Finite element computation of magneto-hemodynamic flow and heat transfer in a bifurcated artery with saccular aneurysm using the Carreau-Yasuda biorheological model.

"Existing computational fluid dynamics studies of blood flows have demonstrated that the lower wall stress and higher oscillatory shear index might be the cause of acceleration in atherogenesis of vascular walls in hemodynamics. To prevent the chances of aneurysm wall rupture in the saccular aneurysm at distal aortic bifurcation, clinical biomagnetic studies have shown that extra-corporeal magnetic fields can be deployed to regulate the blood flow. Motivated by these developments, in the current study a finite element computational fluid dynamics simulation has been conducted of unsteady two-dimensional non-Newtonian magneto-hemodynamic heat transfer in electrically conducting blood flow in a bifurcated artery featuring a saccular aneurysm. The fluid flow is assumed to be pulsatile, non-Newtonian and incompressible. The Carreau-Yasuda model is adopted for blood to mimic non-Newtonian characteristics. The transformed equations with appropriate boundary conditions are solved numerically by employing the finite element method with the variational approach in the FreeFEM++ code. Hydrodynamic and thermal characteristics are elucidated in detail for the effects of key non-dimensional parameters i.e. Reynolds number (Re = 14, 21, 100, 200), Prandtl number (Pr = 14, 21) and magnetic body force parameter (Hartmann number) (M = 0.6, 1.2, 1.5) at the aneurysm and throughout the arterial domain. The influence of vessel geometry on blood flow characteristics i.e. velocity, pressure and temperature fields are also visualized through instantaneous contour patterns. It is found that an increase in the magnetic parameter reduces the pressure but increases the skin-friction coefficient in the domain. The temperature decreases at the parent artery (inlet) and both the distant and prior artery with the increment in the Prandtl number. A higher Reynolds number also causes a reduction in velocity as well as in pressure. The blood flow shows different characteristic contours with time variation at the aneurysm as well as in the arterial segment. The novelty of the current research is therefore to present a combined approach amalgamating the Carreau-Yasuda model, heat transfer and magnetohydrodynamics with complex geometric features in realistic arterial hemodynamics with extensive visualization and interpretation, in order to generalize and extend previous studies. In previous studies these features have been considered separately and not simultaneously as in the current study. The present simulations reveal some novel features of biomagnetic hemodynamics in bifurcated arterial transport featuring a saccular aneurysm which are envisaged to be of relevance in furnishing improved characterization of the rheological biomagnetic hemodynamics of realistic aneurysmic bifurcations in clinical assessment, diagnosis and magnetic-assisted treatment of cardiovascular disease."

Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from the Italian biologics' register GISEA.

To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics' registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p < 0.0001) and 24 months (52.3 vs 33.3 and 34.4%, respectively; p < 0.01). A similar pattern was observed in later lines. The most common AEs reported were infections, reactions to biologics (more frequent among TNFi-treated patients), increased transaminase (more frequent among TCZ-treated patients), and cardiovascular events. In clinical practice, TCZ induced a rapid and long-lasting remission and in a higher percentage of patients compared to abatacept and TNFi, with a good safety profile.

Fibromyalgia syndrome: preventive, social and economic aspects.

There many open questions concerning the concept of primary prevention in FM. Diagnostic or classification criteria are not universally accepted, and this leads to difficulties in establishing the onset and duration of the disease. In the case of FM, primary prevention may consist of the immediate care of acute pain or treatment for affective disturbances as we do not have any specific laboratory or instrumental tests to determine risk factors of the disease. The goal of secondary prevention is early detection of the disease when patients are largely asymptomatic and intervention improves outcome. Screening allows for identification of an unrecognized disease or risk factor, which, for potential FM patients, includes analysis of tender points, Fibromyalgia Impact Questionnaire (FIQ), pain location and intensity, and fatigue and sleep complaints. Tertiary prevention inhibits further deterioration or reduces complications after the disease has developed. In FM the aim of treatment is to decrease pain and increase function via multimodal therapeutic strategies, which, in most cases, includes pharmacological and non-pharmacological interventions. Patients with FM are high consumers of health care services, and FM is associated with significant productivity-related costs. The degree of disability and the number of comorbidities are strongly associated with costs. An earlier diagnosis of FM can reduce referral costs and investigations, thus, leading to a net savings for the health care sector. However, every social assessment is closely related to the socio-economic level of the general population and to the legislation of the country in which the FM patient resides.

[Early rheumatoid arthritis: a prospective study on how to induce the remission]. / Induzione della remissione delle poliartriti reumatoidi all'esordio: studio prospettico.

