Curbing the diabetes and tuberculosis co-epidemic: the potential role of China.

China has been playing an increasingly important role in global health in recent decades. Substantial progress and reform has been made in the country's health care system, but China still hosts one third of the world's diabetes mellitus (DM) patients and one fifth of the world's tuberculosis (TB) patients. Recent economic and public health advancements have provided tools for new drug development and facilitated the implementation of novel strategies. However, a unique set of challenges exist, including regulatory barriers, ethical concerns and the lack of a unified system and approaches across disease areas. This article analyses the current disease situation in China and discusses China's potential role in the global battle against the TB and DM co-epidemic.

Conducting high-quality tuberculosis clinical trials in China: opportunities and challenges.

Tuberculosis (TB) is an ancient disease that is a devastating threat to public health. As the country with the second highest number of TB cases and the highest number of multidrug-resistant TB cases in the world, China is now striving to be at the forefront of TB research and drug development. This article is based on the observations made by the authors during the recent partnership initiative between the National Institutes of Health and the Chinese TB community, as well as an extensive literature review. The article examines the advantages and challenges of conducting large-scale international multicenter TB clinical trials in China. China is becoming an excellent location for new TB drug trials, especially in collaboration with international organizations that bring considerable technical assistance, quality control, training, and oversight with these partnerships.

[Pain syndrome of the musculoskeletal system in children and adolescents]. / Schmerzsyndrome des Bewegungsapparates bei Kindern und Jugendlichen.

Chronic pain syndromes in children and adolescents are defined as continuous or recurrent pain without an underlying causative diagnosis and lasting for more than 3 months. It is estimated that every fourth child in Germany suffers from chronic pain with every twentieth suffering from extreme recurrent pain. The incidence of chronic pain in children and adolescents is increasing with headache, abdominal pain and musculoskeletal pain being the most frequent. The quality of life declines not only due to the pain but to relieving postural and psychological factors, such as fear and sadness. School attendance, social activities and hobbies are mostly affected. This review summarizes the background of chronic pain syndromes and introduces a multimodal therapeutic approach.

Fel d 1-derived synthetic peptide immuno-regulatory epitopes show a long-term treatment effect in cat allergic subjects.

BACKGROUND: Cat-PAD, the first in a new class of synthetic peptide immuno-regulatory epitopes (SPIREs), was shown to significantly improve rhinoconjunctivitis symptoms in subjects with cat allergy up to 1 year after the start of a short course of treatment. OBJECTIVE: To evaluate the long-term effects of Cat-PAD on rhinoconjunctivitis symptoms following standardized allergen challenge 2 years after treatment. METHODS: In a randomized, double-blind, placebo-controlled, parallel group study, subjects were exposed to cat allergen in an environmental exposure chamber (EEC) before and after treatment with two regimens of Cat-PAD (either eight doses of 3 nmol or four doses of 6 nmol) given intradermally over a 3-month period. In this follow-up study, changes from baseline in rhinoconjunctivitis symptoms were reassessed 2 years after the start of treatment. RESULTS: The primary endpoint showed a mean reduction in total rhinoconjunctivitis symptom scores of 3.85 units in the 4 × 6 nmol Cat-PAD group compared to placebo 2 years after the start of treatment (P = 0.13), and this difference was statistically significant in the secondary endpoint at the end of day 4 when the cumulative allergen challenge was greatest (P = 0.02). Consistent reductions in nasal symptoms of between 2 and 3 units were observed for 4 × 6 nmol Cat-PAD compared to placebo between the 2 and 3 h time points on days 1-4 of EEC challenge at 2 years (P < 0.05). The 8 × 3 nmol dose did not show a meaningful effect in this study. CONCLUSION AND CLINICAL RELEVANCE: A persistent, clinically meaningful reduction in rhinoconjunctivitis symptoms was observed on EEC challenge 2 years after the start of a short course of treatment with 4 × 6 nmol Cat-PAD. This study is the first to provide evidence of a long-term therapeutic effect with this new class of SPIREs.

Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center.

OBJECTIVES: Growth failure is a permanent sequelae in juvenile idiopathic arthritis (JIA). The aim of the study was to compare pubertal growth in control and growth hormone (GH) treated JIA subjects. DESIGN: 64 children with JIA at a mean age of 10.38 ± 2.80 years were enrolled and followed until final height (measured in standard deviation (SD) scores). 39 children (20 m) received GH therapy and 24 (9 m) served as controls. GH dose was 0.33 mg/kg/week. Linear regression analysis was performed to identify factors influencing total pubertal growth. RESULTS: Mean total pubertal growth was 21.1 ± 1.3 cm (mean ± SD) in GH treated JIA patients and 13.8 ± 1.5 cm in controls. Final height was significantly higher with GH treatment (-1.67 ± 1.20 SD) compared to controls (-3.20 ± 1.84 SD). Linear regression model identified age at onset of puberty (ß=-4.2,CI: -5.9, -2.6 in controls and ß=-2.3,CI: -3.6, -1.1 in GH treated) as the main factor for total pubertal growth. Final height SDS was determined by the difference to target height at onset of puberty (ß=-0.59;CI: -0.80, -0.37 in controls and ß=-0.30,CI: -0.52, -0.08 in GH treated), age at onset of puberty (ß=0.47;CI:0.02,0.93 in controls and 0.23;CI: -0.00,0.46 in GH treated) and height gain during puberty (ß=0.13;CI:0.05,0.21 in controls and ß=0.11;CI:0.07,0.16 in GH treated). CONCLUSION: Total pubertal growth in JIA patients treated with GH was increased by a factor of 1.5 greater in comparison to controls leading to a significantly better final height. To maximize final height GH treatment should be initiated early to reduce the height deficit at onset of puberty.

[Definition, diagnosis and therapy of chronic widespread pain and so-called fibromyalgia syndrome in children and adolescents. Systematic literature review and guideline]. / Definition, Diagnostik und Therapie von chronischen Schmerzen in mehreren Körperregionen und des sogenannten Fibromyalgiesyndroms bei Kindern und Jugendlichen. Systematische Literaturübersicht und Leitlinie.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION: The diagnosis FMS in children and adolescents is not established. In so-called juvenile FMS (JFMS) multidimensional diagnostics with validated measures should be performed. Multimodal therapy is warranted. In the case of severe pain-related disability, therapy should be primarily performed on an inpatient basis. The English full-text version of this article is available at SpringerLink (under "Supplemental").

[Physiotherapy for juvenile idiopathic arthritis]. / Physiotherapie bei der juvenilen idiopathischen Arthritis.

Control of disease activity and recovery of function are major issues in the treatment of children and adolescents suffering from juvenile idiopathic arthritis (JIA). Functional therapies including physiotherapy are important components in the multidisciplinary teamwork and each phase of the disease requires different strategies. While in the active phase of the disease pain alleviation is the main focus, the inactive phase requires strategies for improving motility and function. During remission the aim is to regain general fitness by sports activities. These phase adapted strategies must be individually designed and usually require a combination of different measures including physiotherapy, occupational therapy, massage as well as other physical procedures and sport therapy. There are only few controlled studies investigating the effectiveness of physical therapies in JIA and many strategies are derived from long-standing experience. New results from physiology and sport sciences have contributed to the development in recent years. This report summarizes the basics and main strategies of physical therapy in JIA.

Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110.

BACKGROUND: Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches. METHODS: Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48. RESULTS: Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm. CONCLUSIONS: Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

[Juvenile fibromyalgia syndrome]. / Fibromyalgiesyndrom bei Kindern und Jugendlichen.

