Can pain intensity in osteoarthritis joint be indicator of the impairment of endothelial function?

We propose that pathological remodeling in joint tissues of osteoarthritis (OA) patients persistently stimulates local secretion of pro-inflammatory mediators, which overflow into the blood, activating leukocytes that impair endothelial function and accelerate the atherosclerotic process. During periods of pain, endothelial dysfunction progresses more aggressively due to elevated secretion of these pro-inflammatory mediators, which are involved in both atherosclerosis and the sensation of pain. Concentrations of pro-inflammatory cytokines and their antagonists, activating and decoy receptors of the broad interleukin (IL)-1 and IL-17 families, IL-15, and monocyte chemotactic protein-1 should be measured in peripheral blood samples of OA patients and compared with (I) OA clinical severity; (II) subclinical parameters of atherosclerosis; (III) ischemic heart disease risk factors; (IV) soluble factors indicating endothelial dysfunction; (V) degree of bone destruction; and (VI) results of a six-minute walk test. Arthroscopy and joint replacement surgery provide an opportunity to estimate mRNA and protein expression of inflammatory mediators in specimens of synovial fluid, synovial membrane, cartilage, and/or subarticular bone. A range of methods, including questionnaires, X-ray, computed tomography, ultrasound, enzyme-linked immunosorbent assay, immunohistology, immunofluorescence, and reverse transcription and in situ polymerase chain reaction are available. Understanding the inflammatory and immune mechanisms underlying OA may allow the early identification of patients at high risk of cardiovascular disease, independently of classical coronary risk factors. Pain may constitute an extrinsic indicator of currently worsening endothelial function.

Cytotoxic T lymphocytes as a potential brake of keratinocyte proliferation in psoriasis.

Psoriasis is a chronic papulosquamous skin disease, histologically characterized by epidermal hyperproliferation and dermal infiltration of inflammatory cells. The majority of T lymphocytes infiltrating dermis are CD4+ T lymphocytes secreting type 1 and type 17 cytokines. These cytokines are responsible for triggering keratinocyte proliferation as well as chemokine secretion and subsequent migration of other inflammatory cells in the skin. Contrarily, lymphocytes that accumulate in epidermis are mainly CD8+ T lymphocytes. According to the recent findings, these cells can also secrete type 1 and type 17 cytokines. However, it is demonstrated so far that epidermal CD8+ T lymphocytes contain higher amounts of cytolytic molecules, such as perforin, granzyme B and granulysin whose role in psoriasis pathogenesis is still unknown. Therefore, in this article we hypothesize the active involvement of cell mediated cytotoxicity in killing the proliferating keratinocytes as a mechanism of potential self-defense and possible brake in psoriatic plaque formation, maintaining skin homeostasis.

Possible role of granulysin in pathogenesis of osteoarthritis.

Increased presence of immune mediator and cytotoxic/apoptotic molecule granulysin was noticed in different tissues during pathological processes with the domination of Th1 over Th2 mediated immunity. Beside granulysin expression in T and NKT cells, activated NK cells are thought to be the major source of chemotactic 15 kDa and cytotoxic 9 kDa granulysin in vivo. As NK cells are the principal joint's tissue-infiltrating lymphocyte subset, we hypothesized that granulysin mediated human cell death (apoptosis) could be responsible for the relatively silent damage of the joint's tissue without clinically notable signs of systemic inflammation in the patients with osteoarthritis (OA). The analyzes of the presence and frequency of granulysin expressing lymphocytes at protein and gene levels in peripheral blood and synovial samples and/or the samples of joint's tissue after the joint replacement therapy in patients with OA could give the initial insight to evaluate our hypothesis. It would be of the particular interest to differentiate the expression of 9 kDa and 15 kDa granulysin forms in the effector cells, since only the shorter form exhibits cytotoxic properties. The measurement of granulysin mediated early apoptosis in human NK sensitive K562 cells could be suitable in vitro model for evaluating granulysin activity. Furthermore, disturbed balance of pro-inflammatory and anti-inflammatory cytokines in OA patients, could influence the level of the granulysin expression. Having in mind that the granulysin and its regulation is still unknown in the pathogenesis of OA, it could be worth to explore this important pro-inflammatory, cytotoxic/apoptotic mediator.