OBJECTIVES: To investigate whether the aggressive use of DMARDs can control the clinical disease in the early arthritis, to define new parameters of the disease aggressivity and to study the effectiveness of RMN in comparison with RX focusing on the articular erosions. METHODS: 45 patients having a case of early arthritis (less 6 months) with 3 or more swollen joints were recruited and treated with 80 mg of steroids in order to distinguish persistent arthritis from non persistent ones. Afterward we began to use DMARDs with persistent arthritis and, if it wasn't helpful, we shifted to anti-TNFalpha therapy. The clinical response was valued by SDAI. RESULTS: After 1 year our therapeutic approach showed a remission in 60% of the patients. The 82% of remaining obtained a significant SDAI improvement and only in 3 cases we used anti-TNFalpha due to a persistent high disease activity. Anti-CCp were positive in 46% of patients in remission and in 53% of the rest. The bone erosions were present in 4 patients only and they were detected by RMN, only 2 by RX. CONCLUSIONS: We observed a clinical remission in the 60% of patients treated with aggressive DMARDs. During our trial, anti-CCp weren't predictive about the therapy response. We observed that RMN is more effective than RX in detecting erosions and it's necessary for diagnosis and follow-up of early arthritis.

[Anti-TNFalpha agents in elderly patients with rheumatoid arthritis: a study of a group of 105 over sixty five years old patients]. / I farmaci biologici anti-TNFalpha nel paziente anziano affetto da artrite reumatoide: studio di una coorte di 105 pazienti ultra-sessantacinquenni.

OBJECTIVE: To evaluate the efficacy and the safety of anti-TNF alfa treatment in elderly patients (>/=65 years old) with active rheumatoid arthritis (RA), in comparison with younger (17-65 years old). METHODS: We considered retrospectively 295 patients, affected by RA and treated with anti-TNF alfa drugs. They were divided in two groups, according to their age, and followed up for two years: over-65-years old patients (190) and under-65-years old patients (105). Effectiveness of drugs was assessed analyzing RA disease activity (DAS28, DAS44, SDAI), functional status (HAQ) and serological parameters (CRP) before and after anti-TNF alfa therapy. Safety was studied considering discontinuation rate of biological disease-modifying antirheumatic drugs, and collateral events rate. RESULTS: At baseline, elderly patients showed higher disease activity's score (DAS 28, DAS44, SDAI, HAQ) with important loss of articular function (worse quality of life, HAQ) than younger patients (p<0.05). During the therapy, improvement in clinical parameters was observed (DAS28, DAS44 and SDAI) with no significant difference between the two groups. In elderly patients disability index, on the contrary, improved less than in younger (p<0.05). After treatment, also CRP decreased less in elderly patients (p<0.05). During the follow-up, 74 over-65-years old patients (38.95%) and 116 under-65-years old patients (38.05%) discontinued anti-TNF alfa therapy because of loss of efficacy (20.52% vs 11.42%), severe adverse events (17.34% vs 25.67%), voluntary discontinuation or good clinical response (1% vs 0.95%). No differences were shown about the frequency and reasons of anti-TNF alfa withdrawal (p>0.05). CONCLUSIONS: Anti-TNF alfa treatment was efficacious and safe in both groups of patients. These drugs induced improvement in disease activity, apart from the age. No functional improvement was observed in HAQ, showing the irreversible loss of articular function and the incomplete recovery in elderly patients. Age doesn't interfere with the possibility to treat elderly patients with anti-TNF alfa drugs.

Fibromyalgia syndrome: definition and diagnostic aspects.

Ever since it was first defined, fibromyalgia (FM) has been considered one of the most controversial diagnoses in the field of rheumatology, to the point that not everybody accepts its existence as an independent entity. The sensitivity and specificity of the proposed diagnostic criteria are still debated by various specialists (not only rheumatologists), whose main criticism of the 1990 American College of Rheumatology criteria is that they identify subsets of particular patients that do not reflect everyday clinical reality. Furthermore, the symptoms characterising FM overlap with those of many other conditions classified in a different manner. Over the last few years, this has led to FM being considered less as a clinical entity and more as a possible manifestation of alterations in the psychoneuroendocrine system (the spectrum of affective disorders) or the stress reaction system (dysfunctional symptoms). More recently, doubts have been raised about even these classifications; and it now seems more appropriate to include FM among the central sensitisation syndromes, which identify the main pathogenetic mechanism as the cause of skeletal and extra-skeletal symptoms of FM and other previously defined "dysfunctional" syndromes.

Etiopathogenetic mechanisms of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmental influences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the development of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supports the comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Central sensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, which leads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMS has advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.

Non pharmacological treatments in fibromyalgia.

Fibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and with substantial financial costs. Once the diagnosis is made, providers should aim to increase patients' function and minimize pain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction with and the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present, pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptom control and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjective pain with greater success than monotherapy. Physical therapies, rehabilitation and alternative therapies are generally perceived to be more "natural," to have fewer adverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitive behavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.

