, the patient's history was reassessed and it was learned that the patient had received subcutaneous infusions of apomorphine for the past 10 years for the treatment of Parkinson's disease. By oxidation, apomorphine may be converted into tetrahydroisoquinoline-melanin, which apparently is the cause for the accumulation of pigment within the deep dermis.

Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.

Fumaric acid esters are thought to improve psoriasis by altering leukocyte, keratinocyte, and/or endothelial functions. To determine specificity, kinetics, and molecular mechanisms of different fumaric acid esters in their ability to inhibit endothelial cell activation, we analyzed CD62E and CD54 expression in endothelial cells in vivo and in vitro. In lesional skin of psoriatic patients, oral fumaric acid ester treatment resulted in a marked reduction of CD62E but not CD54 expression on dermal microvessels. Using human umbilical vein endothelial cells, dimethylfumarate almost completely inhibited tumor-necrosis-factor-induced CD62E, but not CD54 expression at concentrations < or = 70 microM, mimicking the situation in vivo. A 60 min dimethylfumarate preincubation was sufficient to block tumor-necrosis-factor-induced CD62E expression for up to 24 h. In contrast, equimolar concentrations of methylhydrogenfumarate, the hydrolysis product of dimethylfumarate, did not suppress tumor-necrosis-factor-induced CD62E expression. Likewise, all fumaric acid esters other than dimethylfumarate were ineffective. Using CD62E, NF-kappa B, or AP-1-responsive promoter constructs, dimethylfumarate inhibited tumor-necrosis-factor-induced activation of the CD62E and the NF-kappa B but not the AP-1 promoter construct. In summary, at a dose range < or = 70 microM, dimethylfumarate appeared to be a specific inhibitor of CD62E expression in an NF-kappa B-dependent manner.

Interpreting diabetes mellitus: differences between patient and provider models of disease and their implications for clinical practice.

Current medical literature suggests that Type 2 diabetes mellitus can be controlled by diet and hypoglycemic agents or diet and insulin therapy. Nevertheless, adhering to a low glucose dietary regimen remains problematic for a majority of patients, and management of the disease is an ongoing source of frustration for physicians and other providers. While calling for more research on the physician's experience of treating chronic conditions like diabetes, the authors argue that much of the current frustration stems from the different frames or explanatory models that physicians and patients use to understand the disease. By comparing physician narratives collected in several clinical contexts (e.g., medical lectures, precepting sessions, patient care sessions and personal interviews) with patient stories obtained primarily through narrative interviews, the authors highlight crucial differences in the way physicians and patients experience and think about the disease. In particular, the authors highlight differences between physicians and patients across five dimensions: etiology, symptoms/signs, factors which affect blood sugar, ideal blood sugar, and future prospects. In concluding, the authors sketch out elements of a theory of clinical practice involving diabetes care. Data for the study was collected at two family practice training sites in Chicago.

Barriers to communication about diabetes mellitus. Patients' and physicians' different view of the disease.

BACKGROUND: Management of diabetes mellitus is difficult for both the patient and the clinician, and poor communication resulting from different conceptions of the disease and different treatment goals can exacerbate the problem. METHODS: We used qualitative methods, including semistructured interviews with patients and clinicians and direct observation of clinical precepting sessions by trained observers at an inner-city family practice training site. Transcripts from these sessions were analyzed for content (with the help of Nud.ist software) to identify themes that highlight problem areas in clinician-patient communication. RESULTS: The most important themes revolved around the concept of control, which was used in at least 3 different ways, and the concept of frustration. Frustration resulted from different understandings of the biology, physiology, and natural history of the disease, and approaches to treatment. In the interviews, clinicians often spontaneously acknowledged the multiple physical, psychological, and social obstacles to treatment confronted by their patients, but in observed practice they almost always focused entirely on managing blood sugar numbers. CONCLUSIONS: Different conceptions of the term "control" affect the ability of patients and clinicians to communicate effectively. The tendencies of clinicians to view their own management strategy as scientific truth, and their focus on managing numbers rather than attempting to understand their patient's conception of disease and their treatment goals, lead to frustration and are serious obstacles to effective collaboration.

