Vitamin C and scar strength: analysis of a historical trial and implications for collagen-related pathologies.

A double-blind controlled trial initiated in 1944 has led to the common narrative that a 10-mg daily vitamin C intake is adequate to prevent and treat impaired wound healing, and by inference, other collagen-related diseases such as heart disease or stroke. The WHO relies on this narrative to set the recommended nutrient intake for vitamin C. This narrative, however, is based on what is known as the eyeball method of data assessment. The 1944 trial published individual participant data on scar strength providing an opportunity to statistically probe the validity of the 10-mg narrative, something which has not yet been done. The findings show that a vitamin C intake that averages to 10 mg/d over a mean follow-up of 11.5 mo was associated with a 42% weakened scar strength when compared with 80 mg vitamin C intake/d (P < 0.001). The observed dose-response curve between scar strength and vitamin C intake suggests that the daily vitamin C intake needed to prevent collagen-related pathologies is in the range recommended by the National Academy of Medicine and the European Food Safety Authority (75 to 110 mg/d), not the WHO recommendation (45 mg/d). The findings also show that a vitamin C intake that averages to 65 mg/d over a mean follow-up of 6.5 mo failed to restore the normal wound-healing capacity of vitamin C-depleted tissues; such tissues had a 49% weaker scar strength when compared with nondepleted tissues (P < 0.05). Thus, average daily vitamin C intakes ∼50% higher than the WHO recommends may fail to treat existing collagen-related pathologies. It is concluded that the prior lack of statistical analyses of a landmark trial may have led to a misleading narrative on the vitamin C needs for the prevention and treatment of collagen-related pathologies.

Induction and expansion of human PRRX1+ limb-bud-like mesenchymal cells from pluripotent stem cells.

Current protocols for the differentiation of human pluripotent stem cells (hPSCs) into chondrocytes do not allow for the expansion of intermediate progenitors so as to prospectively assess their chondrogenic potential. Here we report a protocol that leverages PRRX1-tdTomato reporter hPSCs for the selective induction of expandable and ontogenetically defined PRRX1+ limb-bud-like mesenchymal cells under defined xeno-free conditions, and the prospective assessment of the cells' chondrogenic potential via the cell-surface markers CD90, CD140B and CD82. The cells, which proliferated stably and exhibited the potential to undergo chondrogenic differentiation, formed hyaline cartilaginous-like tissue commensurate to their PRRX1-expression levels. Moreover, we show that limb-bud-like mesenchymal cells derived from patient-derived induced hPSCs can be used to identify therapeutic candidates for type II collagenopathy and we developed a method to generate uniformly sized hyaline cartilaginous-like particles by plating the cells on culture dishes coated with spots of a zwitterionic polymer. PRRX1+ limb-bud-like mesenchymal cells could facilitate the mass production of chondrocytes and cartilaginous tissues for applications in drug screening and tissue engineering.

Basement membrane collagens and disease mechanisms.

Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major BM collagen, collagens VI, VII, XV, XVII and XVIII are also present. Mutations in these collagens cause rare multi-systemic diseases but these collagens have also been associated with major common diseases including stroke. Developing treatments for these conditions will require a collective effort to increase our fundamental understanding of the biology of these collagens and the mechanisms by which mutations therein cause disease. Novel insights into pathomolecular disease mechanisms and cellular responses to these mutations has been exploited to develop proof-of-concept treatment strategies in animal models. Combined, these studies have also highlighted the complexity of the disease mechanisms and the need to obtain a more complete understanding of these mechanisms. The identification of pathomolecular mechanisms of collagen mutations shared between different disorders represent an attractive prospect for treatments that may be effective across phenotypically distinct disorders.

Impact of Therapeutic Angiogenesis Using Autologous Bone Marrow-Derived Mononuclear Cells Implantation in Critical Limb Ischemia With Scleroderma　- Subanalysis of the Long-Term Clinical Outcomes Survey.

BACKGROUND: Many patients with collagen disease (CD), particularly scleroderma (SSc), develop critical limb ischemia (CLI), which leads to limb amputation. However, conventional therapies, including revascularization via surgical bypass, showed poor outcomes in CLI patients with CD. Many CLI patients with SSc showed poor responses to combination therapies including intravenous iloprost, PDE-5 inhibitors, and bosentan. Therefore, new methods of improving the peripheral circulation for limb salvage are required. This study was a subanalysis of the long-term clinical outcomes after autologous bone marrow-derived mononuclear cells (BM-MNC) in CLI patients with SSc. Methods and Results: We assessed no-option CLI patients with CD who underwent BM-MNC implantation at 10 institutes; 69 patients (39 with SSc-related diseases (SSc group) and 30 with other CDs (non-SSc group)), were included. The median follow-up duration was 36.5 months. The 10-year overall survival rate was 59.1% in the SSc group and 82.4% in the non-SSc group. The 10-year major amputation-free rates were 97.4% and 82.6%, respectively. The number of major or minor amputations in the SSc group trended to be less than that in the non-SSc group. Significant improvements in visual analog scale scores were observed in both groups. CONCLUSIONS: The BM-MNC implantation may be feasible in no-option CLI patients with CD. In the SSc group, limb salvage rate tended to be higher than in the non-SSc group.

Romanian version of SDM-Q-9 validation in Internal Medicine and Cardiology setting: a multicentric cross-sectional study.

