Relation Between Genetic Factors and Frailty in Older Adults

ObjectivesFrailty is a geriatric syndrome that identifies individuals at higher risk of disability, institutionalization, and death. We previously reported that frailty is related to oxidative stress and cognitive impairment-related biomarkers. The aim of this study was to determine whether frailty is associated with genetic variants.DesignLongitudinal population-based cohort of 2488 community-dwelling people from Toledo, Spain, aged 65 years or older.Setting and participantsWe obtained blood samples from 78 individuals with frailty and 74 nonfrail individuals who were nonfrail (according to Fried criteria) from the Toledo Study of Healthy Ageing and extracted DNA using the Chemagic DNA blood kit.MeasuresSample genotyping was carried out by means of Axiom Exome 319 Genotyping Array (Thermo Fisher Scientific), which contains 295,988 markers [single-nucleotide polymorphisms (SNPs) and rare variants], and transferred to the GeneTitan Instrument (Affymetrix).ResultsWe found 15 SNPs (P < .001), 18 genes (P < .005), and 4 pathways (P < .05) related to cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, regulation of autophagy, and renin-angiotensin system as the most strongly associated with frailty.Conclusions/ImplicationsThe specific genetic features related to energy metabolism, biological processes regulation, cognition, and inflammation highlighted by this preliminary analysis offer useful insights for finding biologically meaningful biomarkers of frailty that allow early diagnosis and treatment. Further research is needed to confirm our novel findings in a larger population. Indeed, the EU-funded FRAILOMICS research effort will address this question.     

Main and interactive effects of inflammation and perceived neighbourhood cohesion on psychological distress: results from a population-based study in the UK

Quality of Life Research - Low neighbourhood cohesion and increased levels of inflammation are independent predictors of psychological distress. In this study we explored if they also interact to...     

Evaluation of different strategies to promote a protective immune response against leptospirosis using a recombinant LigA and LigB chimera

Leptospirosis is a zoonosis of worldwide distribution, caused by infection with pathogenic Leptospira species. The vaccines that are currently available are bacterins, with limited human use, that confer short-term, serovar-specific immunity. Lig proteins are considered to be the best vaccine candidates to date. Here, we aimed to construct a recombinant Lig chimera (LC) comprised of LigAni and LigBrep fragments, and to evaluate it as subunit or DNA vaccine using different administration strategies. Vaccines were formulated with 50?µg of recombinant LC associated with different adjuvants or with 100?µg of pTARGET/LC. Four-week-old hamsters received two doses of vaccine with different strategies and were challenged with 5?×?DL₅₀ Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130. The immune response generated by Lig chimera conferred 100% protection to hamsters treated with at least one dose of recombinant LC. Despite the high levels of antibodies that vaccinated animals produced, a sterilizing immunity was not achieved. The lack of a sterilizing immunity could indicate the importance of a mixed humoral and cellular immune response. The present study generated insights that will be useful in the future development of improved subunit vaccines against leptospirosis.     

A systematic review of adult tetanus-diphtheria-acellular (Tdap) coverage among healthcare workers

During the last decades pertussis incidence raised globally. Several vaccination strategies targeting adults to reduce pertussis among young infants have been proposed, including vaccination of healthcare workers (HCWs). The aim of this study was to analyse, by performing a systematic review of literature, published papers that evaluated Tdap coverage among HCWs, variables associated with vaccine uptake and efforts implemented to raise vaccination rates. We searched the MedLine, Embase, SCOPUS, LILACS, Web of Science and Cochrane for full-text studies that evaluated Tdap coverage in HCW. Two independent reviewers screened the articles and extracted the data. Twenty-eight studies published from 2009 to 2018 were reviewed. Most studies were conducted in the USA. Initial Tdap coverage varied from 6.1% to 63.9%. USA and France are the only two countries with studies evaluating Tdap coverage within HCWs using national data. In the USA, Tdap coverage in HCWs raised from 6.1% to 45.1% from 2007 to 2015. In the analysis of French national data, a Tdap coverage of 63.9% was observed. Five studies used interventions to raise Tdap coverage in HCWs. Two intervention studies implemented mandatory vaccination and three used educational strategies. All of them achieved coverages over 86%. Only eleven studies analysed the association of Tdap vaccination with variables of interest. Previous immunization with other vaccines recommended for HCWs (like influenza, hepatitis B and MMR) was positively associated with Tdap uptake in four studies. In conclusion, overall Tdap coverage among HCWs is low, but seems to increase over the years after the vaccine introduction and with implementation of interventions to increase coverage.     

A method for determining groups in multiple survival curves

Survival analysis includes a wide variety of methods for analyzing time-to-event data. One basic but important goal in survival analysis is the comparison of survival curves between groups. Several nonparametric methods have been proposed in the literature to test for the equality of survival curves for censored data. When the null hypothesis of equality of curves is rejected, leading to the clear conclusion that at least one curve is different, it can be interesting to ascertain whether curves can be grouped or if all these curves are different from each other. A method is proposed that allows determining groups with an automatic selection of their number. The validity and behavior of the proposed method was evaluated through simulation studies. The applicability of the proposed method is illustrated using real data. Software in the form of an R package has been developed implementing the proposed method.     