Multicultural curricula in family practice residencies.

BACKGROUND AND OBJECTIVES: In 1985, results from a national survey indicated that 25% of family practice residencies taught about multicultural issues in their programs. Our current study identified the current status and content of the curricula and determined facilitating and impeding factors to multicultural curricula. METHODS: In 1998, the Society of Teachers of Family Medicine's Group on Multicultural Health Care and Education conducted a cross-sectional mail survey of all 476 family practice residency programs. RESULTS: With a 59% response rate, 58% of responding programs have an informal curriculum on multicultural issues, 28% have a formal curriculum, and 14% have no curriculum. Programs with a formal curriculum teach more content, employ more educational methods, use more evaluation techniques, and feel more successful than programs with an informal curriculum. Important factors that facilitate curricula include cultural diversity of communities and residents, multicultural interests of faculty and residents, and faculty's multicultural expertise. Factors that impede curricula include lack of time, money, resources, faculty expertise, and cultural diversity in the community. Programs with formal, informal, and no curriculum identify different facilitators and impediments. CONCLUSION: There was a marked increase in the prevalence of multicultural curricula in family practice residencies from 1985 to 1998.

Effect of trephination technique on the ultrastructure of corneal transplants: guided trephine system v posterior punch technique.

AIM: Different trephination methods may lead to differences in degree of tissue damage and endothelial cell loss, which both influence the outcome of penetrating keratoplasty. Light, transmission, and scanning electron microscopy were used to compare the ultrastructural appearance of the cut edges and the endothelial cell loss in 26 human corneal donor buttons obtained by trephination with the suction fixated guided trephine system (GTS) and with the free hand posterior punch technique (PPT). METHODS: Human corneas were stored between 5 and 14 days in Optisol. One cornea from each pair was used for each technique. Trephinations (7.5 mm) were performed either from the anterior direction with the GTS (n=13) or from the posterior direction with the PPT (n=13) using Pharmacia Superblade trephines. Light microscopy, transmission electron, and scanning electron microscopy were performed according to standard procedures. Widening of the cut edges and the extent of endothelial cell loss were measured at three different areas per corneal button and analysed statistically. RESULTS: In contrast with the PPT, the GTS trephine produced considerable fibrillar disorder at the cut edges of the corneal buttons. The distance to which the endothelial cell loss extended from the edges of the cuts was significantly (p<0. 001) lower for the GTS (42.2 (SD 50.8) microm from the edge) than for the PPT (109.3 (68.1) microm). Stromal widening at the edges (measured as percentage increase in stromal thickness, compared with the thickness of the central cornea) was observed with both techniques. However, the mean stromal widening produced by the GTS was significantly greater than that produced by PPT (106% (24%) v 69% (21%); p<0.002). CONCLUSION: Both trephination techniques produced only minor tissue damage. Nevertheless, there were distinct differences in the fine appearance of the cuts produced by the GTS and the PPT techniques. The extent of the fibrillar dislocation and stromal widening was greater at the edges of the GTS buttons. The GTS technique produced significantly less endothelial cell loss at the cut edges than did the free hand punching technique, PPT.

Efficacy of thrombolytic therapy in pulmonary embolism determined by MION-enhanced MRA: an experimental study in rabbits.

RATIONALE AND OBJECTIVES: This study determined whether contrast-enhanced magnetic resonance angiography could be used as a noninvasive imaging technique to determine the therapeutic effect and endpoint in thrombolysis of acute pulmonary embolism in an animal model. METHODS: New Zealand white rabbits (n = 18) were anesthetized and mechanically ventilated. Single (n = 12 emboli) or dual (n = 12 emboli in 6 animals) pulmonary emboli were created by injecting autologous thrombi through a right internal jugular venous approach. Three-dimensional time of flight (TOF) magnetic resonance angiograms were obtained after intravenous administration of 2 mg Fe of a long circulating monocrystalline iron oxide. Animals then received 5000 IU heparin and 1.3 mg recombinant tissue plasminogen activator/kg intravenously, and magnetic resonance angiography was repeated 30 minutes and 60 minutes after initiation of thrombolytic therapy. RESULTS: MION-enhanced magnetic resonance angiography accurately detected pulmonary emboli in all rabbits. Thrombolysis during the observation period was successful in 8 of the 18 animals. In animals with a single embolus, the revascularization rate was 50% (6 of 12 emboli). The rate was 33% (4 of 12 emboli) in animals with multiple emboli. Magnetic resonance angiography allowed determination of thrombus resolution or thrombus persistence. CONCLUSIONS: It was feasible to diagnose pulmonary embolism accurately in this experimental study and to monitor thrombolysis of pulmonary emboli by MION-enhanced magnetic resonance angiography.

