Impaired gastric ulcer healing in diabetic rats: role of heat shock protein, growth factors, prostaglandins and proinflammatory cytokines

Gastric mucosa of diabetic rats is highly vulnerable to acute injury, but little is known about the influence of diabetic conditions on the healing of gastric ulcers. In this study, streptozotocin (70 mg/kg injected intraperitoneally) was used to induce diabetes mellitus in rats. Four weeks after streptozotocin injection, gastric ulcers were induced using the acetic acid method, and 10 days later, the healing rate and the gastric blood flow (GBF) were measured by planimetry and hydrogen (H(2))-gas clearance method, respectively. Six major groups of rats with gastric ulcers were used: (1) vehicle (saline); (2) streptozotocin alone; (3) insulin (4 IU/day intraperitoneally); (4) streptozotocin plus insulin; (5) pentoxifylline, an inhibitor of synthesis and release of tumor necrosis factor-alpha (TNF alpha); and (6) aspirin, a non-selective inhibitor of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and rofecoxib, the highly selective COX-2. In the diabetic rats, a significant delay in ulcer healing ( approximately by 300%), accompanied by a decrease in the gastric mucosal blood flow was observed. The prolongation of the healing in diabetic animals was associated with an increase in gastric mucosal expression and release of TNFalpha, interleukin-1 beta (IL-1 beta), suppression of the vascular endothelial growth factor (VEGF), platelet endothelial cell adhesion molecule-1 (PECAM-1) and the mucosal overexpression of heat shock protein 70 (HSP 70). Administration of insulin reversed the delay in ulcer healing and significantly decreased the expression of IL-1 beta and TNF-alpha, while producing the rise in the expression of VEGF and PECAM. Pentoxifylline, an inhibitor of TNF-alpha, which by itself accelerated ulcer healing in non-diabetic rats, counteracted the increase in the area of gastric ulcer induced by streptozotocin, raised significantly gastric blood flow and suppressed the plasma TNF-alpha levels. Aspirin and rofecoxib, that significantly suppressed the mucosal prostaglandin E(2) generation in ulcer area, delayed significantly the rate of ulcer healing and decreased the GBF at ulcer margin in non-diabetic rats, and these changes were significantly augmented in diabetic animals. We conclude that: (1) Experimental diabetes dramatically impairs ulcer healing, depending upon the increased release of proinflammatory cytokines and the attenuation of angiogenesis that can limit the ulcer healing effects of locally produced HSP 70 and TNF-alpha. (2) Insulin reversed this impairment of ulcer healing in diabetic rats, mainly due to the enhancement of angiogenesis and reduction in expression of cytokines in the ulcer area. (3) Classic non-steroidal anti-inflammatory drugs such as aspirin prolonged ulcer healing under diabetic conditions due to suppression of endogenous prostaglandins and the fall in the microcirculation at the ulcer margin and these effects were mimicked by selective, so called "safe" COX-2 inhibitor, rofecoxib, suggesting that both COX isoforms are important sources of prostaglandins that are essential in the ulcer healing in diabetes.     

Dendritic cells as vectors for immunotherapy of cancer

Dendritic cells (DCs) initiate and regulate immune responses. Numerous studies in mice showed that tumor antigens-loaded DCs are able to induce therapeutic and protective anti-tumor immunity. The immunogenicity of antigens delivered on DCs has now been demonstrated in cancer patients and some clinical responses without any significant toxicity have been observed. Nevertheless, many parameters of DC vaccination need to be established including: (1) the type of DCs, their maturation stage and stimuli; (2) the quality and the breadth of induced immune responses; (3) host-related factors, such as the extent of metastatic disease and myeloablation; and (4) efficacy as measured by the clinical outcome.     

Antihistaminic activity of carane derivatives in isolated guinea pig ileum

Local anesthetics (LAs) inhibit membrane depolarization by reducing sodium and potassium conductance, and subsequent displacement of calcium ions from binding sites seems to occur. Histamine release appears to be a secretory process in which calcium couples the stimulus to the exocytosis of histamine-containing granules. Furthermore, LAs are structurally similar to histamine H₁-receptor antagonists. Thus, LAs can be considered antihistaminic drugs.Previous pharmacological investigations have shown strong local anesthetic, anti-inflammatory and analgesic activity of the carane derivative KP-23. As it has previously been demonstrated that KP-23R, S and its R, S-diasteroisomers have an inhibitory effect on guinea pig ileum contractions, the aim of the present study was to determine and compare the antihistaminic effects of KP-23R, S and its individual isomers KP-23R and KP-23S on isolated guinea pig ileum.     

