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Background and aims Different population genetics studies showed that interactions between killer-cell immunoglobulin-like receptors (KIR) and HLA play a role in viral disease outcome, but functional correlates are missing. Building upon our previous work pointing to a regulatory role for KIR3DL1/DS1 in hepatitis C virus (HCV) infection, we analysed whether its expression may affect natural killer (NK) cell function in the presence or absence of its principal ligand HLA-Bw4 in KIR haplotype A and B carriers, which are characterized by a different representation of activating and inhibitory KIRs. Methods We performed KIR and HLA class I genotypic analysis in 54 healthy donors (HD) and 50 HCV+ subjects and examined NK cell cytokine secretion and degranulation in the context of KIR3DL1-HLA-Bw4 match stratified by KIR haplotype. Results KIR3DL1-HLA-Bw4 match induced functional NK cell modulation, reflected by reduced interferon (IFN)γ production in haplotype B HCV+ patients compared to HD. This functional impairment could be ascribed to the KIR3DS1 negative HCV-infected patient population, whose NK cells also showed a significantly decreased proportion of KIR3DL1. Haplotype A HCV-infected patients showed increased NK cell degranulation compared with HD in the absence of KIR-HLA-Bw4 match and this activity was associated with increased phosphorylation of signal transducer and activator of transcription (STAT) 1. Conclusions Our data show that NK cells from HCV+ patients have an unbalanced ability to produce IFNγ and to kill target cells in haplotype A and B carriers, suggesting the existence of complex functional differences governed by KIR-HLA interaction, particularly on KIR3DL1 expressing NK cells.

In the last months, the importance of identifying pathophysiological mechanisms for future therapies has emerged with the rapid spread of Covid‐19 pandemic. As matter of fact, several evidences suggest the critical role of Interleukin‐6 (IL‐6) in the cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV2) infection and its correlation with the severity of acute lung injury (1, 2). This article is protected by copyright. All rights reserved.

BACKGROUND Recent findings about the differential gene expression signature of periodontal lesions have raised the hypothesis of distinctive biological phenotypes expressed by generalized chronic periodontitis (GCP) and generalized aggressive periodontitis (GAgP) patients. Therefore, this cross-sectional investigation was planned, primarily, to determine the ability of nuclear magnetic resonance (NMR) spectroscopic analysis of unstimulated whole saliva to discriminate GCP and GAgP disease-specific metabolomic fingerprint and, secondarily, to assess potential metabolites discriminating periodontitis patients from periodontally healthy individuals (HI). METHODS NMR-metabolomics spectra were acquired from salivary samples of patients with a clinical diagnosis of GCP (n = 33) or GAgP (n = 28) and from HI (n = 39). The clustering of HI, GCP, and GAgP patients was achieved by using a combination of the Principal Component Analysis and Canonical Correlation Analysis on the NMR profiles. RESULTS These analyses revealed a significant predictive accuracy discriminating HI from GCP, and discriminating HI from GAgP patients (both 81%). In contrast, the GAgP and GCP saliva samples seem to belong to the same metabolic space (60% predictive accuracy). Significantly lower levels (P

While it seems intuitive that highly visible vaccine-preventable disease outbreaks should impact perceptions of disease risk and facilitate vaccination, few empirical studies exist to confirm or dispel these beliefs. This study investigates the impact of the 2014-2015 Disneyland measles outbreak on parents' vaccination attitudes and future vaccination intentions. The analysis relies on a pair of public opinion surveys of American parents with at least one child under the age of six (N = 1,000 across each survey). Controlling for basic demographics, we found higher levels of reported confidence in the safety and efficacy of childhood vaccinations in our follow-up data collection. However, this confidence was also accompanied by elevated levels of concern toward childhood vaccines among American parents. We then examined how different subgroups in the population scored on these measures before and after the outbreak. We found that parents with high levels of interest in the topic of vaccines and a child who is not fully upto date with the recommended vaccination schedule reported more supportive attitudes toward vaccines. However, future intentions to follow the recommended vaccination schedule were not positively impacted by the outbreak. Possible explanations for these results and implications for vaccination outreach are discussed.

