Acute exanthemas: a prospective study of 98 adult patients with an emphasis on cytokinic and metagenomic investigation.

BACKGROUND: Acute exanthemas (AEs) are frequently seen; they can be caused by drugs or viruses but often the cause is unknown. OBJECTIVES: To describe the clinical, virological and histological aspects of AEs and explore their cytokinic and metagenomic profiles. METHODS: This prospective study examined 98 patients with AE, from February to July 2014. Clinical data were recorded in a standardized chart. Virological investigation and skin biopsies were performed. In addition, blood and skin samples were analysed for cytokines and then by a shotgun metagenomic approach. We identified five groups of patients: those with maculopapular exanthemas (MPEs) that were virally induced (group 1); those with drug-induced MPEs (group 2), those with MPEs that were both viral and drug induced (group 3), those with idiopathic MPEs (group 4) and those with pityriasis rosea (group 5). RESULTS: A virus was identified in 29 cases (human herpesvirus 6, 72%). Cytokinic analysis of the skin (n = 23 MPEs) showed higher levels of interferon-γ and interleukin-1 receptor-α in viral MPEs, higher interleukin-33 levels in idiopathic MPEs, and higher macrophage inflammatory protein 1α levels in drug-induced MPEs. By metagenomics analysis (n = 10 MPEs), viruses identified with routine practice methods were not found in group 1 (n = 4 MPEs). However, Enterovirus A was detected in two cases, especially in a group 1 patient for whom metagenomic analysis rectified the diagnosis of the culprit agent. CONCLUSIONS: Human herpesvirus 6 was the virus most frequently identified, and histology did not discriminate MPEs. In addition, the level of interleukin-33 seen in idiopathic MPEs suggests that an environmental factor may be the trigger for these. The results bring into question the utility of routine polymerase chain reaction analysis and viral serology for determining cause in AE. What's already known about this topic? Acute exanthemas, especially maculopapular exanthemas, are a frequent reason for patients consulting emergency and dermatology departments. It is difficult to evaluate the aetiology of acute exanthema based on the clinical aspects. Few data are available on the investigations needed in routine practice, and no prospective series have been published. What does this study add? Our study provides a global and prospective description of acute exanthemas. Cytokine analysis could help to investigate the pathophysiology of idiopathic eruptions. Metagenomic analysis provides new insights about the value of routine practice virological investigations. We show for the first time the feasibility of metagenomics analysis in the skin, which results question the interest of routine PCR and viral sérologies for the exploration of such acute exanthemas.

Accuracy of injection and short-term pain relief following intra-articular corticosteroid injection in knee osteoarthritis - an observational study.

BACKGROUND: Intra-articular corticosteroid injections (IACI) are effective treatments for pain in knee osteoarthritis (KOA) but treatment response varies. There is uncertainty as to whether structural factors such as accurate placement of IACI affect outcome. We examined this question in a pragmatic observational study, using ultrasound (US) to verify accuracy of IACI. METHODS: 105 subjects with KOA (mean age 63.1 years, 59% female) routinely referred for IACI underwent assessment of demographic factors, x-ray and US of the knee before aspiration and IACI (based on clinical landmarks) with 40 mg triamcinolone acetonide with lignocaine plus a small amount of atmospheric air by an independent physician. US demonstration of intra-articular mobile air, i.e. a positive air arthrosonogram, was used to determine accurate placement of injection. Both patients and injecting physicians were blind to the US findings. Pain at baseline, three and nine weeks post injection was assessed using the 500 mm WOMAC pain subscale and response defined as ≥ 40% reduction in pain from baseline. Inter-observer reliability of air-arthrosonogram assessment was good: κ 0.79 (three raters). RESULTS: Sixty-three subjects (60.6%) were responders at three weeks and 43 (45.7%) at nine weeks. Seventy-four subjects (70.5%) had a positive arthrosonogram. A positive air arthrosonogram did not associate with a higher rate of response to treatment (p 0.389 at three weeks, p 0.365 at nine weeks). There was no difference in US effusion depth, power Doppler signal or radiographic grade between responders and non-responders to the injection, but female gender associated with response at 3 weeks and previous injection with non-response at 9 weeks. CONCLUSIONS: Accurate intra-articular injection of corticosteroid results did not result in superior outcome in terms of pain compared to inaccurate injection in symptomatic knee OA.

