C7a, a biphosphinic cyclopalladated compound, efficiently controls the development of a patient-derived xenograft model of adult T cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd(2) [S(-)C(2), N-dmpa](2) (μ-dppe)Cl(2)}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.     

Identification of the most common problems by patients with ankylosing spondylitis using the international classification of functioning, disability and health

OBJECTIVE: The International Classification of Functioning, Disability and Health (ICF) aims to classify functioning and health by a number of categories divided over 3 components: body functions and body structures, participation and activities, and environmental factors. We identified the common health problems of patients with ankylosing spondylitis (AS) based on the ICF from the perspective of the patient. METHODS: During structured interviews with the extended ICF checklist, trained assessors collected data from 111 patients with AS. ICF categories identified by more than 5% of the patients as at least mildly impaired or restricted were selected. Categories identified by less than 5% were removed. Additional impairments/restrictions reported by more than 5% of the patients, after the structured interviews and not yet included in the checklist, were added. RESULTS: One hundred nineteen (72%) out of 165 categories of the extended ICF checklist were identified to be at least mildly impaired or restricted. Within each of the 4 components of the ICF, at least one-third of the categories were impaired or restricted for more than 50% of the patients. Thirty-nine (33%) categories were related to movement and mobility. Within the component "environmental factors" the categories "support of immediate family" and "health professionals" were the most important facilitators, "climate" was the most important barrier. Eight impairments were additionally mentioned as relevant. These were hierarchically lower levels of ICF categories previously included and they were added. CONCLUSION: One hundred twenty-seven ICF categories represent the comprehensive classification of functioning in AS from the patients' perspective. The results underscore the need to address the 4 ICF components when classifying functioning and to emphasize that functioning implies more than physical functioning.     

Physical disability due to musculoskeletal conditions

Musculoskeletal conditions (MSC) are common throughout the world and their impact on individuals is diverse and manifold. Knowledge of the determinants for disability and of strategies for prevention and rehabilitation management according to the scientific evidence is critical for reducing the burden of MSC. The first section of this chapter reviews the evidence for common determinants of functioning and disability in patients with MSC. We have focussed on environmental factors (EF) and personal factors (PF) and have structured them according to the International Classification of Functioning, Disability and Health (ICF) framework. The second section discusses prevention strategies. Generally, prevention needs to address those EF and PF that were presented in the first section. The final section describes modern principles of rehabilitation and reviews the evidence for specific rehabilitation interventions.     

Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities

OBJECTIVE: To discuss the concepts of the minimal clinically important difference (MCID) and the smallest detectable difference (SDD) and to examine their relation to required sample sizes for future studies using concrete data of the condition-specific Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the generic Medical Outcomes Study 36-Item Short Form (SF-36) in patients with osteoarthritis of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention. METHODS: SDD and MCID were determined in a prospective study of 122 patients before a comprehensive inpatient rehabilitation intervention and at the 3-month followup. MCID was assessed by the transition method. Required SDD and sample sizes were determined by applying normal approximation and taking into account the calculation of power. RESULTS: In the WOMAC sections the SDD and MCID ranged from 0.51 to 1.33 points (scale 0 to 10), and in the SF-36 sections the SDD and MCID ranged from 2.0 to 7.8 points (scale 0 to 100). Both questionnaires showed 2 moderately responsive sections that led to required sample sizes of 40 to 325 per treatment arm for a clinical study with unpaired data or total for paired followup data. CONCLUSION: In rehabilitation intervention, effects larger than 12% of baseline score (6% of maximal score) can be attained and detected as MCID by the transition method in both the WOMAC and the SF-36. Effects of this size lead to reasonable sample sizes for future studies lying below n = 300. The same holds true for moderately responsive questionnaire sections with effect sizes higher than 0.25. When designing studies, assumed effects below the MCID may be detectable but are clinically meaningless.     

