Type 2 diabetes affects bone cells precursors and bone turnover.

BACKGROUND: Here we study the effect of type 2 diabetes (T2DM) on bone cell precursors, turnover and cytokines involved in the control of bone cell formation and activity. METHODS: We enrolled in the study 21 T2DM women and 21 non diabetic controls matched for age and body mass index (BMI). In each subject we measured bone cell precursors, Receptor Activator of Nuclear Factor κB (RANKL), Osteoprotegerin (OPG), Sclerostin (SCL) and Dickoppf-1 (DKK-1) as cytokines involved in the control of osteoblast and osteoclast formation and activity, bone density (BMD) and quality trough trabecular bone score (TBS) and bone turnover. T2DM patients and controls were compared for the analyzed variables by one way ANOVA for Gaussian ones and by Mann-Whitney or Kruskal-Wallis test for non-Gaussian variables. RESULTS: RANKL was decreased and DKK-1 increased in T2DM. Accordingly, patients with T2DM have lower bone turnover compared to controls. BMD and TBS were not significantly different from healthy controls. Bone precursor cells were more immature in T2DM. However the number of osteoclast precursors was increased and that of osteoblasts decreased. CONCLUSIONS: Patients with T2DM have more immature bone cells precursors, with increased number of osteoclasts and decreased osteoblasts, confirming low bone turnover and reduced cytokines such as RANKL and DKK-1. BMD and TBS are not significantly altered in T2DM although, in contrast with other studies, this may be due to the match of patients and controls for BMI rather than age.

Conservative Treatment of Hemorrhoidal Disease.

BACKGROUND: Hemorrhoids are vascular cushions underlying the distal rectal mucosa and contributing to approximately 15-20% of the resting anal pressure with a complete closure of the anal canal. They can become pathological (hemorrhoidal disease, HD) being the most common cause of painless rectal bleeding during defecation with or without prolapsing anal tissue. The treatment of HD must be tailored to both the severity of disease and patient's expectation. METHODS: A narrative review of all the most relevant papers present on the three major databases (PUBMED, EMBASE and WEB OF SCIENCE) regarding conservative treatment was conducted. RESULTS: Conservative treatment is effective in managing the majority of patients complaining of early stages of the disease. Dietary and lifestyle modifications are the first therapeutic step necessary to achieve a regular defecation with soft stool whereas oral phlebotonic drugs can help to control symptoms. The use of topical medications, particularly during the acute phase or in the post-operative period can also be beneficial for all patients complaining of HD. CONCLUSION: Despite a large number of available products in the market and the high incidence of HD, very few randomized controlled trials have been carried out and most of the studies are uncontrolled case series. Larger and better designed studies are necessary to establish the real benefit of all types of drugs for the treatment of early stages of HD.

Crohn's disease and postoperative recurrence. The role of anastomotic configurations and the kono-s anastomosis.

BACKGROUND: The observation that in more than 90% of Crohn's disease patients the postoperative recurrences are located in the pre-anastomotic tract leads us to suppose that the anastomosis would play a role in the appearance of recurrences. AIM AND METHODS: To focus the role of different anastomotic configurations in the incidence of recurrences, the Authors have conducted a review of the literature of the last two decades and have revised critically their experience. RESULTS: The rate of recurrences seem to be lower in patients in whom the anastomotic configuration is such as to present a wide lumen; it seems that they are lower after stapled side-to-side anastomosis. The Kono-S anastomosis, recently introduced technique, seems to offer better results. CONCLUSIONS: The role of the various types of anastomosis remains uncertain. Further large-scale controlled trials with long term follow-up are needed. KEY WORDS: Anastomosis, Crohn's disease, Postoperative Recurrences.

Elective surgery for ulcerative colitis, ileo-rectal anastomosis or restorative proctocolectomy An Update.

BACKGROUND: Despite advances in the medical management of Ulcerative Colitis (UC), surgery is required in about a third of patients. AIMS AND METHODS: A review of the literature of the last 20 years was conducted in order to analyze the results of Ileo-Rectal Anastomosis (IRA) and of Ileal Pouch-Anal Anastomosis (IPAA) in the treatment of mild-to-moderate UC. Postoperative complications, functional results and the risk of cancer were analyzed in each of the two groups of patients. RESULTS: In IRA group postoperative morbidity is low, varying from 8 to 28%. The risk of urinary and sexual dysfunction are rare and fertility rates are higher, compared to IPAA. The cumulative probability of success (working IRA) is 84% at 5 years and 51-69% at 10 years. The postoperative morbidity of IPAA is higher; dehiscence and pelvic sepsis were observed respectively in 9.5% and in 5.5%. A sexual dysfunction is present in 3.4%. In 18.8% occurs pouchitis. The risk of failure of the pouch is 6.8% and increased to 8.5% after 5 years. The risk of cancer is higher after IRA than after IPAA, with a cumulative risk at 20 years of 6-14% and 4.2% respectively. DISCUSSION: The choice between IPAA or IRA is based upon patient's preference and clinical criteria (malignancy or sphincter injury). IPAA, intervention of choice, is burdened by a higher rate of complications, such as anastomotic leak with pelvic sepsis and subsequent functional pouch failure, pouchitis, infertility in young women, lesions of the pelvic nerves and portal vein thrombosis. There have been reports of cancer not only in the anal transitional zone, but also in the same pouch, either after mucosectomy that after stapled anastomosis. IRA is less invasive than IPAA and postoperative complications are lower. Does not require dissection of the pelvic and presents no risk of injury of the nerves of the urogenital sphere. The long-term results of the IRA are generally satisfactory and most of the patients stated that after the intervention improve both the health status and quality of life. CONCLUSION: Today IPAA is the gold standard. The IRA is indicated in selected patients where they meet the following requirements: normal sphincter tone, absence of severe perineal disease, rectum does not actively involved by the disease, absence of dysplasia or cancer. It is also indicated in patients who refuse an ileostomy and it can be proposed as a possible interim procedure in young women, because it does not need a pelvic dissection and because the risk of infertility is minimal or absent when compared to IPAA. Because the risk of cancer is higher, patients undergoing IRA must be adequately informed about the risk, as well as recurrent proctitis, also of cancer, and must fully understand the need for surveillance and accept at least annual endoscopy with rectal biopsies; if these conditions are not met, patients should not be candidates for IRA. KEY WORDS: IPAA, IRA, Surgical treatment, Ulcerative Colitis.

Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients: an in vitro assay.

BACKGROUND: Systemic sclerosis (SSc) is characterized by vasculopathy and progressive fibrosis. CTLA4-Ig (abatacept) is able to interact with the cell surface costimulatory molecule CD86 and downregulate the target cell. The aim of this study was to evaluate the in-vitro effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts isolated from the same SSc patient. METHODS: Circulating fibrocytes and skin fibroblasts were obtained from eight SSc patients with "limited" cutaneous involvement and from four healthy subjects (HSs). Samples were analyzed by fluorescence-activated cell sorter analysis (FACS) at baseline (T0) and after 8 days of culture (T8) for CD45, collagen type I (COL I), CXCR4, CD14, CD86, and HLA-DRII expression. Circulating fibrocytes were treated for 3 h and skin fibroblasts for 24/48 h with CTLA4-Ig (10, 50, 100, 500 µg/ml). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for CD86, COL I, FN, TGFß, αSMA, S100A4, CXCR2, CXCR4, CD11a, and Western blotting was performed for COL I and FN. RESULTS: Using qRT-PCR, the T8-cultured SSc circulating fibrocytes which had not been treated with CTLA4-Ig showed higher gene expression for CD86, αSMA, S100A4, TGFß, and COL I compared with HS circulating fibrocytes. Interestingly, αSMA/COL I gene expression was significantly lower only in the SSc circulating fibrocytes treated with CTLA4-Ig for 3 h (p < 0.01, p < 0.05). On the contrary, no effects were observed for either SSc or HS skin fibroblasts after CTLA4-Ig treatment. COL I and FN protein expression was unchanged in both SSc and HS skin fibroblasts by Western blot. CONCLUSIONS: Circulating fibrocytes seem to be more responsive to CTLA4-Ig treatment than skin fibroblasts from the same SSc patient, likely due to their higher expression of CD86. CTLA4-Ig treatment might downregulate the fibrotic process in SSc patients by downregulating the fibrocytes, circulating progenitor cells.

Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts.

BACKGROUND: Myofibroblasts contribute to fibrosis through the overproduction of extracellular matrix (ECM) proteins, primarily type I collagen (COL-1) and fibronectin (FN), a process which is mediated in systemic sclerosis (SSc) by the activation of fibrogenic intracellular signaling transduction molecules, including extracellular signal-regulated kinases 1 and 2 (Erk1/2) and protein kinase B (Akt). Selexipag is a prostacyclin receptor agonist synthesized for the treatment of pulmonary arterial hypertension. The study investigated the possibility for selexipag and its active metabolite (ACT-333679) to downregulate the profibrotic activity in primary cultures of SSc fibroblasts/myofibroblasts and the fibrogenic signaling molecules involved. METHODS: Fibroblasts from skin biopsies obtained with Ethics Committee (EC) approval from patients with SSc, after giving signed informed consent, were cultured until the 3rd culture passage and then either maintained in normal growth medium (untreated cells) or independently treated with different concentrations of selexipag (from 30 µM to 0.3 µM) or ACT-333679 (from 10 µM to 0.1 µM) for 48 h. Protein and gene expressions of α-smooth muscle actin (α-SMA), fibroblast specific protein-1 (S100A4), COL-1, and FN were investigated by western blotting and quantitative real-time PCR. Erk1/2 and Akt phosphorylation was investigated in untreated and ACT-333679-treated cells by western botting. RESULTS: Selexipag and ACT-333679 significantly reduced protein synthesis and gene expression of α-SMA, S100A4, and COL-1 in cultured SSc fibroblasts/myofibroblasts compared to untreated cells, whereas FN was significantly downregulated at the protein level. Interestingly, ACT-333679 significantly reduced the phosphorylation of Erk1/2 and Akt in cultured SSc fibroblasts/myofibroblasts. CONCLUSIONS: Selexipag and mainly its active metabolite ACT-333679 were found for the first time to potentially interfere with the profibrotic activity of cultured SSc fibroblasts/myofibroblasts at least in vitro, possibly through the downregulation of fibrogenic Erk1/2 and Akt signaling molecules.