Evaluation of a multiprofessional rehabilitation programme for persistent musculoskeletal-related pain: economic benefits of return to work

OBJECTIVE: The aim of this study was to evaluate the economic consequences of an 8-week multiprofessional rehabilitation programme for patients with persistent pain. SUBJECTS: A group of 67 patients following the programme and a comparison group of 322 patients. METHODS: The effect on return to work was estimated using 3 different methods: (i) a matched sample approach; (ii) regression analysis; and (iii) propensity score matching. The economic benefit of the programme was estimated as a reduction in production losses due to sick-leave. This benefit was compared with the actual cost of the programme. RESULTS: The benefit of the programme was estimated to be euro3,799-7,515 per treated patient and year. The total cost of the programme was estimated to be euro5,406 per patient. Based on these figures the total cost of the programme, including costs for patients remaining on sick-leave, had been recovered when the successfully rehabilitated patients had worked for 9-17 months. Any additional work after that yielded net economic benefits. CONCLUSION: Since other studies indicate that a large proportion of the patients working after one year also work after 3 and 6 years, we conclude that this multiprofessional rehabilitation programme for patients with persistent pain most likely generates substantial net economic gains.     

Comparative evaluation of simple indices using a single fasting blood sample to estimate beta cell function after islet transplantation

Six single fasting blood sample–based indices—Secretory Unit of Islet Transplant Objects (SUITO), Transplant Estimated Function (TEF), Homeostasis Model Assessment (HOMA)2‐B%, C‐peptide/glucose ratio (CP/G), C‐peptide/glucose creatinine ratio (CP/GCr), and BETA‐2 score—were compared against commonly used 90‐minute mixed meal tolerance test (MMTT) serum glucose and beta score to assess which of them best recognizes the state of acceptable blood glucose control without insulin supplementation after islet allotransplantation (ITx). We also tested whether the indices could identify the success of ITx based on the Igls classification of beta cell graft function. We analyzed values from 47 MMTT tests in 4 patients with up to 140 months follow‐up and from 54 MMTT tests in 13 patients with up to 42 months follow‐up. SUITO, CP/G, HOMA2‐B%, and BETA‐2 correlated well with the 90‐minute glucose of the MMTT and beta‐score (r 0.54‐0.76), whereas CP/GCr showed a modest performance (r 0.41‐0.52) while TEF showed little correlation. BETA‐2 and SUITO were the best identifiers and predictors of the need for insulin support, glucose intolerance, and ITx success (P < .001), while HOMA2‐B% and TEF were unreliable. Single fasting blood sample SUITO and BETA‐2 scores are very practical alternative tools that allow for frequent assessments of graft function.

     

A 2000 patient retrospective assessment of a new strategy for burn wound management in view of infection prevention and treatment

Infections in burn patients are still the principal cause of complications in burn injuries. The aim of this study is to assess a new strategy for burn wound management in view of infection prevention and treatment in the experience of the Burn Treatment Center in Siemianowice Śląskie. The applied methodology involved the analysis of patient records describing the hospital''s epidemiological situation between 2014 and 2016. The analysis also included the use and cost of antibiotics, silver‐containing dressings, and other antiseptics relative to the number of sepsis cases, including those caused by Pseudomonas aeruginosa, as well as the mortality ratio. The total costs of prevention and treatment of infections were reduced, while the use of silver‐containing dressings and antiseptics increased. The number of patients with sepsis decreased, including cases caused by P. aeruginosa, and the mortality ratio was reduced. Introducing a strategy for burn wound‐oriented infection prevention and treatment in burn patients provides a number of benefits. It is also cost‐effective. Using locally applied active dressings and antiseptics can be a welcome choice for often‐unnecessary antibiotic therapy of a suspected or existing burn wound infection.     

Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy

IgA nephropathy (IgAN) is recognized as most frequent form of primary glomerulonephritis worldwide. IgAN is associated with renal degradation occurring due to irreversible pathological changes leading to glomerulosclerosis and interstitial fibrosis. It remains poorly understood whether and to what extent these changes are followed by the activation of regenerative mechanisms. Therefore, in this study we aimed to evaluate regenerative potential of IgAN patients by quantitating the frequencies of several stem cell types, namely circulating very small embryonic-like stem cells (VSELs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) as well as different monocyte subsets with varying maturation and angiopoietic potential. Moreover, we analyzed whether changes in stem cell and monocyte frequencies were related to alterations of several chemotactic factors (stromal derived-factor (SDF-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)) and a marker of monocyte/macrophage activation, namely soluble form of CD163 receptor (sCD163). We showed that IgAN patients presented with enhanced levels of VSELs, but not other stem cell types. We also demonstrated significantly elevated numbers of intermediate monocytes known for their M2-like properties as well as high angiopoietic potential and CD163 expression. This finding was accompanied by detection of elevated sCD163 plasma levels in IgAN patients. Taking together, we demonstrated here that IgAN is associated with selective mobilization of VSELs and increased maturation of monocytes towards M2-like and angiopoietic phenotype. These findings contribute to better understanding of the role of regenerative mechanisms in the pathogenesis of chronic inflammation in the course of IgAN.