Von Willebrand factor: a possible biomarker for disease activity in vasculitis.

OBJECTIVE: Inflammation markers, e.g. C- reactive protein (CRP) and sedimentation rate, can be normal despite active vasculitis. Von Willebrand factor (vWF) is secreted from endothelial cells in response to vascular damage. Some reports suggest increased vWF levels in vasculitis. This study aimed to evaluate vWF serum concentration in vasculitis patients as a possible biomarker of disease activity and to review the current literature. METHOD: Adult patients with systemic vasculitis were prospectively enrolled. Disease activity was recorded using the Birmingham Vasculitis Activity Score (BVAS) version 3. Blood group-adjusted vWF antigen serum level was evaluated at diagnosis and, when available, after treatment. RESULTS: Twenty-five vasculitis patients were compared to 15 healthy controls. The mean age of patients was 56 ± 17 years and 56% were women. Forty percent had anti-neutrophil cytoplasmic autoantibody-associated vasculitis, 20% giant cell arteritis, 16% polyarteritis nodosa, 8% Takayasu arteritis, and the rest had other vasculitides. The mean disease duration was 3.4 ± 4.8 years. Mean vWF was higher in patients with active vasculitis than in healthy controls (212 ± 81% vs 106 ± 26%, p < 0.001). vWF levels directly correlated with BVAS. In 13 patients with active vasculitis who reached remission or low disease activity after treatment, vWF level at follow-up decreased significantly. In three out of five patients who were treated with interleukin-6 inhibitors, vWF was elevated despite normal CRP levels, while vasculitis was clinically active. CONCLUSION: vWF antigen serum level is increased in active vasculitis and could potentially serve as a biomarker for active disease.

Implante endoscópico de mioblastos autólogos en el tratamiento de la incontinencia urinaria de esfuerzo y evaluación de su eficacia en conejos sometidos a esfinterotomía / Endoscopic implantation of autologous myoblasts for stress urinary incontinence and evaluation of its efficacy in sphincterotomized rabbits

Introducción La incontinencia urinaria de esfuerzo (IUE) constituye uno de los problemas de salud con mayor impacto en la vida de las personas. El objetivo del presente trabajo fue desarrollar una terapia para IUE dentro de la ingeniería de tejidos mediante aislamiento y cultivo de mioblastos autólogos (MAC), su implante endoscópico y el estudio de su eficacia en un modelo de incontinencia por esfinterotomía desarrollado en conejos. Materiales y métodos Se utilizaron conejos Nueva Zelanda, machos, sanos. Los animales fueron primero sangrados para obtención del plasma pobre en plaquetas (PPP) y biopsiados para el aislamiento de mioblastos. Posesfinterotomía, fueron divididos en dos grupos: grupo tratado (representado por aquellos animales que recibieron MAC resuspendidos en PPP) y grupo control (representado por aquellos animales que recibieron solo PPP). Se utilizó el punto de presión de pérdida (LPP) para medir la continencia de ambos grupos en diferentes instancias. Los resultados se evaluaron con modelos de regresión lineal jerárquica. Se efectuaron también estudios histológicos sobre los esfínteres de los conejos una vez finalizado el seguimiento. Resultados No se observaron diferencias estadísticamente significativas entre los valores basales de LPP de cada grupo. Los valores posesfinterotomía de ambos grupos estuvieron por debajo del 50% del valor basal, condición necesaria para considerarlos sujetos incontinentes. Los valores posimplante del grupo tratado fueron superiores al 50% del valor basal, permitiendo suponer una recuperación de la continencia. Se observó una diferencia estadísticamente significativa en los valores de LPP entre los dos grupos de tratamiento (p=0,003). El estudio histológico en el grupo tratado reveló islas interconectadas formadas por fibras musculares, mientras que en el grupo control se observó tejido conectivo periférico a la luz de la uretra e infiltrado inflamatorio. Discusión y conclusiones ... (AU)