Negative and positive life experiences in patients with psoriatic arthritis.

Recent data suggest that childhood and adulthood stressors may play a significant role in the development of an autoimmune disease. The present study explores the relationship between psoriatic arthritis (PsA) and positive and negative life events during childhood and adulthood in psoriatic patients. Forty-five patients with psoriatic arthritis and 101 controls (patients with skin conditions considered to be "non-psychosomatic") were enrolled in the study. All participants completed a specific questionnaire measuring traumatic life experiences [Traumatic Antecedents Questionnaire (TAQ)]. The TAQ assesses positive personal experiences (competence and safety) and negative personal experiences (neglect, separation, secrets, emotional, physical and sexual abuse, trauma witnessing, other traumas and exposure to alcohol/drugs) from early childhood to adulthood. The patients with psoriatic arthritis exhibited lower mean scores of total positive experiences during late childhood (latency) as compared to the control group. Negative experiences during four developmental periods appeared more frequently in patients with psoriatic arthritis than in the controls. The most frequently reported negative experiences were neglect, emotional abuse, physical abuse, sexual abuse, alcohol/drug abuse and other traumas. The present findings add evidence to the relationship between retrospectively reported childhood experiences and psoriatic arthritis. Furthermore, a high amount of reported emotional and physical abuse occurs in patients with psoriatic arthritis during latency and adolescence.

Analysis of granulysin-mediated cytotoxicity in peripheral blood of patients with psoriatic arthritis.

The objective of the present study was to investigate possible changes in granulysin (GNLY)-mediated cytotoxicity of peripheral blood lymphocytes in psoriatic arthritis (PsA) patients with respect to different phases of the disease. We prospectively enrolled 25 PsA patients in the active phase, 26 PsA patients in remission and 24 healthy controls. The simultaneous detection of intracellular GNLY and cell surface antigens (CD3 and CD56) was performed with flow cytometry. GNLY apoptotic protein was visualised by immunocytochemistry. Natural killer (NK) cell cytotoxicity was analysed with a cytotoxicity assay against human erythroleukaemia K-562 cells. The percentage of GNLY(+) cells did not differ significantly between PsA patients in the acute phase and those in remission; however, it was always higher than in healthy examinees due to the increased percentage of GNLY(+) cells within T cells, NKT cells, and both, and in the CD56(+dim) and CD56(+bright) NK subsets. The mean fluorescence intensity for GNLY was higher in all lymphocyte subpopulations in the acute phase than in remission and in healthy controls. Accordingly, GNLY-mediated NK cell cytotoxicity against K-562 cells of active phase PsA patients was significantly higher than that in patients in remission or in healthy controls. These findings demonstrated the involvement of GNLY in the worsening of PsA and suggested that GNLY mediated the development of joint lesions.

Functional independence, diagnostic groups, hospital stay, and modality of payment in three Croatian seaside inpatient rehabilitation centers.

AIM: To determine patients' functional independence, diagnostic groups, duration of hospital stay, and modality of payment of rehabilitation in major special hospitals for rheumatology and medical rehabilitation on the Croatian seaside. METHODS: In a cross-sectional study conducted from October 2006 until January 2009, we surveyed 400 patients treated at 3 special hospitals for medical rehabilitation. Their functional independence was assessed by modified Barthel index and they self-evaluated their health using the first item from the 36-Item Short-Form Health Survey questionnaire. RESULTS: On admission, almost half of the patients (46%) were fully functionally independent, 33% were slightly dependent, while 21% were moderately or severely dependent. At the end of the hospitalization, significant predictors for the increase in Barthel index were longer hospital stay (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.22), diagnosis of post-procedural musculoskeletal disorders (OR, 4.84; 95% CI, 1.90-10.57), diagnosis of conditions following acute ischemic heart disease (OR, 9.71; 95% CI, 3.40-27.75), and lower Barthel index at admission (OR, 0.96; 95% CI, 0.94-0.97). Of the 97 patients with dorsopathy, 73 (75%) were fully functionally independent and 57 (59%) paid for the treatment either themselves or contributed substantially to the total cost. CONCLUSION: Assessment of patients' functional status is important for the organization of inpatient rehabilitation. Patients with dorsopathy could be targeted as a population for medical tourism in rehabilitation medicine in order to maximize the use of rehabilitation hospitals.