BACKGROUND: Shared decision making (SDM) is becoming more and more important for the patient-physician interaction. There has not been a study in Romania evaluating patients' point of view in the SDM process yet. Therefore, the present study aims to evaluate the psychometric parameters of the translated Romanian version of SDM-Q-9. MATERIAL AND METHODS: A multicentric cross-sectional study was performed comprising eight recruitment centers. The sample consisted of in- and outpatients who referred to Hospital Units for treatment for atrial fibrillation or collagen diseases. Furthermore, patients who were members of Autoimmune Disease Patient Society were able to participate via an online survey. All participants completed the Romanian translated SDM-Q-9. RESULTS: Altogether, 665 questionnaires were filled in within the hospital setting (n = 324; 48.7%) and online (n = 341; 51.3%). The Romanian version had good internal consistency (Cronbach α coefficient of 0.96.) Corrected item correlations were good ranging from 0.64 to 0.89 with low corrected item correlations for item 1 and item 7. PCA found a one-factorial solution (similar with previous reports) but the first item had the lowest loading. CONCLUSION: SDM-Q-9 is a useful tool for evaluation and improvement in health care that was validated in Romania and can be used in clinical setting in this country.

Reactive perforating collagenosis: An important differential diagnosis in hemodialysis patients.

This is a case report of a 68-year-old hypertensive, diabetic woman who was on regular thrice weekly hemodialysis (HD). She presented with gradually worsening left lower limb pain and swelling. Clinical examination revealed significant edema over the left calf and ankle joint with significant calf tenderness. Extensive workup including magnetic resonance imaging of the lower limb and venous Doppler failed to show any significant abnormality. In view of developing papular lesions over the area, skin biopsy was performed, which finally confirmed reactive perforating collagenosis. This diagnosis ensured reassurance to the patient with halting of further extensive and probably expensive testing. Simple conservative management and symptomatic relief improved the pain over the next few days. This case report highlights the importance of keeping a wide differential for calf tenderness in diabetic HD patients and projects reactive perforating collagenosis as one of the important but frequently missed entities in such a scenario.

Immunoadsorption for collagen and rheumatic diseases.

The field of therapeutics has seen remarkable progress in the recent years, which has made mainstream drug treatment possible for collagen and rheumatic diseases. However, treatment of intractable cases where drug effectiveness is poor is a challenge. Furthermore, organ damage, concurrent illnesses or allergic reactions make adequate drug therapy impossible. For such cases, therapeutic apheresis is very significant, and it is important how this should be valued related to drug therapies. Therapeutic apheresis for collagen and rheumatic diseases involves the removal of factors that cause and exacerbate the disease; the aim of immunoadsorption, in particular, is to improve the clinical condition of patients with autoimmune disease by selectively removing pathogenic immune complexes and autoantibodies from their plasma. Immunoadsorption, in particular, unlike plasma exchange and DFPP, utilizes a high-affinity column that selectively removes autoantibodies and immune complexes, leaving other plasma components intact. There is no need to replenish fresh frozen plasma or blood products such as albumin and gamma globulin preparations. Immunoadsorption is thus superior in terms of safety, as the risk of infection or allergic reaction relating to these preparations can be avoided. We anticipate future investigations of application of synchronized therapy using drugs and therapeutic apheresis, most notably immunoadsorption, in combination to treat intractable clinical conditions such as collagen and rheumatic diseases. In this paper, our discussion includes the indications for immunoadsorption such as collagen and rheumatic diseases, the relevant conditions and types, as well as the latest understanding related to methods and clinical efficacy.

A retrospective study of prognostic factors in patients with interstitial pneumonia receiving long-term oxygen therapy.

PURPOSE: We retrospectively analyzed patients with clinically diagnosed interstitial pneumonia to investigate the factors which contribute to the difference in prognosis from the initiation of long-term oxygen therapy (LTOT) among subtypes. METHODS: Seventy-six patients with clinically diagnosed idiopathic interstitial pneumonia (IIP; n = 49) or interstitial pneumonia associated with collagen vascular disease (CVD-IP; n = 27) in whom LTOT was initiated in our facility from January 1999 to December 2012 were analyzed. RESULTS: Patients with CVD-IP had significantly longer survival time from the initiation of LTOT than those with IIP with the median survival of 51.7 months versus 18.8 months, respectively. The 1-year survival rate was 92.4% for patients with CVD-IP versus 76.5% for those with IIP, and 2-year survival was 88.6 versus 36.0%, respectively. The patterns classified with high-resolution computed tomography (HRCT) were not associated with prognosis. The association between pulmonary hypertension and prognosis was unclear. In results of the multivariate Cox analysis which included factors demonstrating p < 0.1 in the univariate Cox analysis, male gender, low body mass index, and the absence of collagen vascular disease (CVD) were significantly associated with poor prognosis. CONCLUSIONS: After the initiation of LTOT, patients with IIP had poor prognosis regardless of the patterns classified with HRCT, while those with CVD-IP survived longer. Male gender, low body mass index, and the absence of CVD were the independent negative prognostic factors in patients with interstitial pneumonia receiving LTOT.

[Degenerative lesions of the peripheral retina]. / Lésions dégénératives de la périphérie rétinienne.

Degenerative lesions of the peripheral retina are present from teenage years onwards and increase with age. These abnormabilities are frequent, some of them being benign while others predispose to retinal tears and detachment. In the latter case, the lesions are rhegmatogenous and may justify prophylactic treatment by laser photocoagulation. We distinguish congenital lesions of the peripheral retina and intraretinal, chorioretinal and vitreoretinal degenerations. The holes and tears observed in 2% of the population consist of round atrophic holes, "horseshoe" tears, oral dialyses and giant tears.