Introduction Stress urinary incontinence (SUI) is one of the health problems with more impact on patients’ lives. The aim of the present work was to develop a therapy for SUI using tissue engineering by isolation and culture of autologous myoblasts (CAM) followed by endoscopic implantation. We also evaluated the efficacy of this therapy in a rabbit model of incontinence after sphincterotomy. Materials and methods We used healthy male New Zealand rabbits. The animals were first bled to obtain platelet-poor plasma (PPP) and biopsied for myoblast isolation. Post-sphincterotomy, they were divided into two groups: the treatment group (including animals that received CAM resuspended in PPP) and the control group (including animals receiving only PPP). The leak-point pressure (LPP) was used to measure continence in both groups at different time points. The results were evaluated with hierarchical linear regression models. Histological evaluation of the rabbits’ sphincters was also performed at the end of follow-up. Results No statistically significant differences were observed between the baseline LPP values of each group. The post-sphincterotomy values of both groups were below 50% of the baseline value, which was a mandatory condition for incontinence. The post-implantation values of the treatment group were higher than 50% of the baseline value, which led us to assume continence recovery. A statistically significant difference was observed in the LPP values between the two treatment groups (p=0.003). Histological study revealed interconnected islands formed by muscle fibers in the treatment group, and connective tissue surrounding the urethral lumen and inflammatory infiltrate in the control group. Discussion and conclusions The implantation of CAM significantly improved LPP values in the treatment group, and the improvement remained throughout the evaluation period. ... (AU)

Endoscopic implantation of autologous myoblasts for stress urinary incontinence and evaluation of its efficacy in sphincterotomized rabbits.

INTRODUCTION: Stress urinary incontinence (SUI) is one of the health problems with more impact on patients' lives. The aim of the present work was to develop a therapy for SUI using tissue engineering by isolation and culture of autologous myoblasts (CAM) followed by endoscopic implantation. We also evaluated the efficacy of this therapy in a rabbit model of incontinence after sphincterotomy. MATERIALS AND METHODS: We used healthy male New Zealand rabbits. The animals were first bled to obtain platelet-poor plasma (PPP) and biopsied for myoblast isolation. Post-sphincterotomy, they were divided into two groups: the treatment group (including animals that received CAM resuspended in PPP) and the control group (including animals receiving only PPP). The leak-point pressure (LPP) was used to measure continence in both groups at different time points. The results were evaluated with hierarchical linear regression models. Histological evaluation of the rabbits' sphincters was also performed at the end of follow-up. RESULTS: No statistically significant differences were observed between the baseline LPP values of each group. The post-sphincterotomy values of both groups were below 50% of the baseline value, which was a mandatory condition for incontinence. The post-implantation values of the treatment group were higher than 50% of the baseline value, which led us to assume continence recovery. A statistically significant difference was observed in the LPP values between the two treatment groups (p=0.003). Histological study revealed interconnected islands formed by muscle fibers in the treatment group, and connective tissue surrounding the urethral lumen and inflammatory infiltrate in the control group. DISCUSSION AND CONCLUSIONS: The implantation of CAM significantly improved LPP values in the treatment group, and the improvement remained throughout the evaluation period. It may be associated with the consistency of the implant and its stability at the injection site. Longer follow-up studies and human clinical investigations are required to consider CAM implantation as an alternative treatment for stress urinary incontinence.

Burden of early, advanced and metastatic breast cancer in The Netherlands.

BACKGROUND: The aim of this study was to estimate the total economic and health related burden of breast cancer in the Netherlands. METHODS: Data on incidence, prevalence, mortality and survival were extracted from the Dutch National Cancer Registry and were used to calculate the economic and health related burden of breast cancer for overall, DCIS (stage 0), early- (stage I), locally advanced- (stage II-III) and metastatic- (stage IV) breast cancer by age groups and by year (if applicable). RESULTS: The overall incidence of breast cancer increased from 103.4 up to 153.2 per 100,000 women between 1990 and 2014. The increase was driven by DCIS and early breast cancer as the incidence of locally advanced and metastatic breast cancer remained stable. Between 1990 and 2014, ten-year overall survival rates increased from 87% to 93% for early breast cancer, 41% to 62% for locally advanced- and from 6% to 9% for metastatic disease. Annually, breast cancer in the Netherlands is responsible for approximately 3100 deaths, 26,000 life years lost, 65,000 Disability Adjusted Life Years (DALYs) and an economic burden of €1.27 billion. CONCLUSIONS: This study provides a comprehensive assessment of the burden of breast cancer and subsequent trends over time in the Netherlands.

The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: a meta-analysis.

