Divergent Annexin A1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during SIV infection.

HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection

Remission of severe restless legs syndrome and periodic limb movements in sleep after bilateral excision of multiple foot neuromas: a case report

<p>Abstract</p> <p>Introduction</p> <p>Restless legs syndrome is a sensorimotor neurological disorder characterized by an urge to move the legs in response to uncomfortable leg sensations. While asleep, 70 to 90 percent of patients with restless legs syndrome have periodic limb movements in sleep. Frequent periodic limb movements in sleep and related brain arousals as documented by polysomnography are associated with poorer quality of sleep and daytime fatigue. Restless legs syndrome in middle age is sometimes associated with neuropathic foot dysesthesias. The causes of restless legs syndrome and periodic limb movements in sleep are unknown, but the sensorimotor symptoms are hypothesized to originate in the central nervous system. We have previously determined that bilateral forefoot digital nerve impingement masses (neuromas) may be a cause of both neuropathic foot dysesthesias and the leg restlessness of restless legs syndrome. To the best of our knowledge, this case is the first report of bilateral foot neuromas as a cause of periodic limb movements in sleep.</p> <p>Case presentation</p> <p>A 42-year-old Caucasian woman with severe restless legs syndrome and periodic limb movements in sleep and bilateral neuropathic foot dysesthesias was diagnosed as having neuromas in the second, third, and fourth metatarsal head interspaces of both feet. The third interspace neuromas represented regrowth (or 'stump') neuromas that had developed since bilateral third interspace neuroma excision five years earlier. Because intensive conservative treatments including repeated neuroma injections and various restless legs syndrome medications had failed, radical surgery was recommended. All six neuromas were excised. Leg restlessness, foot dysesthesias and subjective sleep quality improved immediately. Assessment after 18 days showed an 84 to 100 percent reduction of visual analog scale scores for specific dysesthesias and marked reductions of pre-operative scores of the Pittsburgh sleep quality index, fatigue severity scale, and the international restless legs syndrome rating scale (36 to 4). Polysomnography six weeks post-operatively showed improved sleep efficiency, a marked increase in rapid eye movement sleep, and marked reductions in hourly rates of both periodic limb movements in sleep with arousal (135.3 to 3.3) and spontaneous arousals (17.3 to 0).</p> <p>Conclusion</p> <p>The immediate and near complete remission of symptoms, the histopathology of the excised tissues, and the marked improvement in polysomnographic parameters documented six weeks after surgery together indicate that this patient's severe restless legs syndrome and periodic limb movements in sleep was of peripheral nerve (foot neuroma) origin. Further study of foot neuromas as a source of periodic limb movements in sleep and as a cause of sleep dysfunction in patients with or without concomitant restless legs syndrome, is warranted.</p

Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer

<p>Abstract</p> <p>Background</p> <p>Understanding what constitutes an important difference on a HRQL measure is critical to its interpretation. The aim of this study was to provide a range of estimates of minimally important differences (MIDs) in EQ-5D scores in cancer and to determine if estimates are comparable in lung cancer.</p> <p>Methods</p> <p>A retrospective analysis was conducted on cross-sectional data collected from 534 cancer patients, 50 of whom were lung cancer patients. A range of minimally important differences (MIDs) in EQ-5D index-based utility (UK and US) scores and VAS scores were estimated using both anchor-based and distribution-based (1/2 standard deviation and standard error of the measure) approaches. Groups were anchored using Eastern Cooperative Oncology Group performance status (PS) ratings and FACT-G total score-based quintiles.</p> <p>Results</p> <p>For UK-utility scores, MID estimates based on PS ranged from 0.10 to 0.12 both for all cancers and for lung cancer subgroup. Using FACT-G quintiles, MIDs were 0.09 to 0.10 for all cancers, and 0.07 to 0.08 for lung cancer. For US-utility scores, MIDs ranged from 0.07 to 0.09 grouped by PS for all cancers and for lung cancer; when based on FACT-G quintiles, MIDs were 0.06 to 0.07 in all cancers and 0.05 to 0.06 in lung cancer. MIDs for VAS scores were similar for lung and all cancers, ranging from 8 to 12 (PS) and 7 to 10 (FACT-G quintiles).</p> <p>Discussion</p> <p>Important differences in EQ-5D utility and VAS scores were similar for all cancers and lung cancer, with the lower end of the range of estimates closer to the MID, i.e. 0.08 for UK-index scores, 0.06 for US-index scores, and 0.07 for VAS scores.</p

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care

<p>Abstract</p> <p>Background</p> <p>Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common.</p> <p>Methods</p> <p>The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms.</p> <p>Results</p> <p>The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS.</p> <p>Conclusion</p> <p>The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.</p

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

Dementia in Swedish Twins: Predicting Incident Cases

Thirty same-sex twin pairs were identified in which both members were assessed at baseline and one twin subsequently developed dementia, at least 3 years subsequent to the baseline measurement, while the partner remained cognitively intact for at least three additional years. Eighteen of the 30 cases were diagnosed with Alzheimer’s disease. Baseline assessments, conducted when twins’ average age was 70.6 (SD = 6.8), included a mailed questionnaire and in-person testing. Which twin would develop dementia was predicted by less favorable lipid values (higher apoB, ratio of apoB to apoA1, and total cholesterol), poorer grip strength, and—to a lesser extent—higher emotionality on the EAS Temperament Scale. Given the long preclinical period that characterizes Alzheimer’s disease, these findings may suggest late life risk factors for dementia, or may reflect changes that are part of preclinical disease