Calorie Restriction Attenuates Terminal Differentiation of Immune Cells

Immune senescence is a natural consequence of aging and may contribute to frailty and loss of homeostasis in later life. Calorie restriction increases healthy life-span in C57BL/6J (but not DBA/2J) mice, but whether this is related to preservation of immune function, and how it interacts with aging, is unclear. We compared phenotypic and functional characteristics of natural killer (NK) cells and T cells, across the lifespan, of calorie-restricted (CR) and control C57BL/6 and DBA/2 mice. Calorie restriction preserves a naïve T cell phenotype and an immature NK cell phenotype as mice age. The splenic T cell populations of CR mice had higher proportions of CD11a-CD44locells, lower expression of TRAIL, KLRG1, and CXCR3, and higher expression of CD127, compared to control mice. Similarly, splenic NK cells from CR mice had higher proportions of less differentiated CD11b-CD27+cells and correspondingly lower proportions of highly differentiated CD11b+CD27-NK cells. Within each of these subsets, cells from CR mice had higher expression of CD127, CD25, TRAIL, NKG2A/C/E, and CXCR3 and lower expression of KLRG1 and Ly49 receptors compared to controls. The effects of calorie restriction on lymphoid cell populations in lung, liver, and lymph nodes were identical to those seen in the spleen, indicating that this is a system-wide effect. The impact of calorie restriction on NK cell and T cell maturation is much more profound than the effect of aging and, indeed, calorie restriction attenuates these age-associated changes. Importantly, the effects of calorie restriction on lymphocyte maturation were more marked in C57BL/6 than in DBA/2J mice indicating that delayed lymphocyte maturation correlates with extended lifespan. These findings have implications for understanding the interaction between nutritional status, immunity, and healthy lifespan in aging populations

Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

Access to Sterile Syringes through San Francisco Pharmacies and the Association with HIV Risk Behavior among Injection Drug Users

Increased options for syringe acquisition and disposal have been associated with reductions in high-risk behaviors. This study determined the extent of pharmacy uptake in accessing syringes among injection drug users (IDUs) and estimated associations between pharmacy uptake and safer injection/disposal practices. Two years after the implementation of California’s Disease Prevention Demonstration Project, which removed restrictions to non-prescription syringe sales through pharmacies with local authorization, IDUs were recruited through street outreach in San Francisco and interviewed regarding recent syringe acquisition, use, and disposal. The sample of 105 persons included a high proportion of men (67%), people of color (49%), and homeless persons (71%). The most common syringe source was a syringe exchange program (SEP) (80%), with pharmacies being accessed by 39% of respondents. The most commonly cited source of disposal was a SEP (65%), with very few reports of pharmacy disposal (2%). Adjusted analysis showed that unsuccessful attempts to purchase syringes at a pharmacy increased the odds of both injecting with a used syringe and giving away a used syringe. Using a SEP decreased the odds of unsafe injection and disposal practices. Thus, 2 years after the initiation of the California Disease Prevention Demonstration Project, results from this small study suggest that SEPs still provide the majority of syringe distribution and disposal services to San Francisco IDUs; however, pharmacies now augment syringe access. In addition, unsafe injection behavior is reported more often among those who do not use these syringe sources. These results are consistent with prior studies in suggesting that increasing the availability of syringes through SEPs and pharmacies, and developing bridges between them, may further reduce syringe-related risk

Clinical implications of having reduced mid forced expiratory flow rates (FEF25-75), independently of FEV1, in adult patients with asthma

INTRODUCTION:FEF25-75 is one of the standard results provided in spirometry reports; however, in adult asthmatics there is limited information on how this physiological measure relates to clinical or biological outcomes independently of the FEV1 or the FEV1/FVC ratio. PURPOSE:To determine the association between Hankinson's percent-predicted FEF25-75 (FEF25-75%) levels with changes in healthcare utilization, respiratory symptom frequency, and biomarkers of distal airway inflammation. METHODS:In participants enrolled in the Severe Asthma Research Program 1-2, we compared outcomes across FEF25-75% quartiles. Multivariable analyses were done to avoid confounding by demographic characteristics, FEV1, and the FEV1/FVC ratio. In a sensitivity analysis, we also compared outcomes across participants with FEF25-75% below the lower limit of normal (LLN) and FEV1/FVC above LLN. RESULTS:Subjects in the lowest FEF25-75% quartile had greater rates of healthcare utilization and higher exhaled nitric oxide and sputum eosinophils. In multivariable analysis, being in the lowest FEF25-75% quartile remained significantly associated with nocturnal symptoms (OR 3.0 [95%CI 1.3-6.9]), persistent symptoms (OR 3.3 [95%CI 1-11], ICU admission for asthma (3.7 [1.3-10.8]) and blood eosinophil % (0.18 [0.07, 0.29]). In the sensitivity analysis, those with FEF25-75% <LLN had significantly more nocturnal and persistent symptoms, emergency room visits, higher serum eosinophil levels and increased methacholine responsiveness. CONCLUSIONS:After controlling for demographic variables, FEV1 and FEV1/FVC, a reduced FEF25-75% is independently associated with previous ICU admission, persistent symptoms, nocturnal symptoms, blood eosinophilia and bronchial hyperreactivity. This suggests that in some asthmatics, a reduced FEF25-75% is an independent biomarker for more severe asthma