The primary objective of this meta-analysis was to estimate the prevalence of adult community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae in Europe, adjusted for possible independent covariates. Two reviewers conducted a systematic literature search using PubMed on English-language articles that involved human subjects with CAP during the period from January 1990 to November 2011 across European countries. A mixed-effects meta-regression model was developed and populated with 24,410 patients obtained from 77 articles that met the inclusion criteria. The model showed that the observed prevalence of S. pneumoniae in CAP significantly varies between European regions, even after adjusting for explanatory covariates, including patient characteristics, diagnostic tests, antibiotic resistance, and health-care setting. The probability of detecting S. pneumoniae was substantially higher in studies that performed more frequently a diagnostic polymerase chain reaction assay compared to all the other diagnostic tests included. Furthermore, S. pneumoniae was more likely to be confirmed as the cause of a CAP in studies with intensive care unit patients as compared to those with hospital- or community-treated patients. This study provides estimates of the average observed prevalence of S. pneumoniae, which could be used for projecting the health and economic benefits of pneumococcal immunization.

Cost-effectiveness of potential infant vaccination against respiratory syncytial virus infection in The Netherlands.

INTRODUCTION: Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory illness in infants, infecting virtually every child before the age of 2 years. Currently, several Phase 1 trials with RSV vaccines in infants are ongoing or have been completed. As yet, no efficacy estimates are available for these vaccine candidates. Nevertheless, cost-effectiveness estimates might be informative to enable preliminary positioning of an RSV vaccine. METHODS: A decision analysis model was developed in which a Dutch birth cohort was followed for 12 months. A number of potential vaccination strategies were reviewed such as vaccination at specific ages, a two- or three-dosing scheme and seasonal vaccination versus year-round vaccination. The impact of the assumptions made was explored in various sensitivity analyses, including probabilistic analysis. Outcome measures included the number of GP visits, hospitalizations and deaths, costs, quality-adjusted life years and incremental cost-effectiveness ratios (ICERs). RESULTS: Currently, without vaccination, an annual number of 28,738 of RSV-related GP visits, 1623 hospitalizations, and 4.5 deaths are estimated in children in the age of 0-1 year. The total annual cost to society of RSV in the non-vaccination scenario is €7.7 million (95%CI: 1.7-16.7) and the annual disease burden is estimated at 597 QALYs (95%CI: 133-1319). In case all infants would be offered a potentially safe and effective 3-dose RSV vaccination scheme at the age of 0, 1 and 3 months, the total annual net costs were estimated to increase to €21.2 million, but 544 hospitalizations and 1.5 deaths would be averted. The ICER was estimated at €34,142 (95%CI: € 21,652-€ 87,766) per QALY gained. A reduced dose schedule, seasonal vaccination, and consideration of out-of-pocket expenses all resulted in more favorable ICER values, whereas a reduced vaccine efficacy or a delay in the timing of vaccination resulted in less favorable ICERs. DISCUSSION: Our model used recently updated estimates on the burden of RSV disease in children and it included plausible utilities. However, due to the absence of clinical trial data, a number of crucial assumptions had to be made related to the characteristics of potential RSV vaccine. The outcomes of our modeling exercise show that vaccination of infants against RSV might be cost-effective. However, clinical trial data are warranted.

The role of regulatory T cells in familial Mediterranean fever (FMF).

The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 ± 0.4 (0-3). The mean age was 31.6 ± 6.2. The mean age at onset was 9.3 ± 9.3. The mean colchicine dose was 2.6 mg ± 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 ± 2.36 vs. 7.005 ± 0.3 vs. 5.3 ± 1.06 vs. 4.44 ± 1.8; p < 0.05 (Fig.1). The percentage of T-regs in peripheral blood was not statistically different between the four groups. Theexpression of Foxp3 by T-regs increases 7 days after attacks of FMF. Anti-inflammatory cytokines interleukin-10 and TGF-ß are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks.

Modelling the impact of extended vaccination strategies on the epidemiology of pertussis.

The aim of this study was to investigate the optimal pertussis booster vaccination strategy for The Netherlands. A realistic age-structured deterministic model was designed. Assuming a steady-state situation and correcting for underreporting, the model was calibrated using notification data from the period 1996-2000. Several sensitivity analyses were performed to explore the impact of different assumptions for parameters surrounded by uncertainty (e.g. duration of protection after natural infection, underreporting factors, and transmission probabilities). The optimal age of an additional booster dose is in the range of 10-15 years, and implementation of this booster dose will reduce both symptomatic and asymptomatic infections, although the incidence of symptomatic infections in older age groups will increase. The impact of the different assumptions used in the model was in general limited. We conclude that over a wide range of assumptions, an additional booster dose can reduce the incidence of pertussis in the population.

[Intellectual activity and longevity (to memory of academician Vladimir Frol'kis)].