OBJECTIVE: The aim was to develop a guideline for diagnostic procedures and treatment of juvenile fibromyalgia syndrome (JFMS) in cooperation with 10 German medical and psychological associations and 2 patient self-help groups. METHODS: A systematic literature search, including all controlled studies evaluating diagnosis and treatment of JFMS, was performed in the Cochran Collaboration Reviews (1993-12/2006), Medline (1980-12/2006), PsychInfo (1966-12/2006) and Scopus (1980-12/2006). Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. Grading of the strengths of recommendations was performed according to the German program for disease management guidelines. Standardized procedures to reach a consensus on recommendations were used. RESULTS: Pain in children/adolescents involving several body areas and lasting >3 months without an obvious somatic cause is called JFMS or pain amplification syndrome. Therapeutically, a multidisciplinary concept with psychotherapy and physiotherapy, relaxation techniques and patient education is recommended. CONCLUSION: These guideline will contribute to a better recognition and standardized care of patients with JFMS and facilitate clinical studies.

[Physiotherapy, exercise and strength training and physical therapies in the treatment of fibromyalgia syndrome]. / Physiotherapie, medizinische Trainingstherapie und physikalische Therapie beim Fibromyalgiesyndrom.

BACKGROUND: A guideline for the treatment and diagnostic procedures for fibromyalgia syndrome (FMS) was developed in cooperation with 10 German medical and psychological associations and 2 patient self-help groups. METHODS: A systematic literature search including all controlled studies evaluating physiotherapy, exercise and strength training as well as physical therapies was performed in the Cochrane Collaboration Reviews (1993-12/2006), Medline (1980-12/2006), PsychInfo (1966-12/2006) and Scopus (1980-12/ 2006). Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. Grading of the strengths of recommendations was done according to the German program for disease management guidelines. Standardized procedures to reach a consensus on recommendations were used. RESULTS: Aerobic exercise training is strongly recommended (grade A) and the temporary use of whole body hyperthermia, balneotherapy and spa therapy is recommended (grade B). CONCLUSION: The significance which can be assigned to most of the studies on the various procedures for therapy is restricted due to short study duration (mean 6-12 weeks) and small sample sizes.

[Structural quality of rheumatology clinics for children and adolescents. Paper by a task force of the "Society of Pediatric and Adolescent Rheumatology" and of the "Association of Rheumatology Clinics in Germany"]. / Strukturqualität von kinder- und jugendrheumatologischen Akutkliniken und -abteilungen. Projektgruppenarbeit der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR) und des Verbandes Rheumatologischer Akutkliniken (VRA).

Rheumatic diseases in childhood and adolescence differ from those of adulthood according to type, manifestation, treatment and course. A specialized therapy, starting as early as possible, improves the prognosis, can prevent long-term damage and saves the costs of long-term care. Only a specialized pediatric care system can guarantee optimum quality of the processes involved and the results for rheumatology in childhood and adolescence within a global financial system. This requires adequate structural quality of the specialized clinics and departments for pediatric rheumatology. The management of rheumatic diseases in childhood and adolescence is comprehensive and requires a multidisciplinary, specialized and engaged team which can cover the whole spectrum of rheumatic diseases with their various age-dependent aspects. In order to guarantee an adequate, cost-efficient routine, a specialized center which concentrates on inpatient care should treat at least 300 patients with pediatric rheumatic diseases per year. The diagnoses should be divided among the various disease categories with at least 70% of them involving inflammatory rheumatic diseases. For the inpatient care of small children, an accompanying person (parent) is necessary, requiring adequate structures and services. Patient rooms as well as diagnostic (radiography, sonography, etc.) and therapeutic services (physiotherapy, occupational therapy, pool, etc.) must be adequate for small children and school children as well as adolescents. Suitable mother-child units must also be provided and a school for patients is required within the clinic. A pediatric rheumatologist must be available 24 h a day, and it must be possible to reach other specialists within a short time. For painful therapeutic procedures, age-appropriate pain management is obligatory. A continuous adjustment of these recommendations to changing conditions in health politics is intended.