Recent advances in high-throughput (HTP) automated mini-bioreactor systems have significantly improved development timelines for early-stage biologic programs. Automated platforms such as the ambr® 250 have demonstrated the ability, using appropriate scale-down approaches, to provide reliable estimates of process performance and product quality from bench to pilot scale, but data sets comparing to large-scale commercial processes (>10,000 L) are limited. As development moves toward late stages, specifically process characterization (PC), a qualified scale-down model (SDM) of the commercial process is a regulatory requirement as part of Biologics License Application (BLA)-enabling activities. This work demonstrates the qualification of the ambr® 250 as a representative SDM for two monoclonal antibody (mAb) commercial processes at scales >10,000 L. Representative process performance and product quality associated with each mAb were achieved using appropriate scale-down approaches, and special attention was paid to pCO2 to ensure consistent performance and product quality. Principal component analysis (PCA) and univariate equivalence testing were utilized in the qualification of the SDM, along with a statistical evaluation of process performance and product-quality attributes for comparability. The ambr® 250 can predict these two commercial-scale processes (at center-point condition) for cell-culture performance and product quality. The time savings and resource advantages to performing PC studies in a small-scale HTP system improves the potential for the biopharmaceutical industry to get products to patients more quickly.

Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau-negative frontotemporal lobar degeneration with TAR DNA-binding protein 43-positive inclusions (FTLD-TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late-onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ-amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD-TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD-TDP.

Tauopathies are sporadic or familial neurodegenerative diseases characterized by the accumulation of phosphorylated tau in neurons and glial cells and include encephalitis related to measles virus such as subacute sclerosing panencephalitis. We describe a 45-year-old woman, with a history of lymphoma treated with immunosuppressant therapy who underwent an open biopsy of the right frontal cortex for a suspect of encephalitis, and died 4 days later. The neuropathological assessment on the bioptic sample revealed edema, severe gliosis and microglial activation, with lymphomonocytic perivascular cuffing and neurons containing both nuclear and cytoplasmic eosinofilic inclusions that ultrastructurally appeared as tubular and curvilinear non-membrane-bound 12-18 nm structures, leading to the diagnosis of measles inclusion-bodies encephalitis. The biopsy specimen showed several cortical neurons with intense perikaryal immunoreactivity for anti-tau antibodies recognizing phosphorylated epitopes while on autoptic specimens no phosphorylated tau immunoreactivity was detected. Our findings suggest that in specific conditions biopsy-derived human tau may be phosphorylated at sites that may result not phosphorylated in autopsy-derived specimens, most likely caused by post-mortem dephosphorylation.

Metabolomics is the systemic study of all small molecules (metabolites) and their concentration as affected by pathological and physiological alterations or environmental or other factors. Metabolic alterations represent a “window” on the complex interactions between genetic expression, enzyme activity, and metabolic reactions. Techniques, including nuclear magnetic resonance spectroscopy, mass spectrometry, Fourier-transform infrared, and Raman spectroscopy, have led to significant advances in metabolomics. The field is shifting from feasibility studies to biological and clinical applications. Fields of application range from cancer biology to stem cell research and assessment of xenobiotics and drugs in tissues and single cells. Cross-validation across high-throughput platforms has allowed findings from expression profiling to be confirmed with metabolomics. Specific genetic alterations appear to drive unique metabolic programs. These, in turn, can be used as biomarkers of genetic subtypes of prostate cancer or as discovery tools for therapeutic targeting of metabolic enzymes. Thus, metabolites in blood may serve as biomarkers of tumor state, including inferring driving oncogenes. Novel applications such as these suggest that metabolic profiling may be utilized in refining personalized medicine.