The article presents results of studies. These results show dependence of life expectancy from the social status and intellectual activity. Quality of life of scientists of advanced age in comparison with other pensioners has been analyzed. Continuation of scientific activity became guarantee of their health and longevity.

Excess drug prescriptions during influenza and RSV seasons in the Netherlands: potential implications for extended influenza vaccination.

Influenza and respiratory syncytial virus (RSV) infections are responsible for considerable morbidity, mortality and health-care resource use. For the Netherlands, we estimated age and risk-group specific numbers of antibiotics, otologicals and cardiovascular prescriptions per 10,000 person-years during periods with elevated activity of influenza or RSV, and compared these with peri-season rates. Data were taken from the University of Groningen in-house prescription database (www.iadb.nl) and virological surveillance for the period 1998-2006. During influenza and RSV periods excess antibiotic prescriptions were estimated for all age groups. In the age groups 0-1 and 2-4 years, excess antibiotic prescriptions during periods with elevated RSV activity (65% and 59% of peri-seasonal rates) exceeded the surpluses estimated during the influenza-activity periods (24% and 34% of peri-seasonal rates) while for otologicals excess prescriptions were higher for influenza (22% and 27%) than for RSV (14% and 17%). Among persons of 50 years and older, notably those without medical high-risk conditions, excess prescriptions for cardiovascular medications were estimated during the influenza periods at approximately 10% (this was also already seen in persons aged 45-49). Our results may have implications for influenza vaccination policies. In particular, extension of influenza vaccination to groups of non-elderly adults and young children may lower excess prescriptions during these influenza periods for all three types of drug prescriptions investigated.

Cost-effectiveness estimates for antenatal HIV testing in the Netherlands.

This paper provides an estimation of the lifetime health-care cost of HIV-infected children and an update of the cost-effectiveness of universal HIV-screening of pregnant women in Amsterdam (The Netherlands). During 2003-2005, we collected data concerning the prevalence of newly diagnosed HIV-infected pregnant women in Amsterdam. Also, data on resource utilization and HAART regimen for HIV-infected children was gathered from a national registry. Using Kaplan-Meier survival analysis, we estimated the life-expectancy of a vertically HIV-infected child at 19 years, with the corresponding lifetime health-care costs of 179,974 Euros. HIV-screening of pregnant women could prevent 2.4 HIV transmissions annually in Amsterdam, based on an estimated prevalence of nine yet undiagnosed HIV-positive pregnant women per 10,000 pregnancies. We show that universal HIV screening during pregnancy generates significant net cost savings and health benefits in most situations. Universal antenatal HIV screening is justified in Amsterdam from a health-economic point of view.

[A complex psychological assessment of health care quality of medical personnel and quality of life of four generation of Ukrainians].

The article presents experience of the assessment of labour quality and professionalism of medical personnel (physicians and nurses) after the study conducted in 20 medical institutions in Kiev and 20 in Moscow. Expert-points method of assessment was used, correlation analysis of finalized qualifying assessment and social status of staff in each department was the mechanism of check of obtained results. Quality of life of population depends a lot on professionalism of specialists (physicians, teachers, scientists and others). The article presents results of four year (2003-2006) study of quality of life of four generations of Ukrainians aged from 11 to 85 years. Regularity was revealed in different sides of life of four group of responders, including personal, behavioral and psychological aspects.

Behcet disease in adult Druzes in north Israel: the influence of ethnic origin on disease expression and severity.

BACKGROUND: Behcet's disease (BD) is known to vary in severity and manifestations in different populations. OBJECTIVE: In an attempt to sort out genetic and environmental influences on disease expression, we carried out a study to assess the clinical features of BD in the adult Druze and Arab populations in north Israel, comparing 2 disparate ethnic groups of similar genetic background inhabiting the same geographic region. METHODS: We compared 23 Druze and 30 Arab patients with BD. All patients fulfilled the classification criteria of the International Study Group for BD. RESULTS: Manifestations were similar in 2 groups. The most frequent BD manifestations among the Druzes were recurrent oral aphthae (100%) and genital aphthae (61%) versus 100% and 53% in Arab patients, followed by inflammatory ocular involvement, 65% versus 53%, respectively. Arthritis was noted in 39% of Druze, with 27% in Arabs. Anterior uveitis occurred in 9 Druze patients (48%) and panuveitis in 4, with no case of blindness when compared with 30% with anterior uveitis, 4 with panuveitis, and 4 cases of blindness (P < 0.04) among the Arabs. One Druze BD patient had deep vein thrombosis versus 8 Arab patients (P < 0.017). No pulmonary embolism, aortic aneurysm, nor valvular involvement was documented in the Druze versus 1 case of each in Arabs. No case of neuro-Behcet was reported in Druzes versus 6 cases of neuro-Behcet among Arabs (P < 0.023). The severity score was 4.0 (SD, 1.2) in Druze and 5.8 (SD, 1.9) in Arabs (P = 0.0004). The prevalence of HLA B51 did not differ significantly between the groups. CONCLUSION: Druze BD patients in Israel have a milder disease than do Arabs, similar to observations in familial Mediterranean fever. Druze BD patients had significantly less severe ocular disease and neurologic manifestations. Our results suggest an ethnic influence on expression of BD not related to HLA B 51.