Musculoskeletal and functional muscle-bone analysis in children with rheumatic disease using peripheral quantitative computed tomography.

Bone demineralization is a severe complication of juvenile idiopathic arthritis (JIA) and other rheumatic diseases. To identify patients, who are at risk of bone disease, musculoskeletal analysis is performed. Furthermore, a more functional approach is needed to assess, whether bone strength is adequate for muscle force and whether muscle force is adequate for body size. In patients with a chronic disease it is most important to differentiate between primary bone problems and those that are secondary to low muscle force. To implement this approach, we measured musculoskeletal parameters of the radius in 94 patients with juvenile idiopathic arthritis of different subtypes and connective tissue disease using peripheral quantitative computed tomography. The four groups consisted of patients with oligoarticular (n = 31), polyarticular (n = 27), systemic JIA (n = 20) and connective tissue disease (CTD) (n = 16). All patients with systemic JIA and CTD and 56% of the patients with polyarticular JIA were under treatment with glucocorticoids. In general, the longer the duration of the disease and the more severe the subtype of the rheumatic disease, the shorter the height and the lower the bone density and bone strength parameters. Mean height, bone mineral content (BMC) and muscle cross-sectional area (CSA) were low for age, but muscle CSA was normal for height with the exception of patients with polyarticular disease. In the systemic JIA group the ratio of BMC per muscle CSA was decreased by -1.7+/-2.7 SD (P < 0.05), suggesting that bone strength was not adequately adapted to muscle force. This was even more expressed in females than in males (14 versus 3). These patients need closer follow up and potential specific therapeutic intervention.

Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study.

OBJECTIVE: To evaluate the efficacy and safety of growth hormone treatment in severely growth retarded children with juvenile idiopathic arthritis (JIA) receiving glucocorticoids. STUDY DESIGN: Children with systemic and polyarticular idiopathic arthritis (22 F, 16 M) with a mean age of 10.1 years were enrolled in this controlled study. Eighteen patients (9 F, 9M; mean age, 10.5 years) received growth hormone in a dose of 0.20 to 0.33 mg/kg body weight per week for 4 years. Twenty patients (13 F, 7 M; mean age, 9.6 years) served as an untreated control group. RESULTS: Mean improvement in height in the treated group was 1 SD, whereas the patients of the control group lost 0.7 SD. Disease activity markers correlated significantly with the mean growth velocity standard deviation score. In general, children with mild or moderate disease and lower comedication grew and responded better to growth hormone therapy than those with active disease. No adverse events were noted. CONCLUSION: Our data suggest that long-term growth hormone therapy has a beneficial effect in children with severe forms of JIA. Further data are needed to confirm the efficacy and safety of growth hormone and its effect on final height.

The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10.

OBJECTIVE: To test the hypothesis that T cell reactivity to self heat-shock protein 60 (Hsp60) in patients with remitting juvenile idiopathic arthritis (JIA) is part of an antiinflammatory, regulatory mechanism. METHODS: Using peripheral blood-derived mononuclear cells (PBMCs) and synovial fluid-derived mononuclear cells (SFMCs) obtained from patients with JIA, we analyzed the expression of CD30 and the induction of regulatory cytokines in response to human and mycobacterial Hsp60. RESULTS: In oligoarticular JIA patients, in vitro activation of PBMCs and SFMCs with Hsp60 induced a high expression of CD30 on CD4+, activated (HLA-DR-positive), memory (CD45RO+) T cells. The expression of CD30 induced by human Hsp60 was much higher than that induced by mycobacterial Hsp60. In oligoarticular JIA patients with active disease, the expression of CD30 in response to human Hsp60 was paralleled by a high interleukin-10 (IL-10):interferon-gamma (IFNgamma) ratio. In addition, restimulated human Hsp60-specific T cell lines from oligoarticular JIA patients showed a high production of IL-10 and a low production of IFNgamma. In contrast, PBMCs and SFMCs from polyarticular JIA patients responded to human Hsp60 with virtually no expression of CD30 and a low IL-10:IFNgamma ratio. CONCLUSION: The results show that T cells responding to human Hsp60 in oligoarticular JIA patients express CD30, and during active phases of the disease, these T cells have a cytokine profile with a high IL-10:IFNgamma ratio. These findings suggest that in oligoarticular JIA patients, human Hsp60-specific CD4+ cells have a regulatory function and contribute to disease remission.