Inpatient rehabilitation for hip or knee osteoarthritis: 2 year follow up study

OBJECTIVE: To examine the course of pain, physical function, and other health dimensions after a comprehensive inpatient rehabilitation intervention in patients with osteoarthritis (OA) of the hip or knee. METHODS: An observational, prospective cohort study with assessments at baseline (entry into clinic), 1 (discharge from inpatient rehabilitation), 3, 6, 9, 12, and 24 months after baseline. Consecutively referred patients to an inpatient rehabilitation centre fulfilling the inclusion criteria were studied. 3-4 week comprehensive rehabilitation intervention, including strengthening exercise, flexibility training, endurance training, relaxation strategies, and consultations for preventive measures, was carried out. Individual home rehabilitation programmes were taught. Generic health status was measured using the SF-36, condition specific health was measured with the WOMAC questionnaire. Effects were analysed with sensitivity statistics (effect size, ES) and non-parametric tests. RESULTS: Data from 128 patients with complete follow up data were analysed. Both pain and physical function improved moderately (WOMAC pain: ES = 0.56, WOMAC function ES = 0.44) until discharge. Although the effect in pain reduction remained significant by month 24 (WOMAC: ES = 0.26), physical function deteriorated close to baseline values after 12 months. CONCLUSIONS: Comprehensive inpatient rehabilitation of patients with OA of the hip or knee may improve pain and physical function in the mid-term, and pain in the long term.     

In Vitro free radical production in rat esophageal mucosa induced by nicotine

Oxidative stress induced by nicotine was investigated in the esophageal mucosa of rats. The homogenized mucosa was incubated for 30 min with 50, 100, 200, 400, and 800 ng/mg protein/ml nicotine or with 200 ng/mg protein/ml nicotine for 15, 30, 45, and 60 min. Esophageal mucosa was also incubated for 30 min with 200 ng/mg protein/ml nicotine with or without the scavengers superoxide dismutase (SOD), catalase, SOD + catalase, inactivated SOD, inactivated catalase, or albumin. Incubation with 0.9% NaCl served as control. There was a strong correlation between chemiluminescence and the nicotine dose (r=0.75) or the nicotine incubation time (r=0.77). Thirty-minute incubation of the esophageal mucosa with 200 ng/mg protein/ml nicotine increased chemiluminescence 5.5-fold and lipid peroxidation 3.3-fold. This response was dampened by SOD or catalase and abolished by SOD + catalase. Inactivated enzymes or albumin had no scavenging effect. These results demonstrate that nicotine causes oxidative stress to the esophageal mucosa.     

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR. Addition of geranylgeranyl pyrophosphate (GG-PP), but not of farnesyl pyrophosphate (F-PP), was able to inhibit simvastatin-induced CAM-DR reversal. Our data suggest that the 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)/GG-PP/Rho/Rho-kinase pathway mediates CAM-DR and that targeting this pathway may improve the efficacy of antimyeloma therapies by reduction of CAM-DR.     

Towards an ICF Core Set for chronic musculoskeletal conditions: commonalities across ICF Core Sets for osteoarthritis,rheumatoid arthritis,osteoporosis, low back pain and chronic widespread pain