Changes in macrophage function after rituximab treatment in patients with rheumatoid arthritis.

OBJECTIVE: To assess changes in macrophage phenotype and function after rituximab-induced B cell depletion in patients with rheumatoid arthritis (RA). METHODS: 10 patients with RA were treated with rituximab, achieving significant B cell depletion 4 months later. Clinical improvement, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, mRNA of B cell activating factor (BAFF), interleukin (IL) 10 and CD86 in human monocyte-derived macrophages (HMDMs) and tumour necrosis factor alpha (TNFalpha) secretion from cultured HMDMs were assessed at baseline and after the depletion. RESULTS: A clinical response of American College of Rheumatology (ACR) 50% improvement was noted in six patients, and another two patients responded with moderate improvement, equivalent to ACR 20-50% improvements. RF and anti-CCP antibodies were positive at baseline in seven of ten patients. RF disappeared or declined in six patients 4 months after treatment, correlating with clinical improvement. By contrast, anti-CCP remained unchanged in six patients. After rituximab treatment, and in association with clinical improvement, BAFF, IL10 and CD86 mRNA expression in HMDM were significantly upregulated compared with values at baseline. A significant decrease in TNFalpha in the supernatant of cultured HMDM was also noted. CONCLUSIONS: In addition to B cell depletion and attenuation in some of the specific autoantibodies, clinical improvement in rituximab-treated patients with RA occurred in association with changes in macrophage function.

Elevated serum B-Lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity.

In this study we aimed to determine whether serum B-lymphocyte activating factor (BAFF) level is increased in patients with chronic hepatitis C virus (HCV) infection, and to assess its association with HCV-related autoimmunity. Sixty-five patients with chronic HCV infection were compared with two disease control groups [57 patients with systemic lupus erythematosus (SLE) and 15 with chronic hepatitis B virus (HBV) infection] and a healthy control group of 35 individuals. A special attention was given to HCV-related arthralgia and or vasculitis. Serum BAFF was assessed in all studied individuals, whereas rheumatoid factor (RF), anti-cardiolipin antibodies (aCL), and cryoglobulins were determined in HCV and HBV infected patients, and anti-dsDNA antibodies and aCL were assessed in patients with SLE. Mean serum BAFF was increased in patients with HCV infection and SLE (2.4+/-0.8 ng/ml and 3.1+/-1.34 ng/ml respectively) compared to 1.1+/-0.14 ng/ml in patients with HBV; and to 1.1+/-0.27 in healthy controls (all, p<0.0001). The elevation in serum BAFF was associated with HCV-related arthralgia and or vasculitis (p<0.0001), and with the presence of aCL and of cryoglobulins. HBV patients lacked features suggestive of autoimmunity. In SLE patients, elevated serum BAFF was in association with the presence of anti-dsDNA (p=0.002). As in other autoimmune diseases, increased serum BAFF was also found in patients with chronic HCV infection. Elevated serum BAFF levels were associated with clinical and laboratory features of autoimmunity, suggesting that BAFF may play a role in HCV-related autoimmunity.

The emergency room in systemic rheumatic diseases.

Complications of systemic rheumatic diseases frequently have protean manifestations and may present a diagnostic problem. Patients with connective tissue diseases and vasculitides may have dangerous or life threatening conditions, which must be recognised and treated promptly to prevent rapidly evolving morbidity and mortality. Knowledge of possible emergencies in the context of a defined rheumatic disease may aid in promoting a high index of suspicion and contribute significantly to the timely diagnosis of many potentially dangerous conditions. This review is written for the emergency room physician and discusses the early recognition of selected emergencies in the context of a defined rheumatic disease.