[Imaging and differentiation of atherosclerotic plaque with magnetic resonance tomography]. / Darstellung und Differenzierung atherosklerotischer Plaques mittels Magnetresonanz.

Magnetic resonance (MR) imaging studies have allowed the imaging of an atheroma, its size, shape, and lipid contents. The aim of our study was to characterize atherosclerotic lesions using a 0.5 T magnet, to delineate plaque components, and to compare MR results with histology. Thirty necropsy specimens of human iliac arteries were studied. Magnetic resonance imaging studies were carried out on a 0.5 Tesla superconducting magnet using a 5 cm surface coil. The position for the coronal MR planes was oriented by an external marker. The matrix size was 256 x 256, 4 NEX, and the FOV was 45 mm. The pulse sequences used included SE 520/29 and SE 2200/28 and 90. Signal intensity (SI) of fibrous plaques increased significantly from 28.3 +/- 3.8 to 49.1 +/- 8.2 (p < or = 0.0001) and decreased at SE 2200/90 to 24.1 +/- 6.8 (p < or = 0.0001). However, lipid plaque components showed no significant change in SI between T1-weighted pulse-sequences (28.2 +/- 5.4) and T2-weighted pulse-sequences (25.5 +/- 5.9). Only at SE 2200/90 SI of lipid plaques decreased significantly (11.8 +/- 3.9, p < or = 0.0001). As compared to histology, MR has shown a high sensitivity and specificity in the detection of fibrous and lipid plaque components. In conclusions, our study demonstrated that MR is highly effective in the characterization of atherosclerotic lesions.

Doctor talk and diabetes: towards an analysis of the clinical construction of chronic illness.

During the last two decades the illness narrative has emerged as a popular North American literary form. Through poignant stories, well-educated patients have recounted their struggle with disabling diseases as well as with the hospitals and health care bureaucracies from whom they seek service. However, much less has been written about the doctor's narrative construction of chronic diseases either in the process of learning medicine or through diagnosing, treating and counseling chronically ill patients. Indeed, following Kleinman's lead, the physician's narrative has been narrowly viewed as a discourse on the verifiable manifestations of pathophysiology. Drawing on contemporary theories of storytelling--including the conception of narrative as conversational interaction--the present paper argues that doctor narratives are equally complex if quite different than patient stories. Indeed, through an analysis of doctor talk centering on diabetes mellitus collected in several distinct venues--case presentations, narrative interviews and medical consultations--it is argued that physician stories not only employ very evocative tropes, but that these stories combine didactic, rhetorical and soterological elements in the telling. The research was conducted at two, urban family practice training sites in Chicago.

Training family medicine faculty to teach in underserved settings.

BACKGROUND AND OBJECTIVES: Because minority physicians are more likely to practice in minority or medically underserved communities, meeting the health care needs of underserved populations requires that programs not only train such physicians but train minority faculty to act as teachers and role models. The Faculty Development Center in Family Medicine at Cook County Hospital has had more than 120 graduates, most of whom are teaching and practicing in underserved settings. Nearly half have been minorities, the result of the priority given to recruitment of minority fellows. The curriculum is specifically geared to prepare faculty to work in underserved settings and nurture future physicians for these settings. Workforce diversity can be achieved only by major changes in the institutional culture of medical education, which federal policy can encourage by setting high standards for grant funding preferences and supporting centers of excellence for training minority physicians and faculty.