Rituximab, a new treatment for difficult-to-treat chronic erythema multiforme major? Five cases.

BACKGROUND: Erythema multiforme major (EMM) is an inflammatory disease affecting skin and mucosae, often triggered by infection with Herpes simplex virus. Some patients have a chronic disease associated with antidesmoplakin autoantibodies, but the pathophysiology remains to be elucidated. First-line treatment is antiviral therapy. With treatment failure or in patients without herpes-triggered disease, thalidomide is effective but has neurological side-effects. Alternatives (dapsone, immunosuppressant agents) are not codified. For many patients, systemic steroids use is chronic. The immunosuppressant drug rituximab (RTX) may be effective. OBJECTIVES: We report five cases of severe chronic EMM treated with rituximab (RTX). METHODS: Five patients with severe chronic EMM for 9-20 years received RTX after failure or side-effects of several treatments, especially antiviral therapy and thalidomide. All had chronic use of steroids. Four patients had antidesmoplakin autoantibodies. RESULTS: Four patients experienced complete or quasi-complete remission of EMM with withdrawal of steroids and one patient partial remission, for 3-11 months. Disease relapsed in all patients, and three received a second cycle of RTX with shorter duration of efficacy. Two patients received a third cycle, one without efficacy. CONCLUSION: The use of RTX for many autoimmune diseases, especially pemphigus, is increasing. Chronic EMM, especially EMM associated to antidesmoplakin autoantibodies, is an inflammatory disease in which the role of B cells is not well understood. However, we report a favourable benefit of RTX treatment for months in five patients with severe disease. RTX could be a therapeutic option in severe, difficult-to-treat EMM.

[Furuncular myiasis caused by Dermatobia hominis. Fortuitous diagnosis on extemporaneous macroscopic analysis of an excised cutaneous nodule]. / Myiase furonculoïde à Dermatobia hominis: diagnostic fortuit sur la coupe macroscopique extemporanée d'un nodule cutané.

BACKGROUND: Furuncular myiasis is a parasitic disease caused by the development of human botfly larva in the skin. It affects people living in tropical countries and travelers returning from these countries and concerns a number of medical specialties. One form of treatment involves surgical extraction of the parasites. PATIENTS AND METHODS: We report the case of a 47-year-old man returning from Guyana presenting two furuncle-like nodules of the skin on the right buttock and on the right shoulder blade. Extemporaneous intraoperative macroscopic examination of the buttock nodule resulted in diagnosis of myiasis caused by the human botfly, Dermatobia hominis. DISCUSSION: The diagnosis of furuncular myiasis is made primarily on clinical grounds and should be suspected on observation of an abscess in subjects returning from a tropical region. It is consequently rare to find D. hominis in biopsy specimens. In the present case, macroscopic examination showed an extremely rare image of the edge of the intact larva in a longitudinal cut, which to our knowledge has never been published to date.

Stronger hepatitis C virus-specific CD8+ T-cell responses in HIV coinfection.

Hepatitis C virus (HCV) is a widespread chronic infection that shares routes of transmission with human immunodeficiency virus (HIV). Thus, coinfection with these viruses is a relatively common and growing problem. In general, liver disease develops over years with HIV coinfection, when compared to decades in HCV monoinfection. The role of the immune system in the accelerated pathogenesis of liver disease in HIV/HCV coinfection is not clear. In this study, we compared the frequency, magnitude, breadth and specificity of peripheral blood CD4+ and CD8+ T-cell responses between HCV-monoinfected and HCV/HIV-coinfected individuals and between HIV/HCV-coinfected subgroups distinguished by anti-HCV antibody and HCV RNA status. While HIV coinfection tended to reduce the frequency and breadth of anti-HCV CD8+ T-cell responses in general, responses that were present were substantially stronger than in monoinfection. In all groups, HCV-specific CD4+ T-cell responses were rare and weak, independent of either nadir or concurrent CD4+ T-cell counts of HIV-infected individuals. Subgroup analysis demonstrated restricted breadth of CD8+ HCV-specific T-cell responses and lower B-cell counts in HIV/HCV-coinfected individuals without anti-HCV antibodies. The greatest difference between HIV/HCV-coinfected and HCV-monoinfected groups was substantially stronger HCV-specific CD8+ T-cell responses in the HIV-coinfected group, which may relate to accelerated liver disease in this setting.

Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction.

Adriamycin (ADR) is an established, life-saving antineoplastic agent, the use of which is often limited by cardiotoxicity. ADR-induced cardiomyopathy is often accompanied by depressed myocardial high-energy phosphate (HEP) metabolism. Impaired HEP metabolism has been suggested as a potential mechanism of ADR cardiomyopathy, in which case the bioenergetic decline should precede left ventricular (LV) dysfunction. We tested the hypothesis that murine cardiac energetics decrease before LV dysfunction following ADR (5 mg/kg ip, weekly, 5 injections) in the mouse. As a result, the mean myocardial phosphocreatine-to-ATP ratio (PCr/ATP) by spatially localized (31)P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 + or - 0.18 vs. 1.39 + or - 0.30, means + or - SD, control vs. ADR, respectively, P < 0.05) when indices of systolic and diastolic function by magnetic resonance imaging were unchanged from control values. At 8 wk, lower PCr/ATP was accompanied by a reduction in ejection fraction (67.3 + or - 3.9 vs. 55.9 + or - 4.2%, control vs. ADR, respectively, P < 0.002) and peak filling rate (0.56 + or - 0.12 vs. 0.30 + or - 0.13 microl/ms, control vs. ADR, respectively, P < 0.01). PCr/ATP correlated with peak filling rate and ejection fraction, suggesting a relationship between cardiac energetics and both LV systolic and diastolic dysfunction. In conclusion, myocardial in vivo HEP metabolism is impaired following ADR administration, occurring before systolic or diastolic abnormalities and in proportion to the extent of eventual contractile abnormalities. These observations are consistent with the hypothesis that impaired HEP metabolism contributes to ADR-induced myocardial dysfunction.

Maturation of renal organic acid transport: substrate stimulation by penicillin.

Renal p-aminohippurate transport in rabbits increased rapidly from birth to 4 weeks of age and then declined to that observed in adults. Penicillin administration to pregnant does or newborn rabbits stimulated the developing transport system, but did not increase the peak observed at 4 weeks. Therefore the continued presence of substrate (penicillin) during development significantly enhances the rate of maturation.

C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A.

Immunosuppressive treatments are available to suppress acute cardiac rejection; however, no viable treatment exists for long-term cardiac graft failure. Moreover, extended use of calcineurin inhibitor immunosuppressants, the mainstay of the current therapeutic for cardiac transplantation, leads to significant associated pathologies such as nephrotoxicity and increased risk of cardiac disease. For the last ten years alternatives to calcineurin inhibitors, or adjuvant therapies designed to complement their activities, have been explored. In tandem with this development, there has been considerable interest in Traditional Chinese Medicines (TCM) as sources for novel therapeutics. Our study examines the ability of the TCM Cordyceps sinensis to reduce acute and chronic rejection associated with cardiac transplantation. The objectives of this study were to first determine if oral delivery of the extract could reduce acute rejection in a rat heterotopic heart model of transplantation. The second objective was to determine, in vitro, if a sterile, aqueous extract of C. sinensis could decrease CD8+ T cell activity. The third objective was to determine if oral delivery of the extract could ablate allograft vasculopathy in a mouse abdominal aortic transplant model. We found that oral delivery of the extract demonstrated a reduction in acute rejection when used in conjunction with a sub-therapeutic dose of Cyclosporine. Further, we found, using a mixed lymphocyte reaction, that the extract was able to significantly reduce CD8+ T cell activity. Finally, we demonstrate that oral delivery of the extract, used with a therapeutic dose of Cyclosporine to suppress acute rejection, ablates allograft vasculopathy.

Adaptive Biomedical Innovation.

Adaptive Biomedical Innovation (ABI) is a multistakeholder approach to product and process innovation aimed at accelerating the delivery of clinical value to patients and society. ABI offers the opportunity to transcend the fragmentation and linearity of decision-making in our current model and create a common collaborative framework that optimizes the benefit and access of new medicines for patients as well as creating a more sustainable innovation ecosystem.

Adaptive Biomedical Innovation: Evolving Our Global System to Sustainably and Safely Bring New Medicines to Patients in Need.

