Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents

Background & Aims: This multi-center study aimed to prospectively evaluate the safety and efficacy of a genotype-based Pegylated Interferon alfa-2a/Ribavirin therapy in treatment-naive hepatitis C virus (HCV), positive HCV serology, and quantifiable HCV RNA, infected children. Methods: Eighteen children with genotypes 2 and 3 patients (group A) were assigned to medication for 24 weeks, and 47 children with genotypes 1, 4, 5 and 6 patients (group B) for 48 weeks. Results: Early response at week 12 was observed in 83% of group A patients and in 57% of group B patients (p <0.05). End of treatment response was achieved in 94% of patients in group A and in 57% in group B (p <0.001). Sustained virologic response was maintained in 89% of patients in group A and in 57% of patients in group B (p <0.01). Ten patients stopped prematurely the treatment, 2 for serious adverse event (acute hepatitis and thyrotoxicosis), and 8 because of no virologic response at week 24. Peginterferon alfa-2a and Ribavirin dose was adjusted in 15 patients (23%), 11 for neutropenia (17%), and 3 patients (5%), for anemia, respectively. Treatment-related adverse events included fever and flu-like symptoms (54%), irritability depression change of mood (34%), vomiting (23%), abdominal pain (38%), loss of appetite (21.5%) and dermatitis (29%). No influence on height growth was observed. Conclusions: Pegylated inteferon alfa-2a and Ribavirin treatment allowed to achieve SVR in 57% of pediatric patients with genotypes 1, 4, 5 and 6, and in 94% of genotypes 2 and 3. These results show an improved SVR as compared to reference series in adults with similar regimen. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Subchronic effects of nasally instilled diesel exhaust particulates on the nasal and airway epithelia in mice

Diesel exhaust is the major source of ultrafine particles released during traffic-related pollution. Subjects with chronic respiratory diseases are at greater risk for exacerbations during exposure to air pollution. This study evaluated the effects of subchronic exposure to a low-dose of diesel exhaust particles (DEP). Sixty male BALB/c mice were divided into two groups: (a) Saline: nasal instillation of saline (n = 30); and (b) DEP: nasal instillation of 30 mu g of DEP/10 mu l of saline (n = 30). Nasal instillations were performed 5 days a week, over 30 and 60 days. Animals were anesthetized with pentobarbital sodium (50 mg/kg intraperitoneal [i.p.]) and sacrificed by exsanguination. Bronchoalveolar lavage (BAL) fluid was performed to evaluate the inflammatory cell count and the concentrations of the interleukin (IL)-4, IL-10, and IL-13 by enzyme-linked immunosorbent assay (ELISA). The gene expression of oligomeric mucus/gel-forming (Muc5ac) was evaluated by real-time polymerase chain reaction (PCR). Histological analysis in the nasal septum and bronchioles was used to evaluate the bronchial and nasal epithelium thickness as well as the acidic and neutral nasal mucus content. The saline group (30 and 60 days) did not show any changes in any of the parameters. However, the instillation of DEP over 60 days increased the expression of Muc5ac in the lungs and the acid mucus content in the nose compared with the 30-day treatment, and it increased the total leukocytes in the BAL and the nasal epithelium thickness compared with saline for 60 days. Cytokines concentrations in the BAL were detectable, with no differences among the groups. Our data suggest that a low-dose of DEP over 60 days induces respiratory tract inflammation.

Chronic polyarthritis as the first manifestation of juvenile systemic lupus erythematosus patients

