Long-term treatments for systemic sclerosis: what are the perspectives?

Systemic sclerosis (SSc) is responsible for fibrosis of the dermis and other organs as well as vascular abnormalities. While the pathogenesis of SSc is continually being better understood, there is still no single therapeutic agent that has been shown to increase survival in a prospective randomized trial. Traditional medications such as colchicine and D-penicillamine are disappointing in clinical practice, and the latter one failed to clearly show benefit when tested in a prospective placebo controlled trial comparing conventional high dose versus low dose. Conversely, new disease modifying agents are emerging such as cyclophosphamide (CYC) in interstitial pulmonary disease and stem cell autograft after high dose CYC therapy in patients who develop visceral involvement in the three first years of evolution of the disease. Organ specific therapy may show dramatic benefit, such as angiotensin converting enzyme inhibitors in renal crisis and epoprostenol in primary pulmonary hypertension. We will try to review disease modifying agents available in SSc and emphasize new therapeutic agents that are currently being evaluated, including vasodilators, anti-inflammatory, anti-fibrosing agents and immunosuppressive molecules.     

Prevalence of mutations of the NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn disease

BACKGROUND: We assessed the prevalence of R702W, G908R, and L1007fs coding mutations in the NOD2/CARD15 gene and the genotype-phenotype relation in Spanish patients with Crohn disease. METHODS: A cohort of 204 unrelated patients with Crohn disease and 140 healthy controls were studied. The phenotype was established before commencement of genotyping. Genotyping of the R702W, G908R, and L1007fs gene polymorphisms of NOD2/CARD15 was performed by two independent laboratories using different techniques. In the case of discordant results, specific sequencing of DNA strands was performed. RESULTS: At least one mutation was present in 32.8% of patients compared to 10.7% in controls (OR = 4.08, 95% CI 2.21 to 7.50). In patients with Crohn disease, the frequency of R702W, G908R, and L1007fs carriers was 13.7%, 8.3%, and 14.2%, respectively. Compound heterozygotes and homozygotes occurred in 3.4% and 2.9% of patients and in none of the controls. The correlation of genotype-Vienna classification showed a significant association with ileal disease (RR = 1.61, 95% CI 1.21-2.15, P = 0.001) and an inverse association with colonic localization (RR = 0.29, 95% CI 0.11-0.80, P = 0.007). There was a significant association between G908R carriership and previous appendectomy, surgical interventions, and stricturing behavior. A gene-dosage effect on phenotypic characteristics was not observed. CONCLUSIONS: In a Spanish population from Madrid, mutations of the NOD2/CARD15 gene were a marker of susceptibility to Crohn disease and were associated with ileal disease. Carriers of the G908R mutation showed a stricturing disease behavior, history of appendectomy, and surgical interventions over the course of the disease.     

Signals involved in wound-induced proteinase inhibitor II gene expression in tomato and potato plants

Chemical and physical signals have been reported to mediate wound-induced proteinase inhibitor II (Pin2) gene expression in tomato and potato plants. Among the chemical signals, phytohormones such as abscisic acid (ABA) and jasmonic acid (JA) and the peptide systemin represent the best characterized systems. Furthermore, electrical and hydraulic mechanisms have also been postulated as putative Pin2-inducing systemic signals. Most of the chemical agents are able to induce Pin2 gene expression without any mechanical wounding. Thus, ABA, JA, and systemin initiate Pin2 mRNA accumulation in the directly treated leaves and in the nontreated leaves (systemic) that are located distal to the treated ones. ABA-deficient tomato and potato plants do not respond to wounding by accumulation of Pin2 mRNA, therefore providing a suitable model system for analysis of the signal transduction pathway involved in wound-induced gene activation. It was demonstrated that the site of action of JA is located downstream to the site of action of ABA. Moreover, systemin represents one of the initial steps in the signal transduction pathway regulating the wound response. Recently, it was reported that heat treatment and mechanical injury generate electrical signals, which propagate throughout the plant. These signals are capable of inducing Pin2 gene expression in the nontreated leaves of wounded plants. Furthermore, electrical current application to tomato leaves leads to an accumulation of Pin2 mRNA in local and systemic tissues. Examination of photosynthetic parameters (assimilation and transpiration rate) on several types of stimuli suggests that heat-induced Pin2 gene expression is regulated by an alternative pathway from that mediating the electrical current and mechanical wound response.     

Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment.

The episodes of hypoxia/re-oxygenation associated with the respiratory disturbances observed in patients with obstructive sleep apnoea syndrome (OSAS) may induce the generation of oxygen free radicals. Indeed, several studies suggest that OSAS is associated with oxidative stress. The present study tested the hypothesis that patients with OSAS have an alteration in antioxidant defences. The plasma levels of total antioxidant status (TAS), glutathione peroxidase (GPX), gamma-glutamyltransferase (GGT), vitamins A, E, B12 and folate, and homocysteine were determined in 47 patients with OSAS and 37 healthy subjects. Of these, 27 patients who used continuous positive airway pressure (CPAP) for >4 h.night-1 were re-examined 12 months later. Patients with OSAS had lower TAS (1.4+/-0.16 versus 1.50+/-0.10 mmol.L-1), vitamin A (64+/-19 versus 74+/-17 microg.dL-1) and vitamin E levels (1,525+/-499 versus 1,774+/-503 microg.dL-1), and increased values of GGT (42+/-22 versus 32+/-16 U.L-1) than controls. There was no difference between groups in GPX, homocysteine, vitamin B12 and folate plasma levels. CPAP treatment normalised the levels of TAS (1.50+/-0.13 mmol.L-1) and the activity of GGT (30+/-14 U.L-1) without any influence on vitamins levels. In conclusion, the results indicate that patients with obstructive sleep apnoea syndrome have a decreased antioxidant capacity that is partially reversed by continuous positive airway pressure treatment.     