The current system of biomedical innovation is unable to keep pace with scientific advancements. We propose to address this gap by reengineering innovation processes to accelerate reliable delivery of products that address unmet medical needs. Adaptive biomedical innovation (ABI) provides an integrative, strategic approach for process innovation. Although the term "ABI" is new, it encompasses fragmented "tools" that have been developed across the global pharmaceutical industry, and could accelerate the evolution of the system through more coordinated application. ABI involves bringing stakeholders together to set shared objectives, foster trust, structure decision-making, and manage expectations through rapid-cycle feedback loops that maximize product knowledge and reduce uncertainty in a continuous, adaptive, and sustainable learning healthcare system. Adaptive decision-making, a core element of ABI, provides a framework for structuring decision-making designed to manage two types of uncertainty - the maturity of scientific and clinical knowledge, and the behaviors of other critical stakeholders.

Transmyocardial laser revascularization remodels the intrinsic cardiac nervous system in a chronic setting.

BACKGROUND: Prospective trials have demonstrated that transmyocardial laser revascularization (TMLR) imparts symptomatic relief to patients with refractory angina. Because peak clinical effectiveness of TMLR is usually delayed by several months, it has been proposed that ventricular denervation is one mechanism whereby TMLR imparts symptomatic relief. We have demonstrated that TMLR does not denervate the heart in the acute setting, nor does it modify the intrinsic cardiac nervous system (ICNS) in the acute setting. However, the long-term effects of TMLR on the ICNS remain unknown. METHODS AND RESULTS: A holmium:yttrium-aluminum-garnet laser created 20 channels through the anterolateral left ventricular free wall of 10 dogs. Four weeks later, the function of cardiac sensory inputs to the ICNS was studied by applying veratridine (7.5 micromol/L) to ventricular sensory fields. Chronotropic and inotropic responses elicited by cardiac sympathetic or parasympathetic efferent neurons stimulated electrically (10 Hz, 4 V, 4 ms) or chemically (nicotine 5 to 20 microgram/kg IV) were also assessed. Chemical activation of epicardial sensory neurites with veratridine elicited expected ICNS excitatory responses. Electrical stimulation of sympathetic and parasympathetic efferent neurons induced expected altered cardiac responses. In contrast, the responsiveness of the ICNS to systemically administered nicotine was obtunded. CONCLUSIONS: Although chronic TMLR does not affect cardiac afferent or extracardiac efferent neuronal function, it does "remodel" the ICNS so that its responsiveness to a known potent chemical agonist (ie, nicotine) becomes obtunded. Remodeling of the ICNS may account in part for the delayed symptomatic relief that TMLR imparts to patients with refractory angina.

Waiting for cardiac surgery: results of a risk-stratified queuing process.

BACKGROUND: The Queen Elizabeth II Health Sciences Centre uses a weekly peer-review conference of cardiovascular experts to prioritize each surgical case to 1 of 4 queues with the use of standardized criteria of coronary anatomy, stress test result, and symptoms. We examined the hazard of waiting as well as the impact of waiting on surgical outcomes. METHODS AND RESULTS: Analysis was performed for 2102 consecutive patients queued for CABG, aortic valve replacement, or CABG+aortic valve replacement between January 1, 1998, and December 31, 1999. Among 1854 patients undergoing surgery, median waiting times on the respective queues were as follows: in-house urgent group, 8 days; semiurgent A group, 37 days; semiurgent B group, 64 days; and elective group, 113 days. There were 13 deaths (12 cardiac) that occurred during the waiting period (0.7% of the patients). Of the 8.7% patients upgraded to a more urgent queue, 86.1% required hospitalization before surgery. Although female sex was not associated with prolonged waiting time, it was predictive of urgent status (P=0.001). The incidence of postoperative complications was 25.0%, and operative mortality was 2.86%. Both were more frequent among patients undergoing surgery early (P=0.01); however, this difference was attributable to the in-house urgent queue. The median length of stay was 7 days for all patients and was not affected by waiting time. CONCLUSIONS: Death and upgrades while the patients were waiting tended to occur early in the queuing process, and prolonged waiting was not associated with worse surgical outcomes. The cost of reducing waiting times could in part be offset by prevention of hospital admissions among upgraded patients.

Amino acid substitution: its use in detection and analysis of genetic variants.