Objective: To evaluate the prevalence of chronic polyarthritis in juvenile systemic lupus erythematosus (JSLE) and to describe the manifestations, treatments, and outcomes in these patients. Methods: From January 1983 to July 2010, 5419 patients were followed up at the Pediatric Rheumatology Unit of the University Hospital and 271 (5%) of them had JSLE (American College of Rheumatology [ACR] criteria). `Rhupus` was classified as the overlap of juvenile idiopathic arthritis (International League of Associations for Rheumatology [ILAR] criteria) and JSLE. We evaluated demographic data, polyarthritis and other clinical manifestations, disease activity and damage, laboratory exams, radiographic findings, treatments, and outcomes. Results: The prevalence of chronic polyarthritis in this JSLE population was 2.6% (7/271). This articular involvement was the initial manifestation in all seven JSLE patients. The median duration of chronic polyarthritis was 11 months (range 2-15 months). Interestingly, rhupus with chronic polyarthritis and limitation of movement, presence of rheumatoid factor, autoantibodies, and/or radiographic abnormalities (juxtaarticular osteopenia, joint-space narrowing, or erosions) was evidenced in three patients. No patient had deformities of hands and feet associated with Jaccoud`s arthropathy or osteonecrosis. All patients were treated with nonsteroidal anti-inflammatory drugs (NSAIDs, naproxen 10-15 mg/kg/day) when polyarthritis diagnosis was established. Prednisone and antimalarials were administered at JSLE diagnosis. The three non-responsive rhupus patients were treated in conjunction with immunosuppressive drugs (methotrexate, azathioprine, and/or cyclosporine). Conclusions: Chronic polyarthritis was a rare lupus manifestation in active pediatric patients. The interesting overlap between chronic arthritis and lupus, called rhupus suggests a new entity with a different clinical profile and a poor response to treatment with NSAIDs alone. In addition, the occurrence of this association in JSLE patients could be classified as a clinical sub-group of JSLE with possible specific genetic determinants. Lupus (2011) 20, 960-964.

Salbutamol improves markers of epithelial function in mice with chronic allergic pulmonary inflammation

We investigated the effects of salbutamol on the markers of epithelial function in a murine model of chronic allergic pulmonary inflammation by recording the ciliary beat frequency (CBF) and the transepithelial potential difference (PD) in vivo. Mice were sensitized and received four challenges of ovalbumin (OVA group) or 0.9% saline (control group). Forty-eight hours after the 4th inhalation, we observed eosinophilia in the bronchoalveolar lavage and epithelium remodeling with stored acid mucus in the OVA group (P < 0.001). No difference in the baseline CBF was noticed between the groups; however, the OVA group had a significantly lower baseline PD (P = 0.013). Salbutamol increased the CBF in all groups studied, and the dose response curve to salbutamol increased the PD in the OVA group from 10(-4) M to 10(-2) M. We suggest that salbutamol affects the CBF and the depth of the periciliary layer, which, in great part, determines the ability of the cilia to propel the mucus layer. This effect may have a positive impact on airway mucociliary transport in asthma and may have clinical implications. (C) 2011 Elsevier B.V. All rights reserved.

Allergic rhinitis in the child and associated comorbidities

Allergic rhinitis (AR) typically presents after the second year of life, but the exact prevalence in early life is unknown. AR affects 10-30% of the population, with the greatest frequency found in children and adolescents. It appears that the prevalence has increased in the pediatric population. As the childs` immune system develops between the 1st and 4th yr of life, those with an atopic predisposition begin to express allergic disease with a clear Th(2) response to allergen exposure, resulting in symptoms. In pediatric AR, two or more seasons of pollen exposure are generally needed for sensitization, so allergy testing to seasonal allergens (trees, grasses, and weeds) should be conducted after the age of 2 or 3 years. Sensitization to perennial allergens (animals, dust mites, and cockroaches) may manifest several months after exposure. Classification of AR includes measurement of frequency and duration of symptoms. Intermittent AR is defined as symptoms for < 4 days/wk or < 4 consecutive weeks. Persistent AR is defined as occurring for more than 4 days/wk and more than 4 consecutive weeks. AR is associated with impairments in quality of life, sleep disorders, emotional problems, and impairment in activities such as work and school productivity and social functioning. AR can also be graded in severity - either mild or moderate/severe. There are comorbidities associated with AR. The chronic effects of the inflammatory process affect lungs, ears, growth, and others. AR can induce medical complications, learning problems and sleep-related complaints, such as obstructive sleep apnea syndrome and chronic and acute sinusitis, acute otitis media, serous otitis media, and aggravation of adenoidal hypertrophy and asthma.