Accuracy of magnetic resonance studies in the detection of chondral and labral lesions in femoroacetabular impingement : systematic review and meta-analysis

Background: Several types of Magnetic resonance imaging (MRI) are commonly used in imaging of femoroacetabular impingement (FAI), however till now there are no clear protocols and recommendations for each type. The aim of this meta-analysis is to detect the accuracy of conventional magnetic resonance imaging (cMRI), direct magnetic resonance arthrography (dMRA) and indirect magnetic resonance arthrography (iMRA) in the diagnosis of chondral and labral lesions in femoroacetabular impingement (FAI). Methods: A literature search was finalized on the 17th of May 2016 to collect all studies identifying the accuracy of cMRI, dMRA and iMRA in diagnosing chondral and labral lesions associated with FAI using surgical results (arthroscopic or open) as a reference test. Pooled sensitivity and specificity with 95% confidence intervals using a random-effects meta-analysis for MRI, dMRA and iMRA were calculated also area under receiver operating characteristic (ROC) curve (AUC) was retrieved whenever possible where AUC is equivocal to diagnostic accuracy. Results: The search yielded 192 publications which were reviewed according inclusion and exclusion criteria then 21 studies fulfilled the eligibility criteria for the qualitative analysis with a total number of 828 cases, lastly 12 studies were included in the quantitative meta-analysis. Meta-analysis showed that as regard labral lesions the pooled sensitivity, specificity and AUC for cMRI were 0.864, 0.833 and 0.88 and for dMRA were 0.91, 0.58 and 0.92. While in chondral lesions the pooled sensitivity, specificity and AUC for cMRI were 0.76, 0.72 and 0.75 and for dMRA were 0.75, 0.79 and 0.83, while for iMRA were sensitivity of 0.722 and specificity of 0.917. Conclusions: The present meta-analysis showed that the diagnostic test accuracy was superior for dMRA when compared with cMRI for detection of labral and chondral lesions. The diagnostic test accuracy was superior for labral lesions when compared with chondral lesions in both cMRI and dMRA. Promising results are obtained concerning iMRA but further studies still needed to fully assess its diagnostic accuracy

Perception of limb orientation in the vertical plane depends on center of mass rather than inertial eigenvectors

We performed two experiments to test the hypothesis that the perception of limb orientation depends on inertial eigenvectors (

Microparticle-mediated transfer of the viral receptors CAR and CD46, and the CFTR channel in a CHO cell model confers new functions to target cells

Cell microparticles (MPs) released in the extracellular milieu can embark plasma membrane and intracellular components which are specific of their cellular origin, and transfer them to target cells. The MP-mediated, cell-to-cell transfer of three human membrane glycoproteins of different degrees of complexity was investigated in the present study, using a CHO cell model system. We first tested the delivery of CAR and CD46, two monospanins which act as adenovirus receptors, to target CHO cells. CHO cells lack CAR and CD46, high affinity receptors for human adenovirus serotype 5 (HAdV5), and serotype 35 (HAdV35), respectively. We found that MPs derived from CHO cells (MP-donor cells) constitutively expressing CAR (MP-CAR) or CD46 (MP-CD46) were able to transfer CAR and CD46 to target CHO cells, and conferred selective permissiveness to HAdV5 and HAdV35. In addition, target CHO cells incubated with MP-CD46 acquired the CD46-associated function in complement regulation. We also explored the MP-mediated delivery of a dodecaspanin membrane glycoprotein, the CFTR to target CHO cells. CFTR functions as a chloride channel in human cells and is implicated in the genetic disease cystic fibrosis. Target CHO cells incubated with MPs produced by CHO cells constitutively expressing GFP-tagged CFTR (MP-GFP-CFTR) were found to gain a new cellular function, the chloride channel activity associated to CFTR. Time-course analysis of the appearance of GFP-CFTR in target cells suggested that MPs could achieve the delivery of CFTR to target cells via two mechanisms: the transfer of mature, membrane-inserted CFTR glycoprotein, and the transfer of CFTR-encoding mRNA. These results confirmed that cell-derived MPs represent a new class of promising therapeutic vehicles for the delivery of bioactive macromolecules, proteins or mRNAs, the latter exerting the desired therapeutic effect in target cells via de novo synthesis of their encoded proteins