Symptoms and signs in fibromyalgia syndrome.

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronic widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completely understood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions. Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervous system; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal, non-musculoskeletal, or a combination of both; and many patients will also experience a host of associated symptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms; but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Several other associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probably a part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) has a significant psychological disturbance. Psychological factors are an important determinant of any type of pain, and psychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, but psychiatric illness is not a necessary factor in the etiopathogenesis of FM.

Fibromyalgia syndrome: the pharmacological treatment options.

Pharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capable of fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definite conclusions concerning the best pharmacological approach to managing FM because results of randomized clinical trials present methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. However, a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. In this review, we will evaluate those pharmacological therapies that have produced the most significant clinical results in treating FM patients. The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and nonpharmacologic therapies seems to be the most appropriate treatment strategy to date.

The evaluation of the fibromyalgia patients.

Fibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11 of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many of the existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by an extensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treating physicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evaluation for all the patients with suspected FM. Functional neuroimaging methods have revealed a large number of supraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are used in FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. To address the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop convened a meeting to develop consensus recommendations for chronic pain clinical trials.

Efficacy and safety of anti-TNF agents in the Lombardy rheumatoid arthritis network (LORHEN).

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damages, which consist of joint destruction. Clinical trials have shown that anti-tumour necrosis factor (TNF) drugs are effective in patients with rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs). At about the same time as the European approval of the third anti-TNF agent for treating rheumatoid arthritis (RA) patients, the Italian Society of Rheumatology (Società Italiana di Reumatologia [SIR]) started a database for the registration and active follow-up of patients with RA treated with biological response modifiers. Since 1999, all patients with RA (ACR criteria) and treated with at least one dose of an anti-TNF agent at four Rheumatology Centres in Lombardy (northwest Italy) have been included in the Lombardy Rheumatology Network (LORHEN) registry in order to track the efficacy and safety of the three available TNF inhibitors during the first three years of treatment.

[Anti-TNFalpha treatment in patients with rheumatoid arthritis and anti-Ro/SSA antibodies]. / Terapia con anti-TNFα in pazienti con artrite reumatoide e anticorpi anti-Ro/SSA.

OBJECTIVE: To analyse clinical efficacy, onset of new autoantibodies or symptoms of autoimmune disease in patients affected by rheumatoid arthritis with anti-Ro/SSA treated with anti-TNFalpha agents. METHODS: Six anti-Ro/SSA positive subjects with RA were studied every six months until 24th month of treatment in order to detect ANA titer (IFI), anti-dsDNA (Farr), anti-cardiolipin and anti-beta2glycoprotein I (ELISA), anti-ENA (CIE). The titre of anti-Ro/SSA were analysed by ELISA. Four patients were diagnosed as overlap RA/SS. RESULTS: Six female patients (mean age 58 ys, SD 9.8 ys), with long-standing RA (mean 7 ys, range 5-22 ys) were treated with anti-TNFalpha agents for a mean of 31 months (SD: 20.4 m): 4 with Infliximab and 2 with Etanercept. All the patients showed a significant reduction of DAS until 24th month (p < 0.006) with stability of sicca symptoms. The titer of ANA and anti-Ro/SSA was stable, while 4 subjects developed anti-dsDNA at low titer within 6-12 months. One patient withdrawn the treatment, because of lupus-like features; another one, with HCV hepatitis, interrupted Etanercept because of elevation of liver enzymes. No anticardiolipin or antibeta2GPI antibodies were detected. One subject with RA-SS also presented a primary biliary cirrhosis: clinical and histological features of cholangitis remained stable during Etanercept treatment. CONCLUSIONS: Anti-TNFalpha treatment showed good efficacy and safety in anti-Ro/SSA positive patients with RA. Anti-ds-DNA antibodies at low titer appeared in most patients while the onset of lupus-like disease could be considered a rare event also in RA patients with a rich autoimmune repertoire.

Neonatal outcome in patients with rheumatic disease.

Rheumatic autoimmune diseases have a higher prevalence in women, particularly during their childbearing age. Due to improved management, an increasing number of patients plan and carry out one or more pregnancies. Therefore, a growing interest is being paid to the possible consequences of maternal disease and associated treatment on the fetus and newborn infant. If maternal disease is characterized by the presence of IgG isotype autoantibodies, these can cross the placenta with possible antibody-mediated damage to the fetus. This is typically the case of the so called neonatal lupus erythematosus (NLE); a similar mechanism has been shown in infants of patients with immune thrombocytopenic purpura (ITP) and, less frequently, in those from mothers with antiphospholipid syndrome (APS). Indeed, this last condition is often responsible for placental, rather than neonatal, pathology. In addition, immunosuppressive and other drugs administered to the mothers during pregnancy and lactation might affect the fetal and neonatal immune system development. Finally, mothers disease and/or treatment could be related to neuropsychological alteration reported in some of their children.