Nutritional knowledge, eating attitudes and chronic dietary restraint among men with eating disorders

We compared nutritional knowledge, eating attitudes and chronic dietary restraint scores among 17 men (10 with bulimia nervosa and 7 with anorexia nervosa) and 50 women (20 with bulimia nervosa and 30 with anorexia nervosa), who were consecutive patients at a major treatment center in Brazil. There were no differences in nutritional knowledge and concern with food between men and women. For both genders, chronic dietary restraint scores were higher among bulimics. Men with eating disorders had better eating attitudes scores than women. Anorexic men tended to have worse eating attitudes scores than bulimic men, while the opposite was observed for women, suggesting an interaction between gender and diagnosis. (C) 2009 Published by Elsevier Ltd.

Phototherapy Promotes Healing of Chronic Diabetic Leg Ulcers That Failed to Respond to Other Therapies

Objective: We tested the hypothesis that combined 660 and 890 nm LED phototherapy will promote healing of diabetic ulcers that failed to respond to other forms of treatment. Research Design and Methods: A double-blind randomized placebo controlled design was used to study 23 diabetic leg ulcers in two groups of 14 patients. Group one ulcers were cleaned, dressed with 1% silver sulfadiazine cream and treated with ""placebo"" phototherapy (<1.0 J cm(-2)) twice per week, using a Dynatron Solaris 705 (R) device. Group two ulcers were treated similarly but received 3 J cm(-2) dose. Results: At each of 15,30,45,60,75, and 90 days of healing, mean ulcer granulation and healing rates were significantly higher for group two than the ""placebo"" group (P < 0.02). While ""placebo"" treated ulcers worsened during the initial 30 days, group two ulcers healed rapidly; achieving 56% more granulation and 79.2% faster healing by day 30, and maintaining similarly higher rates of granulation and healing over the ""placebo"" group all through. By day 90, 58.3% of group two ulcers had healed fully and 75% had achieved 90-100% healing. In contrast, only one ""placebo"" treated ulcer healed fully by day 90; no other ulcer attained >90% healing. Conclusion: Combined 660 and 890 nm light promotes rapid granulation and healing of diabetic ulcers that failed to respond to other forms of treatment. Lasers Surg. Med. 41:433-441, 2009. (C) 2009 Wiley-Liss, Inc.

Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey

Degenerative aortic valve disease (DAVD), a common finding in the elderly, is associated with an increased risk of death due to cardiovascular causes. Taking advantage of its longitudinal design, this study evaluates the prevalence of DAVD and its temporal associations with long-term exposure to cardiovascular risk factors in the general population. We studied 953 subjects (aged 25-74 years) from a random sample of German residents. Risk factors had been determined at a baseline investigation in 1994/95. At a follow-up investigation, 10 years later, standardized echocardiography determined aortic valve morphology and aortic valve area (AVA) as well as left ventricular geometry and function. At the follow-up study, the overall prevalence of DAVD was 28%. In logistic regression models adjusting for traditional cardiovascular risk factors at baseline age (OR 2.0 [1.7-2.3] per 10 years, P < 0.001), active smoking (OR 1.7 [1.1-2.4], P = 0.009) and elevated total cholesterol levels (OR 1.2 [1.1-1.3] per increase of 20 mg/dL, P < 0.001) were significantly related to DAVD at follow-up. Furthermore, age, baseline status of smoking, and total cholesterol level were significant predictors of a smaller AVA at follow-up study. In contrast, hypertension and obesity had no detectable relationship with long-term changes of aortic valve structure. In the general population we observed a high prevalence of DAVD that is associated with long-term exposure to elevated cholesterol levels and active smoking. These findings strengthen the notion that smoking cessation and cholesterol lowering are promising treatment targets for prevention of DAVD.