Techniques of chemical analysis, amino acid sequencing and autoradiography are being used to study the frequency of incorporation of normally noncoded amino acids into hemoglobins and seminal fluid proteins. We are studying, by the sequencing of radiolabeled proteins followed by the recovery of [3H]isoleucine phenylthiohydantoin by high-performance liquid chromatography, the frequency at which normally noncoded isoleucine is incorporated into hemoglobin because of base-substitution mutations versus translational errors. Irradiation increases the isoleucine content of human hemoglobin and the frequency of substitution of isoleucine for specific amino acids in rabbit hemoglobin. Studies to date indicate that these techniques have been developed sufficiently for initial analysis of the potential of drugs and environmental pollutants to induce base-substitution mutations in mammalian somatic cells.

De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed.

Allospecific memory T cells are a recognized threat to the maintenance of solid-organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post-transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme-linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p<0.001), but not 6days post-prime. Following a boost challenge, these memory CD8+ T cells were capable of producing a similarly sized population of secondary effectors as recipients not treated with CyA (p>0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Vitamin D-dependent calcium binding protein in rat uterus: differential effects of estrogen, tamoxifen, progesterone, and pregnancy on accumulation and cellular localization.

The present studies were undertaken to characterize the expression of calcium binding protein (CaBP or calbindin-D9k) in uterine tissues. Using immunohistochemical techniques, calbindin-D9k was localized to the uterine (luminal) epithelium of pregnant rats, but not present in the uterine epithelium of nonpregnant rats. Calbindin was found also in the uterine smooth muscle and endometrial stromal cells of pregnant animals. These latter localizations were reproduced in uteri of 21-day-old nonpregnant rats by administration of tamoxifen or physiological doses of estrogens. Estrogen and tamoxifen produced half-maximal increases of uterine calbindin at daily doses of 0.1 and 10 micrograms, respectively, and maximal responses at 0.3 and 40 micrograms/day. Testosterone and progesterone, at doses which increased the growth of the uterus, did not induce calbindin-D, and both hormones blocked estradiol's effect on uterine calbindin-D appearance. The epithelial localization of calbindin in pregnant uteri was not reproduced in nonpregnant animals by either estradiol (3 micrograms/day) or progesterone (1 mg/day). The localization of calbindin in uterine epithelium during pregnancy appears to be dependent upon an as yet unknown factor. In view of the large surface area of the luminal epithelium in pregnant animals, and the pregnancy-related expression of calbindin in these cells, we propose that uterine epithelium plays an important role in transport of calcium during pregnancy.

Epidermal growth factor increases intestinal calbindin-D9k and 1,25-dihydroxyvitamin D receptors in neonatal rats.

Epidermal growth factor (EGF) has been reported to increase intestinal calcium absorption in suckling rats. The mechanism of this effect is unknown, as are the roles of vitamin D-dependent and independent pathways. The present studies were undertaken to investigate the ability of EGF to accelerate the postnatal induction of the vitamin D-dependent intestinal calcium-binding protein, calbindin-D9k. Subcutaneous administration of EGF increased duodenal calbindin-D9k in suckling rats by more than 100% (P less than 0.001). The effect of EGF was not seen in older weaned animals or when EGF was given to suckling rats by gavage. Administration of EGF simulated the changes of normal development. 1) It increased calbindin-D9k, and the effect was greater in proximal than distal duodenum. 2) EGF increased alkaline phosphatase activity to the same extent in proximal and distal duodenum. 3) EGF increased sucrase more markedly in distal than in proximal epithelium. Maximal and half-maximal effects of EGF on each of these proteins were observed at twice daily doses of 0.1 and 0.04 microgram/g BW, respectively. 4) EGF at the maximally effective dose produced a small (30%) but statistically significant (P less than 0.005) increase in serum 1,25-dihydroxyvitamin D. 5) Most importantly, EGF treatment resulted in a 2-fold increase in intestinal 1,25-dihydroxyvitamin D receptors (VDR) in the proximal segments of the small intestine (P less than 0.001). EGF effects on calbindin-D9k and VDR were specific for the intestine, as EGF did not change kidney calbindin-D9k or kidney VDR. Thus, EGF was able to prematurely initiate a complex series of molecular changes that occur during normal development. The mechanism of EGF's action to stimulate calcium absorption appears to involve a maturation effect on the vitamin D-dependent pathway.