GH therapy in juvenile chronic arthritis: results of a two-year controlled study on growth and bone.

Disturbance of growth frequently occurs in children suffering from juvenile chronic arthritis (JCA). Recognition of growth impairment is important because reduced final height is one of the permanent consequences. The aim of this study was to evaluate the efficacy and safety of human GH (hGH) in growth-retarded prepubertal children with JCA. Thirty-five children were tested for GH deficiency (GHD) and randomly assigned to a study and an untreated control group; five were GH deficient and were part of the GHD group. All received glucocorticoids. The study group was treated with 1 IU/kg BW.wk hGH; the GHD group was given 0.5 IU. During 2 yr of hGH treatment growth velocity and height SD score increased compared with baseline values. There was a marked increase in growth velocity in the treated groups, but also some increase in the control group. Plasma levels of IGF-I and IGF-binding protein-3 increased with GH treatment. These results suggest that hGH might be useful in the treatment of growth impairment in JCA. GH may counteract the adverse effects of glucocorticoid therapy, but its effect is dependent on the disease activity. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in JCA.

Evaluation of the ILAR criteria for juvenile idiopathic arthritis.

OBJECTIVE: A pediatric rheumatology committee of ILAR has proposed new classification criteria for chronic childhood arthritis. The umbrella term "juvenile idiopathic arthritis (JIA)" was chosen and the disease was subdivided into 7 categories. Evaluation for these criteria is under way. METHODS: We analyzed data of 200 consecutive children with rheumatic diseases. RESULTS: In total 172 patients fulfilled criteria for JIA. Twenty-seven of these (15.7%) had to be grouped into the category "other arthritis": 16 met criteria for 2 categories; the other 11 did not fit into any category. CONCLUSION: We suggest minor changes in the classification in order to classify 24 of these 27 patients into one of the specific categories without losing the claim for homogeneity in the different patient groups. Among the 44 patients with rheumatoid factor negative polyarthritis, 26 resembled oligoarthritis, with an extended oligoarticular joint pattern of 5 to 8 involved joints within the first 6 months. 18 had positive antinuclear antibodies, and 7 chronic uveitis. For these patients the introduction of a separate category "extended oligoarthritis at onset" should be considered to establish comparable patient groups.

Emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome.

In sequential clinical trials of treatment for histoplasmosis in patients with acquired immunodeficiency syndrome, therapy with fluconazole failed in a higher proportion of patients than did therapy with itraconazole. To determine the cause for failure with fluconazole, antifungal susceptibility testing that used modified National Committee on Clinical Laboratory Standards procedures was performed on all baseline and failure isolates. Failure occurred more frequently in patients with baseline isolates with fluconazole minimum inhibitory concentrations (MICs) > or =5 microg/mL versus lower MICs; 29% versus 3%, respectively. There was at least a 4-fold increase in fluconazole MIC in the isolates from 10 (59%) of 17 patients for whom paired pretreatment and failure or relapse isolates were available. Cross-resistance to itraconazole was not seen. In conclusion, fluconazole is less active than itraconazole for Histoplasma capsulatum and induces resistance during therapy, which accounted for treatment failure in some patients.

A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to > 200 x 106 /l.

OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.

CARD15 mutations in Blau syndrome.

We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Our findings indicate that, in addition to Crohn disease, CARD15 is involved in the susceptibility to a second granulomatous disorder.