Strategies for anti-fibrotic therapies.

The fibrotic diseases encompass a wide spectrum of entities including such multisystemic diseases as systemic sclerosis, nephrogenic systemic fibrosis and sclerodermatous graft versus host disease, as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering their devastating effects, these diseases pose one of the most serious health problems in current medicine and a serious economic burden to society. Despite these considerations there is currently no accepted effective treatment. However, remarkable progress has been achieved in the elucidation of their pathogenesis including the identification of the critical role of myofibroblasts and the determination of molecular mechanisms that result in the transcriptional activation of the genes responsible for the fibrotic process. Here we review the origin of the myofibroblast and discuss the crucial regulatory pathways involving multiple growth factors and cytokines that participate in the pathogenesis of the fibrotic process. Potentially effective therapeutic strategies based upon this new information are considered in detail and the major challenges that remain and their possible solutions are presented. It is expected that translational efforts devoted to convert this new knowledge into novel and effective anti-fibrotic drugs will be forthcoming in the near future. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset.

OBJECTIVE: A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset. METHODS: Twenty-five previously untreated consecutive patients with recent-onset (\u3c 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients. RESULTS: At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes. CONCLUSION: Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function. Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes

Systemic sclerosis disease modification clinical trials design: quo vadis?

The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should be of at least 12 months. Sample size calculations should consider differences that exceed the Minimal Important Difference. Other relevant trial designs and potential threats to study validity are also discussed. Previous SSc-disease modifying trials have been beset by high dropout rates. Analyses on the subset of subjects completing the trial or applying the last observation- carried-forward approach can potentially lead to biased estimates and false conclusions. Strategies for retention of subjects should be included at the design stage and analyses to account for missing data should be performed

In situ degradability of soyabean meal treated with Acacia saligna and Atriplex halimus extracts in sheep

The effects of Acacia saligna (AC) and Atriplex halimus (AT) extracts were evaluated on ruminal soyabean meal (SBM) degradability using the nylon bag technique. Samples of SBM were treated with 0, 4, or 8 g of AC or AT extracts per 100 g SBM. Bags were incubated in two cannulated sheep for 2, 4, 6, 8, 12, 24, and 48 h. The chemical constituents (CCs) of extracts was determined using GC-MS. Rate and potential degradability of dry matter (DM) were decreased (P=0.015) to a greater extent than N degradability (P=0.145) with AC and AT doses. DM and N degradation were decreased (P<0.05) by 15% and 29%; 24% and 47% with AC, and 21% and 29%; 23% and 37% with AT at 4% and 8% for DM and N, respectively. The data suggest the possibility of using these extracts as feed additives to reduce ruminal degradability of SBM in ruminant diets

A Comparison of Botulinum Toxin A and Intralesional Steroids for the Treatment of Plantar Fasciitis: A Randomized, Double- Blinded Study

Plantar fasciitis is the most frequent cause of chronic heel pain. This pathology generally presents in patients who are 40 years of age or older, overweight, sedentary, or engage in intense physical activity. 14,32 Because of its anatomic orientation and its tensile strength, the plantar fascia functions to prevent foot collapse. It is a piece of thick connective tissue that originates at the base of the calcaneus and extends distally to the phalanges. Stretching of the plantar fascia prevents the displacement of the calcaneus and the metatarsals and helps to maintain the medial longitudinal arch. The plantar fascia simulates a cable between the calcaneus and the metatarsophalangeal joints. The windlass mechanism described by Hicks 13 for the action of the plantar fascia explains that during dorsiflexion of the toes, the length of the plantar fascia is effectively shortened, causing an elevation of the arch. Extension of the toes increases the arc of tension with the metatarsophalangeal joints, similar to an axis or anchor point. Shortening of the plantar fascia that results from dorsiflexion of the hallux is the essence of the reel mechanism. When a complete fasciotomy is performed, this mechanism is lost, decreasing the stability of the arch and interfering with stability during the terminal stance phase. Methods: The patients were randomly divided into 2 groups according to the treatment received. The patients were evaluated over 6 months. The evaluation scores included the Visual Analog Scale (VAS), Maryland Foot and Ankle, Foot and Ankle Disability Index (FADI), and American Orthopaedic Foot and Ankle Society (AOFAS) score. Moreover, patients were instructed to perform plantar fascia stretching exercises over the course of the study. The final number of patients was 36, of whom 19 received BTX-A (10 men and 9 women) and 17 (6 men and 11 women) received steroids. Results: When compared to patients who received steroids, the patients who received BTX-A exhibited more rapid and sustained improvement over the duration of the study. Conclusion: A combination of BTX-A and plantar fascia stretching exercises yielded better results for the treatment of plantar fasciitis than intralesional steroids. Level of Evidence: Level I, therapeutic studies

Volume-Targeted Ventilation and Arterial Carbon Dioxide in Neonates

Objectives: To review the arterial carbon dioxide tensions (PaCO2) in newborn infants ventilated using synchronized intermittent mandatory ventilation (SIMV) in volume guarantee mode (using the Drager Babylog 8000+) with a unit policy targeting tidal volumes of approximately 4 mL/kg. Methods: Data on ventilator settings and arterial (PaCO2 levels were collected on all arterial blood gases (ABG; n = 288) from 50 neonates ( 65 mmHg) were determined. Results: The mean (SD) (PaCO2 during the first 48 h was 46.6 (9.0) mmHg. The mean (SD) (PaCO2 on the first blood gas of those infants commenced on volume guarantee from admission was 45.1 (12.5) mmHg. Severe hypo- or hypercapnoea occurred in 8% of infants at the time of their first blood gas measurement, and i

Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation

The p85α protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85α mutations located within the N-terminal domains of p85α previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85α mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85α mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85α mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85α towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85α BH domain mutants (E137K, E217K, R262T E297K) for bovine p85α BH and found that the mutations did not alter the overall domain structure. Thus, several p85α mutations found in human cancers may deregulate PTEN and/or Rab5 regulated pathways to contribute to oncogenesis. We also engineered several experimental mutations within the p85α BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activit