The long-term follow-up of 1000 patients with a valve replacement by the prosthesis of the Instituto Nacional de Cardiología Ignacio Chávez]

The long-term follow-up of patients with bioprosthetic valves manufactured at the Instituto Nacional de Cardiología Ignacio Chávez is presented. From February 1983 to May 1990, 1068 patients were operated and 1252 valves were replaced. Eighty two percent had rheumatic heart disease with one or more injured valves. In 17% it was a replacement of a failing valve. Seventy three percent of the patients had a low or medium-low socioeconomical status. There were 176 perioperative deaths in the first month after the operation and 150 patients were lost to follow-up. The rest (740) are the subject of this report. Mortality associated with valve related complications had a probability of 0.74 +/- 0.05, it had a significative increase after month 70th, with a 88% survival at that time. The functional class in the whole group improved 90%, with confidence limits for binomial distribution between 85 and 97%. There was also a significant reduction in heart enlargement. There were 161 prosthesis dysfunctions due to valve calcification or rupture, 50 were replaced. Twenty-three patients had hemolysis, and 19 infective endocarditis. There were 6.5% with systemic embolism in spite that only one half of those in which there was an indication, different of the valve replacement, received anticoagulant medication. The use of this prosthesis is on economical and medical satisfactory solution for the problem of a great number of our population of patients.     

Implant Abutment Cleaning by Plasma of Argon: 5‐Year Follow‐Up of a Randomized Controlled Trial

Background: Contamination of implant abutments could potentially influence the peri‐implant tissue inflammatory response. The aim of the present study is to assess the radiographic bone changes around customized, platform‐switched abutments placed according to the “one‐abutment‐one‐time” protocol, with and without plasma of argon cleaning treatment. Methods: Thirty healthy patients with thin gingival biotype (<1 mm) and history of periodontal disease received one maxillary implant each. Immediately before abutment connection, patients were randomly assigned to control group (cleaning protocol by steaming) or test group (plasma of argon treatment). Outcome measures were: 1) success rate of implants and prostheses; 2) biologic and prosthetic complications; 3) peri‐implant marginal bone loss (MBL); 4) esthetic and periodontal parameters; and 5) patient satisfaction. Results: Neither implants nor prostheses were lost in either group at the 5‐year follow‐up examination. Overall, both groups showed a slight amount of peri‐implant bone loss from baseline to 5 years. A statistically higher mean MBL was found in the control group compared with the test group at 6, 24, and 60 months after crown connection. Nevertheless, during the entire follow‐up period, intragroup comparison demonstrated statistically significant mean MBL in the control group, but not in the test group. The test group showed a higher mean gain at the soft tissue margin, but not for the papilla. All implants showed good periodontal parameters, with no significant differences between groups. Conclusion: Plasma of argon could be used to disinfect implant abutments before insertion to minimize future peri‐implant bone resorption.     

Decreased plasma levels of orexin-A in sleep apnea

BACKGROUND: Orexin-A, also known as hypocretin, is a neuropeptide implicated in appetite and sleep regulation. Because the obstructive sleep apnea syndrome (OSAS) is characterized by obesity and excessive daytime sleepiness, we hypothesized that orexin-A levels may be abnormal in patients with OSAS. Further, since treatment with continuous positive airway pressure (CPAP) in patients with OSAS is very effective in normalizing daytime sleepiness, we also hypothesized that the chronic use of CPAP may influence plasma levels of orexin-A in these patients. OBJECTIVE: To evaluate plasma levels of orexin-A in patients with OSAS and the effect of CPAP treatment. PATIENTS AND METHODS: We compared the plasma levels of orexin-A in 13 healthy controls, 27 untreated patients with OSAS and 14 patients treated with CPAP during at least 1 year (4.5 +/- 0.5 h/night; mean +/- SEM). All patients had severe OSAS (apnea-hypopnea index, 57 +/- 4 h(-1)). Results: Orexin-A plasma levels were significantly lower in untreated (9.4 +/- 1.9 pg.ml(-1), p < 0.01) and treated patients with OSAS (4.2 +/- 1.5 pg.ml(-1), p < 0.001) than in healthy subjects (20.6 +/- 4.5 pg.ml(-1)). In untreated patients, orexin-A levels were not significantly related to daytime somnolence assessed by Epworth scale (r = -0.18, p = 0.37) or the body mass index (r = -0.13, p = 0.52). CONCLUSIONS: Orexin-A plasma levels are abnormally low in patients with OSAS, independently of the level of somnolence and/or presence of obesity. These results suggest that these low orexin-A levels may be related to the pathogenesis of OSAS.