Nonlinear theory of tear film rupture.

Nonlinear thin film rupture has been analyzed by investigating the stability of tear films to finite amplitude disturbances. The dynamics of the liquid film is formulated using the Navier-Stokes equations, including a body force term due to van der Waals attractions. The governing equation was solved by the finite difference method as part of an initial value problem for spatial periodic boundary conditions. The rupture of the tear film covering the cornea and the formation of dry spots is an important phenomenon in various pathological states associated with a dry eye.

Study of spontaneous apoptosis in HIV+ patients: correlation with clinical progression and T cell loss.

In vitro spontaneous apoptosis (SA) of lymphocytes was studied in HIV infection to evaluate possible clinical and prognostic correlations, in a transsectional study of 101 individuals in different clinical categories and in a prospective longitudinal study of 18 asymptomatic individuals (mean follow-up, 17.2 months). The rate of SA was higher in HIV+ patients than in healthy controls (p < 0.001) and was higher in patients with AIDS than in the other HIV+ individuals (p < 0.001). It was inversely correlated with the peripheral blood CD4+ (R -0.61; p < 0.001) and CD8+ (R -0.46; p < 0.001) cell numbers. In a group of long-term survivors (LTS), it was significantly lower than in a control group of asymptomatic HIV+ patients with a similar number of circulating CD4+ lymphocytes but a shorter follow-up (p < 0.02). In the five asymptomatic HIV-infected individuals who showed a clinical progression, peaks of SA rates above the normal range before the clinical event were much more frequent than in those who remained asymptomatic (p < 0.0001), even though they were fairly homogeneous as far as CD4+ cell count and viral load were concerned. The median levels of SA rates were moreover correlated with the rate of total T cell loss (R -0.46; p 0.053). This study suggests that evaluation of the SA levels may provide a predictive factor for clinical and immunological progression of HIV-related immunodeficiencies and strengthen the hypothesis for the role of this phenomenon in the pathogenesis of this progression.

Oligoclonal CD4+ CD57+ T-cell expansions contribute to the imbalanced T-cell receptor repertoire of rheumatoid arthritis patients.

A peculiar feature of rheumatoid arthritis patients is that they carry clonally expanded CD4+ and CD8+ cells in the peripheral blood. While the distortion of the repertoire of CD8+ cells has been ascribed to the increase of CD8+ CD57+ large granular lymphocytes, often detected in these patients, the mechanism responsible for the clonal expansion of CD4+ cells remains unexplained. Here, we report that CD4+ CD57+ cells, that in healthy individuals represent a small subset of peripheral CD4+ lymphocytes, are significantly expanded in the peripheral blood of a considerable percentage of rheumatoid arthritis patients. Furthermore, the expansion of these lymphocytes appears to correlate with the presence of rheumatoid factor. The molecular analysis of the T-cell receptor variable beta segments expressed by the CD4+ CD57+ cells enriched in rheumatoid arthritis patients showed that they use restricted repertoires, that partially overlap with those of their CD4- CD57+ counterpart. The structural feature of the receptor ligand expressed by these cells revealed that their expansion is most likely mediated by strong antigenic pressures. However, since we also found that CD4+ CD57+ and CD4- CD57+ cells can share the same clonal specificity, it is likely that their selection is not mediated by conventional major histocompatibility complex restricted mechanisms. Thus, while our data demonstrate that CD4+ CD57+ cells play an important role in establishing the imbalance of the CD4+ cell repertoire observed in rheumatoid arthritis patients, they also suggest that these cells have common features with mouse CD4+ CD8- NK1.1+/T cells.

Detection of clonal T cell populations with closely related T cell receptor junctional sequences in persons at high risk for human immunodeficiency virus (HIV) infection and in patients acutely infected with HIV.

The T cell repertoires were characterized for CD4+ and CD4 lymphocytes derived from 2 patients with acute human immunodeficiency virus (HIV) infection and from 25 HIV-seronegative persons at high risk for acquiring HIV. Oligoclonal expansions of CD4 cells were detected in the HIV-infected patients and in 2 of 3 uninfected high-risk subjects with a reduced number of CD4+ lymphocytes. Furthermore, nucleotide sequencing revealed that some of the T cell receptor (TCR) beta variable segments (TCRBV), which were highly selected in the high-risk subjects, shared closely related junctional sequences, with the TCRBV predominantly expanded in the HIV-infected patients. Since the likelihood that these similarities occurred by chance is extremely low, these data provide direct molecular evidence in support of several cellular and serologic studies suggesting that some persons remain uninfected despite exposure to HIV.