Serotonin and Sensitivity to Trauma-Related Exposure in Selective Serotonin Reuptake Inhibitors-Recovered Posttraumatic Stress Disorder

Background: Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for posttraumatic stress disorder (PTSD). Serotonergic (5HT) attenuation of stress sensitivity is postulated from SSRIs` effects in other anxiety disorders, and we studied this in PTSD. Methods: Ten patients with PTSD fully recovered on SSRIs (Clinical Global Impression Scale-I 1 and 2) were enrolled in the study. Patients were tested on two occasions I week apart; in each session, they received a drink containing large neutral amino acids (LNAAs) either with (sham tryptophan depletion [STD], control) or without (acute tryptophan depletion [ATD]) tryptophan. At 5.5 hours after the drink, subjects were exposed to a trauma-related exposure challenge. Self-reports of PTSD (visual analogue scales [VAS] and the Davidson Trauma Scale [DTSI), anxiety (Spielberger State Inventory [STAI] Form Y-1), and mood (Profile of Mood States [POMS]) were obtained. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure were also measured. Results: The trauma-related exposure challenge induced anxiety on both days, with more marked responses on the ATD day according to VAS, DTS, POMS, and DBP (p < .05). A trend of significance (.1 > p >.05) was observed for STAI Form Y-1, HR, and SBP. Conclusions: These data demonstrate that ATD accentuates responses to trauma-related stimuli in SSRI-recovered PTSD. They also suggest that SSRI-induced increases in serotonin function restrain PTSD symptoms, especially under provocation, supporting a role for serotonin in mediating stress resilience.

Home blood pressure monitoring in paediatric chronic hypertension

Blood pressure (BP) measurement is the basis for the diagnosis and management of arterial hypertension. The aim of this study was to compare BP measurements performed in the office and at home (home blood pressure monitoring, HBPM) in children and adolescents with chronic arterial hypertension. HBPM was performed by the patient or by his/her legal guardian. During a 14-day period, three BP measurements were performed in the morning or in the afternoon (daytime measurement) and in the evening (night-time measurement), with 1-min intervals between measurements, totalling six measurements per day. HBPM was defined for systolic blood pressure (SBP) and diastolic blood pressure (DBP) values. HBPM was evaluated in 40 patients (26 boys), mean age of 12.1 years (4-18 years). SBP and DBP records were analysed. The mean differences between average HBP and doctor`s office BP were 0.6 +/- 14 and 4 +/- 13 mm Hg for SBP and DBP, respectively. Average systolic HBPM (daytime and night-time) did not differ from average office BP, and diastolic HBPM (daytime and night-time) was statistically lower than office BP. The comparison of individual BP measurements along the study period (13 days) by s.d. of differences shows a significant decline only for DBP values from day 5, on which difference tends to disappear towards the end of the study. Mean daytime and night-time SBP and DBP values remained stable throughout the study period, confirming HBPM as an acceptable methodology for BP evaluation in hypertensive children and adolescents. Journal of Human Hypertension (2009) 23, 464-469; doi:10.1038/jhh.2008.167; published online 12 March 2009

Prognostic heterogeneity among patients with chronic stable coronary disease: determinants of long-term mortality after treatment with percutaneous intervention

Aims: To evaluate the risk and predictors of death in a large population of patients with stable coronary disease treated with percutaneous intervention. Methods and results: The study population comprised 1,276 patients with chronic angina or silent ischaemia who underwent elective coronary angioplasty. Baseline and in-hospital mortality data were prospectively collected for all patients during the index hospitalisation. Post-discharge outcome was assessed at out-patient clinic, by review of the patients` records, or direct phone contact. Deaths were classified as cardiac and non-cardiac. Age, peripheral arterial disease, congestive heart failure with NYHA class Ill, triple-vessel disease, and procedural success (i.e. angiographic success for all lesions in the absence of pen-procedural infarction) remained as multivariate independent predictors of death. For the entire population 4-year cumulative all-cause and cardiac mortality were respectively 5.4% and 4.1%. Four-year mortality for patients without any multivariate predictor was 2.4%, while for patients with two or more predictors the death rate was 16.3% after four years. Conclusions: Patients with stable coronary disease undergoing percutaneous treatment have an overall low mortality rate after four years. Nevertheless, stable patients comprise a heterogeneous population in terms of risk profile, ranging from patients at very low risk of late death to individuals with a poor long-term prognosis.