Bowel-associated dermatosis-arthritis syndrome in a patient with appendicitis.

BACKGROUND: Bowel-associated dermatosis-arthritis syndrome (BADAS) is defined by the presence of pustular vasculitic skin lesions usually associated with blind loops of the bowel, either after Billroth II or ileojejunal bypass surgery or caused by a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis. CASE REPORT: A 50-year-old patient is presented with an unusual case of pustulo hemorrhagic vasculitis over the lower arms and legs that appeared ten days before the first symptoms of appendicitis, partially regressed, and reappeared five days after appendectomy. Laboratory tests showed anemia, an elevated erythrocyte sedimentation rate, and C-reactive protein as well as a polyclonal increase in IgG and IgA levels, erythrocyturia and proteinuria. Histopathological examination of a skin biopsy indicated the suspected diagnosis. During hospitalization the patient developed arthropathy with swelling of the metacarpophalangeal and interphalangeal joints and ankles. The patient was treated with systemic antibiotics and corticosteroids, which caused resolution of the symptoms. CONCLUSIONS: This report speculates that appendicitis was the possible cause of BADAS in this case.

Analysis of perforin expression in peripheral blood and lesions in severe and mild psoriasis.

BACKGROUND: Perforin is a membrane-disrupting protein that allows the entry of granzymes into a target cell inducing degradation of target substances in the cytoplasm and nucleus thus leading to programmed cell death or apoptosis. Recent work demonstrated a possible involvement of perforin mediated cytotoxicity in immunopathogenesis of psoriasis. OBJECTIVES: To investigate a difference in systemic (peripheral blood) and local (lesions) expression and distribution of perforin in psoriatic patients with severe and mild disease. METHODS: Flow cytometry was used for simultaneous detection of intracellular (perforin) and cell surface antigens in peripheral blood lymphocytes. The expression of perforin in skin lesions was evaluated by immunohistochemistry. RESULTS: Significant increase of perforin expression in T lymphocytes, especially cytotoxic CD8+ cells was found in severe psoriasis compared to mild disease (p<0.01 and p<0.05, respectively). There was also an increase of CD56+P+ NK cells (p<0.05) in severe compared to mild psoriasis. The psoriatic plaque of both, severe and mild disease were abundant with perforin showing no significant difference on local level. CONCLUSION: Based on our results we suggest the association between perforin expression and disease severity.

SMS 201-995 enhances S-phase block induced by 5-fluorouracil in a human colorectal cancer cell line.

The action of the somatostatin analog SMS-201.995 (SMS) was tested in monotherapy and in combined therapy with the cytotoxic agent 5-fluorouracil (5-FU) on cell cycle kinetics of the human colon cancer cell line WiDr, expressing a mutant p53 (mp53). The data, obtained by flow cytometric DNA analysis, showed that SMS at 0.2 microg/ml increased apoptosis, augmenting the proportion of cells with subdiploid DNA content by 65 and 48% after 3 and 6 h, respectively. In cultures lasting 24 and 36 h, it also decreased the percentages of cells in G0/G1 phase by 22.9 and 14.3%; whereas at a dose of 0.1 microg/ml, SMS decreased the percentage of cells in G2/M by 14.3%. In contrast to SMS, 5-FU (0.1 microg/ml) augmented the apoptosis at 12 h, and markedly increased the fraction of cells in S phase, increasing its value from 24 and 72 h by 108 and 234%, respectively, in comparison to the control. The most evident finding after the combination of SMS (0.2 microg/ml) and 5-FU (0.1 microg/ml) was a potentiation of 5-FU-induced S-phase block by a further 7.9, 12.9 and 42.1% at 24, 36 and 72 h, respectively. Treatment with 5-FU also upregulated HLA class I expression of the cancer cells. In this sense, SMS was less effective and when given in combination with 5-FU did not change the effects induced by 5-FU. The data emphasize that SMS exhibits pro-apoptotic and anti-proliferative effects, which in proper dose combinations might enhance the effects of 5-FU on human colorectal cancer cells expressing mp53.