The objective of the study was to identify commonalities among the International Classification of Functioning, Disability and Health (ICF) Core Sets of osteoarthritis (OA), osteoporosis (OP), low back pain (LBP), rheumatoid arthritis (RA) and chronic widespread pain (CWP). The aim is to identify relevant categories for the development of a tentative ICF Core Set for musculoskeletal and pain conditions. The ICF categories common to the five musculoskeletal and pain conditions in the Brief and Comprehensive ICF Core Sets were identified in three steps. In a first step, the commonalities across the Brief and Comprehensive ICF Core Sets for these conditions were examined. In a second and third step, we analysed the increase in commonalities when iteratively excluding one or two of the five conditions. In the first step, 29 common categories out of the total number of 120 categories were identified across the Comprehensive ICF Core Sets of all musculoskeletal and pain conditions, primarily in the component activities and participation. In the second and third step, we found that the exclusion of CWP across the Comprehensive ICF Core Sets increased the commonalities of the remaining four musculoskeletal conditions in a maximum of ten additional categories. The Brief ICF Core Sets of all musculoskeletal and pain conditions contain four common categories out of a total number of 62 categories. The iterative exclusion of a singular condition did not significantly increase the commonalities in the remaining. Based on our analysis, it seems possible to develop a tentative Comprehensive ICF Core Set across a number of musculoskeletal conditions including LBP, OA, OP and RA. However, the profile of functioning in people with CWP differs considerably and should not be further considered for a common ICF Core Set.     

Selection of Patients with Gastroesophageal Reflux Disease for Antireflux Surgery Based on Esophageal Manometry

Gastroesophageal reflux disease (GERD) is caused by a mechanically defective lower esophageal sphincter (LES) and may be worsened by impaired esophageal peristalsis. The aim of this study was to evaluate the efficacy of medical treatment depending on the function of the LES and esophageal peristalsis. We studied 128 GERD patients with mild esophagitis. Group 1 (N = 26) consisted of patients with a normal LES and normal esophageal peristalsis. Group 2 (N = 63) comprised patients with a defective LES but normal peristalsis. Patients of group 3 (N = 39) had a defective LES as well as impaired esophageal peristalsis. The patients were continuously treated with omeprazole. Clinical evaluation and endoscopy were repeated after 3, 6, and 12 months. Recurrence of GERD was diagnosed if there was relapse of heartburn and/or esophagitis. The recurrence rate was 7.7% in group 1, 38.1% in group 2 (P < 0.05) and 79.5% in group 3 (P < 0.05). In conclusion, in GERD patients with a mechanically defective LES, especially in those with deteriorated esophageal peristalsis, antireflux surgery should be considered since medical therapy reveals a high recurrence rate.     

Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term follow-up.

OBJECTIVES: The purpose of this study was to evaluate retrospectively a single-center experience with the use of ICDs in patients with long QT syndrome (LQTS) concerning outcome, complications, and optimal programming. BACKGROUND: Use of implantable cardioverter-defibrillator (ICD) in patients with congenital LQTS is controversial but is generally accepted in high-risk patients. METHODS: We enrolled 27 symptomatic patients with LQTS undergoing ICD therapy (QTc 540 +/- 64 ms(1/2); 85% female, 63% cardiac arrest; 33% syncope despite beta-blockers; 4% with severe phenotype) and 81 genotyped patients with LQTS undergoing conventional drug therapy (28 LQT1, 39 LQT2, 1 LQT3, 13 LQT5). During a mean follow-up of 65 +/- 34 months, one death occurred in the ICD group that was not LQTS related. A total of 178 appropriate shocks were observed in 10/27 patients (37%), mostly in survivors of cardiac arrest (in 58% of cardiac arrest patients vs. in 20% of non-cardiac arrest patients). RESULTS: In a logistic regression analysis, only QTc interval (121/178 shocks (68%) for QTc > 500 ms(1/2)) and "survived cardiac arrest" were prognostic for ICD shocks. In 30% of patients in the ICD group, multiple shocks occurred and could be reduced after increase of antibradycardia pacing rate, adding beta-blocker therapy, or starting the rate-smoothing algorithm (average 7.1 shocks before to 0.75 shocks after additional intervention annually). CONCLUSION: ICD therapy is a safe and useful tool in high-risk patients with LQTS. QTc interval and cardiac arrest survivors were prognostic factors for appropriate ICD shocks. The results of this large single-center experience suggest that beta-blockers should always be added to ICD therapy. In addition, some patients might benefit from additional antibradycardia pacing, prolonged detection time, and a rate-smoothing algorithm to prevent recurrent episodes.