Differential glycosaminoglycan expression and hyaluronan homeostasis in juvenile hyaline fibromatosis.

BACKGROUND: Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive disease characterized histologically by deposition of hyaline material and clinically by multiple skin lesions. Clarification of the molecular and structural changes involved in JHF skin lesions may unravel targets for pharmacotherapy. OBJECTIVE: We sought to investigate the expression of glycosaminoglycans and their metabolizing enzymes in lesional as compared with lesion-free skin tissue specimens in JHF. METHODS: Glycosaminoglycans were isolated, purified, and fractionated by electrophoresis on cellulose acetate membranes and agarose gels. Hyaluronic acid (HA) was quantitated by enzyme-linked immunosorbent assay and the expression of HA metabolizing enzymes was investigated using reverse transcriptase-polypeptide chain reaction. RESULTS: JHF lesions exhibited significantly less HA and elevated amounts of dermatan sulfate and chondroitin sulfate, whereas gene expression of HA synthase-1 and HA synthase-3 was significantly down-regulated, as compared with lesion-free skin tissue specimens. LIMITATIONS: Because JHF is a rare disease, a limitation to our study was that we collected skin tissue specimens from only one patient. CONCLUSION: The significant alterations of HA homeostasis in JHF lesions provide further understanding of JHF pathogenesis and may offer a target for pharmacologic intervention to treat the skin lesions associated with JHF.

Efficacy of pregabalin and gabapentin for neuropathic pain in spinal-cord injury: an evidence-based evaluation of the literature.

BACKGROUND: Spinal-cord injury (SCI) is a leading cause of neuropathic pain (NP). Current pharmaceutical treatments for NP in SCI patients are not effective. Two promising options are gabapentin (GP) and pregabalin (PB). Their predominant mechanism of action is believed to be the inhibition of calcium currents, leading in turn to reduced neurotransmitter release and attenuation of postsynaptic excitability. This could explain much of their efficacy in the treatment of both seizure disorders and pain syndromes. However, evidence for their efficacy in attenuating NP of SCI is still controversial. OBJECTIVE: To efficiently integrate valid information and provide a basis for rational decision making, through determining PB and GP efficacy in treating NP in SCI. METHODS: Literature was systematically reviewed. Medline, Embase, CINAHL and Cochrane Database were searched using search terms 'gabapentin', 'pregabalin', 'neurontin', 'lyrica', 'neuropathic pain' and 'spinal-cord injury'. Studies were assessed independently by two authors. RESULTS: Five studies were eligible for inclusion. Two of them studied PB and three GP. Both GP and PB appear to be efficacious for NP in SCI. A clear comparison between the two drugs could not be performed. The literature data suggest that PB is more efficacious than GP in many important variables for NP in SCI, although PB use is followed by more side effects than GP. PB reduced Visual Analogue Score (VAS) in both studies (P < 0.001 and P = 0.016). On the other hand, for GP a maximum dosage of 3,600 mg/day reduced VAS score (P = 0.000), whereas a maximum dosage of 1,200 mg/day failed to do so. CONCLUSION: There is a lack of studies comparing GP and PB in treating NP in SCI. This systematic review indicates the possible efficacy of PB and GP in NP of SCI. Recommendations for future research to inform clinical practice should include cost-effectiveness studies and dose-response analysis in order to determine the schema employed and the duration of treatment.

Disseminated refractory pyoderma gangraenosum during an ulcerative colitis flare. Treatment with infliximab.

BACKGROUND: Pyoderma gangraenosum is an immune-mediated, inflammatory, neutrophilic dermatosis of unknown etiology, which represents one of the extraintestinal manifestations of inflammatory bowel disease. It is a rare disease that occurs in less than 1% of patients with inflammatory bowel disease and with the same ratio in patients with Crohn's disease and ulcerative colitis. MAIN OBSERVATIONS: A 36-year-old woman was diagnosed with ulcerative colitis 6 years before admission to our dermatology department with an acute disseminated pyoderma gangraenosum with mucosal involvement, during a flare of ulcerative colitis. Disease progression was interrupted by intravenous administration of the tumor necrosis factor-α inhibitor infliximab at 5 mg/kg at weeks 0, 2, and 6 (1st cycle) and every 8 weeks thereafter. Improvement of intestinal, skin and oral manifestations was evident already after the 1st cycle of treatment and has been maintained since (at least 16 months). CONCLUSIONS: This case report is one of very few on disseminated pyoderma gangraenosum with oral involvement complicating ulcerative colitis, where infliximab was shown to have a rapid efficacy on skin, mucosal and bowel symptoms.

Differential expression of matrix metalloproteinases and proteoglycans in Juvenile Hyaline Fibromatosis.

