Clinical analysis and prognostic significance of haemophagocytic lymphohistiocytosis‐associated anaplastic large cell lymphoma in children

Haemophagocytic lymphohistiocytosis (HLH) has been rarely described in children treated for an anaplastic large‐cell lymphoma (ALCL). We evaluated the incidence, the clinical and histological characteristics and the prognosis of HLH associated‐ALCL. The medical, biological, cytological and histological data of patients treated for ALK‐positive ALCL in the paediatric department of a single institution between 1975 and 2008 were analysed and assessed for HLH according to diagnosis criteria of the Histiocyte Society. Data concerning a series of 50 consecutive children with ALCL were reviewed. HLH‐associated ALCL was observed in 12% of the patients. Lung involvement was significantly more frequent in HLH‐associated ALCL patients than in the group without HLH (P = 0·004), as well as central nervous system (CNS) and bone marrow involvement (P = 0·001 and P = 0·007 respectively). The histological subtype in children with HLH‐associated ALCL did not differ from that of the group without HLH. There was no significant difference between the two groups in 5‐year EFS and OS (P = 0·91 and P > 0·99 respectively). In conclusion, HLH is not rare in paediatric ALCL. Despite a high incidence of visceral, CNS and bone marrow involvement, HLH does not seem to exert a significant impact on outcome in children treated for ALCL.     

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.     

The additional value of bioelectrical impedance analysis-derived muscle mass as a screening tool in geriatric assessment for fall prevention

Background: The decline in skeletal muscle in old age is a factor in the development of functional limitations. Objective: The objective of this study was to assess if there is a correlation between muscle mass based on bioelectrical impedance analysis (BIA) detection and the fall incidence in nursing home residents and to examine the risk factors for falling in nursing home residents. Methods: This prospective cohort study was part of a longitudinal study on nutritional issues in 52 nursing homes in Antwerp (Belgium) from October 2007 to April 2008. Two hundred and seventy-six people aged 65 years and older were included. Each subject was assessed with BIA, the timed get-up-and-go test, the Katz score, the Mini Nutritional Assessment - Short Form and the 36-Item Short Form Health Survey. The primary outcome parameter was fall incidence during the study. Results: The prevalence of sarcopenia varied from 24.3 to 81.5% depending on which definition was used. No association was found between BIA-derived muscle mass and fall incidence. Logistic regression analysis showed that gait speed (odds ratio 1.029; p = 0.003) and mental health (odds ratio 0.981; p = 0.015) are significantly associated with fall incidence in nursing homes. A receiver operating characteristic curve showed that none of the BIA-derived muscle parameters are good predictors of the risk of falling. Conclusions: This study shows that there is no association between sarcopenia based on BIA and fall incidence and that BIA-derived muscle mass has no additional value in predicting fall incidents compared to the timed get-up-and-go test.     

Association Between Race, Depression, and Antiretroviral Therapy Adherence in a Low-Income Population with HIV Infection

Background

Racial disparities exist in many aspects of HIV/AIDS. Comorbid depression adds to the complexity of disease management. However, prior research does not clearly show an association between race and antiretroviral therapy (ART) adherence, or depression and adherence. It is also not known whether the co-existence of depression modifies any racial differences that may exist.

Objective

To examine racial differences in ART adherence and whether the presence of comorbid depression moderates these differences among Medicaid-enrolled HIV-infected patients.

Design

Retrospective cohort study.

Setting

Multi-state Medicaid database (Thomson Reuters MarketScan®).

Participants

Data for 7,034 HIV-infected patients with at least two months of antiretroviral drug claims between 2003 and 2007 were assessed.

Main Measures

Antiretroviral therapy adherence (90 % days covered) were measured for a 12-month period. The main independent variables of interest were race and depression. Other covariates included patient variables, clinical variables (comorbidity and disease severity), and therapy-related variables.

Key Results

In this study sample, over 66 % of patients were of black race, and almost 50 % experienced depression during the study period. A significantly higher portion of non-black patients were able to achieve optimal adherence (≥90 %) compared to black patients (38.6 % vs. 28.7 %, p < 0.001). In fact, black patients had nearly 30 % decreased odds of being optimally adherent to antiretroviral drugs compared to non-black patients (OR = 0.70, 95 % CI: 0.63–0.78), and was unchanged regard less of whether the patient had depression. Antidepressant treatment nearly doubled the odds of optimal ART adherence among patients with depression (OR = 1.92, 95 % CI: 1.12–3.29).

Conclusions

Black race was significantly associated with worse ART adherence, which was not modified by the presence of depression. Under-diagnosis and under-treatment of depression may hinder ART adherence among HIV-infected patients of all races.KEY WORDS: HIV, adherence, depression, race, Medicaid     

Continuous efficacy of etanercept in severe and advanced ankylosing spondylitis: results from a 12-week open-label extension of the SPINE study

Objective. To evaluate the longer-term efficacy of etanercept in patients with severe and advanced active AS. Methods. Seventy-seven patients who completed the randomized, double-blind, placebo-controlled 12-week SPINE study enrolled in a 12-week open-label extension and received s.c. etanercept 50?mg once weekly. The etanercept/etanercept group received a total of 24 weeks treatment with etanercept (n?=?38); the placebo/etanercept group received placebo during the double-blind study then 12 weeks' etanercept treatment during the open-label extension (n?=?39). Results. At the end of the open-label extension, BASDAI scores in the etanercept/etanercept group had further decreased beyond reductions observed during the double-blind study [mean (s.d.) change from baseline -37.6 (22.4) at end of extension vs -27.4 (23.8) at end of double-blind study]. Mean (s.d.) BASDAI scores also improved in the placebo/etanercept group once switched to etanercept [-28.6 (24.3) vs -15.0 (20.0)]. Similar trends were observed in BASFI and BASMI scores. In the placebo/etanercept group, total back pain decreased to similar levels achieved in the etanercept group in the double-blind study. Pain levels continued to decrease with longer-term etanercept therapy in the etanercept/etanercept group. Conclusion. Despite the improvements in symptoms and inflammatory markers observed shortly after initiation of once-weekly etanercept, there was no notable plateauing effect on patient-reported outcomes. Indeed, signs and symptoms of severe and advanced active AS continued to improve after up to 24 weeks, treatment with etanercept. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov/ct2/home, NCT00420238.     

Balance control and adaptation of kinematic synergy in aging adults during forward trunk bending

The present study focuses on the organization of kinematic synergy and its adaptation to an unstable support surface during upper trunk movements in aging adults. Seven healthy aging adults (49-66 years old) were instructed to bend the trunk forward (the head and the trunk together) by about 40 degrees and to stabilize their final position, in the standard condition (both feet on the ground), and on a seesaw swinging in the sagittal plane. Kinematic synergy was quantified by performing a principal components analysis on the hip, knee and ankle angle changes during the movement. The results indicate that trunk bending was represented by a single component (PC1) in both conditions, indicating a strong coupling between the angle changes during the movement. The results also show a reorganization of the contribution of PC1 to the three angles when the balance constraints are increased in the seesaw condition. It is concluded that kinematic synergy is preserved during trunk bending in aging adults, regardless of the support conditions. It can also be adapted when the balance constraints are increased by changing the ratio between the angles, indicating a modification of interjoint coordination without modifying the movement's trajectory.     

Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.