Mild chronic kidney dysfunction and treatment strategies for stable coronary artery disease

Objective: Our objective was to evaluate the association of chronic kidney dysfunction in patients with multi-vessel chronic coronary artery disease, preserved left ventricular function, and the possible interaction between received treatment and cardiovascular events. Methods: The glomerular filtration rate was determined at baseline on 611 patients who were randomized into three treatment groups: medical treatment, percutaneous coronary intervention, and coronary artery bypass surgery. Incidence of myocardial infarction, angina requiring a new revascularization procedure, and death were analyzed during 5 years in each group. Results: Of 611 patients, 112 (18%) were classified as having normal renal function, 349 (57%) were classified as having mild dysfunction, and 150 (25%) were classified as having moderate dysfunction. There were significant differences among the cumulative overall mortality curves among the three renal function groups. Death was observed more frequently in the moderate dysfunction group than the other two groups (P < .001). Interestingly, in patients with mild chronic kidney dysfunction, we observed that coronary artery bypass treatment presented a statistically higher percentage of event-free survival and lower percentage of mortality than did percutaneous coronary intervention or medical treatment Conclusions: Our results confirm that coronary artery disease accompanied by chronic kidney dysfunction has a worse prognosis, regardless of the therapeutic strategy for coronary artery disease, when renal function is at least mildly impaired. Additionally, our data suggest that the different treatment strategies available for stable coronary artery disease may have differential beneficial effects according to the range of glomerular filtration rate strata.

Protein disulfide isomerase overexpression in vascular smooth muscle cells induces spontaneous preemptive NADPH oxidase activation and Nox1 mRNA expression: Effects of nitrosothiol exposure

Mechanisms regulating NADPH oxidase remain open and include the redox chaperone protein disulfide isomerase (PDI). Here, we further investigated PDI effects on vascular NADPH oxidase. VSMC transfected with wild-type PDI (wt-PDI) OF PDI mutated in all four redox cysteines (mut-PDI) enhanced (2.5-fold) basal cellular ROS production and membrane NADPH oxidase activity, with 3-fold increase in Nox1, but not Nox4 mRNA. However, further ROS production, NADPH oxidase activity and Nox1 mRNA increase triggered by angiotensin-II (AngII) were totally lost with PDI overexpression, suggesting preemptive Nox1 activation in such cells. PDI overexpression increased Nox4 mRNA after AngII stimulus, although without parallel ROS increase. We also show that Nox inhibition by the nitric oxide donor GSNO is independent of PDI. PDI silencing decreased specifically Nox1 mRNA and protein, confirming that PDI may regulate Nox1 at transcriptional level in VSMC. Such data further strengthen the role of PDI as novel NADPH oxidase regulator. (C) 2009 Elsevier Inc. All rights reserved.

Oral tolerance attenuates airway inflammation and remodeling in a model of chronic pulmonary allergic inflammation

We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1-5 mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P < 0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P < 0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics. (C) 2008 Elsevier B.V. All rights reserved.

Influence of Single-Nucleotide Polymorphisms on C-Reactive Protein Levels in Chronic Kidney Disease Before and After Kidney Transplantation

Introduction. We sought to evaluate 2 sing] e-nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene promoter region for their effects on CRP levels in chronic kidney disease (CKD) patients before and after a successful kidney transplantation. Methods. Fifty CKD patients were evaluated before and at the first and second years after the graft. Two SNPs were studied, a bi-allelic (G -> A) at the -409 and a tri-allelic (C -> T -> A) variation at the -390 position in the CRP gene. Results. All patients presented the -409GG genotype. At the -390 position, the ""A"" allele was not found; there were 15 ""CC"" patients, 11 ""TT"" patients, and 24 ""CT"" patients. CRP levels were different among patients with various genotypes (P < .019). Also the presence of the allele ""T"" was sufficient to determine differences in CRP levels both in pretransplantation (P = .045) and at 1 year posttransplantation (P = .011), but not at the second year (P = .448). Conclusion. SNPs at the -390 position of the CRP gene promoter region influence CRP basal levels in such a way that the ""C"" allele correlated with the lowest and the ""T"" with the highest. We did not observe this influence in our patients at the second year posttransplantation.