BACKGROUND: Juvenile Hyaline Fibromatosis (JHF) is a rare autosomal recessive disorder, histologically characterized by the production and deposition of an unidentified hyaline material in the skin and other organs. Extracellular matrix molecules are implicated in the development of skin lesion which is debilitating and recurrent and, so far, no treatment is satisfactory. OBJECTIVE: To investigate the expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and proteoglycans in lesional as compared to site-matched lesion-free skin tissue specimens of a JHF patient, aiming to elucidate the aetiopathological mechanisms involved in the development of JHF skin lesions. METHODS: Gelatinase activity of MMP-2 and MMP-9 was investigated by gelatine zymography. Protein levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in skin tissue extracts were measured by ELISA. Gene expression of MMPs, TIMPs and proteoglycans was examined by quantitative RT-PCR. RESULTS: JHF lesions exhibited significantly higher activity as well as elevated protein and gene expression of MMP-2 and MMP-9, as compared to lesion-free skin tissue specimens. Decorin was downregulated and aggrecan was upregulated in lesional skin, as compared to normal skin. CONCLUSION: The results presented in this study indicate that MMPs and proteoglycans may be involved in the pathogenesis of JHF and therefore these molecules may offer alternative targets for pharmacological intervention to achieve more radical and effective treatment.

Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome.

BACKGROUND: The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed. METHODS: A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. RESULTS A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77-1.21)], Hcy [2.25 (1.46-3.03)], PAI-1 antigen [16.96 (7.25-26.28)], PAI-1 activity [0.71 (0.18-1.23)], VEGF [1.72 (0.96-2.48)], ADMA [0.19 (0.08-0.3)], AGEs [3.91 (2.36-5.45)] and Lp(a) [0.81 (0.58-1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07-1.44)], ET-1 [1.06 (0.52-1.59)] and fibrinogen [0.20 (0.01-0.39)], whereas no difference was detected for IL-6 [0.71 (-0.16 to 1.59)]. CONCLUSIONS Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.

Selenium supplementation in the treatment of Hashimoto's thyroiditis: a systematic review and a meta-analysis.

BACKGROUND: Evidence suggests that selenium (Se) supplementation could be useful as an adjunctive therapy to levothyroxine (LT4) in the treatment of Hashimoto's thyroiditis (HT). To summarize evidence regarding its effect on thyroid autoantibodies' titers, demands in LT4 replacement therapy, ultrasonographic thyroid morphology, and mood in patients with HT under LT4 treatment, a systematic review and meta-analysis of relevant literature were performed. METHODS: Systematic review of prospective studies involving patients with HT under LT4 treatment and meta-analysis of studies on randomized, placebo-controlled, blinded trials were performed. RESULTS: Patients with HT assigned to Se supplementation for 3 months demonstrated significantly lower thyroid peroxidase autoantibodies (TPOab) titers (four studies, random effects weighted mean difference: −271.09, 95% confidence interval: −421.98 to −120.19, p< 10⁻4) and a significantly higher chance of reporting an improvement in well-being and/or mood (three studies, random effects risk ratio: 2.79, 95% confidence interval: 1.21-6.47, p= 0.016) when compared with controls. Demands in LT4 replacement therapy and ultrasonographic thyroid morphology were found either unaltered or underreported. CONCLUSIONS: On the basis of the best available evidence, Se supplementation is associated with a significant decrease in TPOab titers at 3 months and with improvement in mood and/or general well-being. Evidence suggests a different pattern of response to Se supplementation in HT relative to baseline TPOab titers, and this, if confirmed, could be used to identify which patients would benefit most from treatment. An improvement in thyroid function and morphology should be demonstrated before Se routine supplementation can be recommended in the treatment of HT.

Pernicious anemia in a patient with Type 1 diabetes mellitus and alopecia areata universalis.

A 27-year-old male, who had developed diabetes mellitus type 1 (DMT1) since the age of eighteen and alopecia areata universalis nine months later, attended the outpatient clinics complaining of general fatigue and shortness of breath. A Schilling test was indicative of pernicious anemia. Antigastric parietal cell (AGPA) and anti-intrinsic factor antibodies were positive, confirming diagnosis of pernicious anemia. Thyroid and Addison's disease were excluded. Gastroscopy revealed atrophic gastritis without any evidence of carcinoid tumors. The aim of this case, which, to our knowledge, is the first one to describe a correlation between diabetes mellitus Type 1 (DMT1), pernicious anaemia, and alopecia areata universalis, is to remind the clinician of the increased risk of pernicious anaemia and gastric carcinoids in DMT1 patients. Screening for AGPA followed by serum gastrin and vitamin B(12) levels constitute the most evidence-based diagnostic approach.