The effects of a sensitisation campaign on unrecognised migraine: the Casilino study

A striking feature of migraine is the difference between the estimated migraine prevalence and the actual number of migraineurs consulting their general practitioners (GPs). We investigated the impact of a sensitisation campaign on migraine in a large cohort of patients, living in a district of Rome. The study involved 10 GPs and a population of about 12 000 people, contacted by mail and posters located in GP clinics. Both the letter and poster stressed the impact of headache on quality of life and included the Italian version of the three-item Identification of Migraine (ID Migraine) screening test, consisting of questions on disability, nausea and photophobia. If the subjects suffered from headaches, they were invited to contact their GPs for a visit and a free consultation with a headache expert. By means of this sensitisation campaign, 195 headache patients consulted their GPs. Ninety-two percent of them (n=179) were migraineurs; 73% of them had never consulted a physician for headache. The ID Migraine test had a sensitivity of 0.92 (95% CI 0.86–0.95), a specificity of 0.75 (95% CI 0.47–0.91) and a positive predictive value (PPV) of 0.97 (95% CI 0.93–0.99) for a clinical diagnosis of migraine, according to the International Headache Society (IHS) criteria. This study confirms that a large number of migraine patients never see a doctor for their headache. This awareness campaign is likely to identify the severest cases of undiagnosed migraineurs. However, mailing campaigns do not seem to be so effective in bringing undiagnosed migraine patients into the primary care setting, and more efficient strategies have to be planned.     

Manganese‐induced downregulation of astroglial glutamine transporter SNAT3 involves ubiquitin‐mediated proteolytic system

SNAT3 is a major facilitator of glutamine (Gln) efflux from astrocytes, supplying Gln to neurons for neurotransmitter synthesis. Our previous investigations have shown that, in primary cortical astrocyte cultures, SNAT3 protein is degraded after exposure to manganese (Mn²⁺). The present studies were performed to identify the processes responsible for this effect. One of the well‐established mechanisms for protein‐level regulation is posttranslational modification via ubiquitination, which leads to the rapid degradation of proteins by the 26S proteasome pathway. Here, we show that astrocytic SNAT3 directly interacts with the ubiquitin ligase, Nedd4‐2 (neural precursor cells expressed developmentally downregulated 4‐2), and that Mn²⁺ increases both Nedd4‐2 mRNA and protein levels. Additionally, we have found that Mn²⁺ exposure elevates astrocytic ubiquitin B mRNA expression, free ubiquitin protein levels, and total protein ubiquitination. Furthermore, Mn²⁺ effectively decreases astrocytic mRNA expression and the phosphorylation of serum and glucocorticoid‐inducible kinase, a regulatory protein, which, in the active phosphorylated form, is responsible for the phosphorylation and subsequent inactivation of Nedd4‐2. Additional findings establish that Mn²⁺ increases astrocytic caspase‐like proteolytic proteasome activity and that the Mn²⁺‐dependent degradation of SNAT3 protein is blocked by the proteasome inhibitors, N‐acetyl‐leu‐leu‐norleucinal and lactacystin. Combined, these results demonstrate that Mn²⁺‐induced SNAT3 protein degradation and the dysregulation of Gln homeostasis in primary astrocyte cultures proceeds through the ubiquitin‐mediated proteolytic system. © 2010 Wiley‐Liss, Inc.     

Focal liver diseases in neonatal and pediatric liver transplant candidates: a pictorial essay

Caruso S, Mamone G, Marrone G, Milazzo M, Carollo V, Miraglia R, Maruzzelli L, Pasta A, Minervini MI, Spada M, Riva S, Luca A, Gridelli B. Focal liver diseases in neonatal and pediatric liver transplant candidates: a pictorial essay.
Clin Transplant 2009: DOI: 10.1111/j.1399‐0012.2009.01139.x
© 2009 John Wiley & Sons A/S. Abstract: The aim of this review is to present the wide spectrum of common and uncommon focal liver diseases affecting neonatal and pediatric liver transplant candidates, analyzed using ultrasonography (US), 16‐ or 64‐multidetector row helical CT (MDCT) and 1.5‐T magnetic resonance (MR) fast imaging. Correlation of imaging findings and explanted liver or histology is illustrated in representative cases. Associated uncommon congenital anomalies are shown.     

Autoimmune cytopaenia after paediatric intestinal transplantation: a case series

Autoimmune cytopaenia is a rare, but severe complication after solid organ transplantation. We retrospectively analysed 57 paediatric intestinal transplants performed in 49 patients between 1999 and 2009. Autoimmune cytopaenia was observed in six patients; it appeared after an average of 10 months post‐transplant. Warm autoimmune haemolytic anaemia was developed in three patients, cold autoimmune haemolytic anaemia in one and two presented a mixed type. Incidence and causes for haematological cytopaenia such as the following were investigated: immunosuppression, major blood mismatch, viral infection, malignancy, passenger lymphocyte syndrome and lymphoproliferative disorders. Initial treatment included high‐dose steroids, intravenous immunoglobulin, plasmapheresis and maintenance of body temperature above 37 °C in those with cold autoantibodies. Inclusion of the spleen in multivisceral transplants seems to be an important risk factor. All patients, except one, relapsed after classic therapy, requiring additional treatments. Sirolimus conversion was performed in four patients. One died after infection. The immunosuppressive therapies associated with other concomitant factors, such as viral infections, lymphoproliferative disorders, graft‐versus‐host disease, passenger lymphocyte syndrome and the inclusion of the spleen as part of multivisceral graft seem to play an important part in the development of autoimmune processes after intestinal transplantation. Therapy is not well established, especially in those resistant to first‐line treatment.