Background Frailty is a clinical syndrome generally associated with a greater risk for adverse outcomes such as falls, disability, institutionalization, and death. Cognition and dementia have already been considered as components of frailty, but the role of frailty as a possible determinant of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) has been poorly investigated. We estimated the predictive role of frailty syndrome on incident dementia and its subtypes in a nondemented, Italian, older population. Methods We evaluated 2581 individuals recruited from the Italian Longitudinal Study on Aging sample population consisting of 5632 subjects aged 65 to 84 years and with a 3.9-year median follow-up. A phenotype of frailty according to a modified measurement of Cardiovascular Health Study criteria was operationalized. Dementia, AD, and VaD were classified using current published criteria. Results Over a 3.5-year follow-up, 65 of 2581 (2.5%) older subjects, 16 among 252 frail individuals (6.3%), of which 9 were affected by VaD (3.6%), developed overall dementia. In a proportional hazards model, frailty syndrome was associated with a significantly increased risk of overall dementia (adjusted hazard ratio: 1.85; 95% confidence interval: 1.01–3.40) and, in particular, VaD (adjusted hazard ratio: 2.68; 95% confidence interval: 1.16–7.17). The risk of AD or other types of dementia did not significantly change in frail individuals in comparison with subjects without frailty syndrome. Conclusion In our large population-based sample, frailty syndrome was a short-term predictor of overall dementia and VaD.

The death of a child around the time of birth is one of the most profoundly distressing events any parent will experience. These deaths are not uncommon, but are often hidden, along with the grief of mothers, fathers and families. Social stigma and negative attitudes are inextricably linked to underreporting of babies’ deaths in low- and middle-income countries. A failure to recognise the value of these lost lives leads to disenfranchised grief and diminished preventive efforts to reduce stillbirth and neonatal deaths. Acknowledging these deaths to bring them ‘out of the shadows’17 and compassionate, respectful care for parents suffering perinatal loss, irrespective of country or resources, are critical to addressing the totality of the burden of this public health problem.

Objectives To describe the sonographic features of paraovarian cysts and to compare these features with pathological findings in order to define the best treatment options (surgical vs. conservative). Methods Fifty patients (mean age 48 (range, 14–68) years), each with a surgically proven paraovarian cyst, were retrospectively recruited. Preoperative transvaginal ultrasonographic B-mode and power Doppler observations were re-evaluated and histological reports were analyzed. Results All cysts were correctly diagnosed as paraovarian at preoperative transvaginal sonography (TVS). Paraovarian cysts appeared as unilocular (‘simple’) cysts in 33 (66%) cases and multilocular in two (4%). In 15 patients (30%) the cyst showed a variable number of papillary projections growing from the cyst wall (unilocular–solid cysts). Power Doppler examination of the papillae showed the presence of blood vessels in four of these patients (27%). Histological analysis of the masses containing papillary projections diagnosed eight cystadenofibromas, five cystadenomas and two serous papillary borderline tumors, while analysis of paraovarian cysts without papillations revealed benign, serous cysts of paramesonephric or mesothelial origin. Conclusions Paraovarian cysts can show a wide range of sonographic features. Their risk of malignancy is low if no papillary projections are detected at transvaginal sonography, but when mural proliferations are present a borderline tumor can be found at pathological examination. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.

15 pags.; 12 figs.; 2 tabs., The rate coefficients for N2-N2 collision-induced vibrational energy exchange (important for the enhancement of several modern innovative technologies) have been computed over a wide range of temperature. Potential energy surfaces based on different formulations of the intramolecular and intermolecular components of the interaction have been used to compute quasiclassically and semiclassically some vibrational to vibrational energy transfer rate coefficients. Related outcomes have been rationalized in terms of state-to-state probabilities and cross sections for quasi-resonant transitions and deexcitations from the first excited vibrational level (for which experimental information are available). On this ground, it has been possible to spot critical differences on the vibrational energy exchange mechanisms supported by the different surfaces (mainly by their intermolecular components) in the low collision energy regime, though still effective for temperatures as high as 10,000 K. It was found, in particular, that the most recently proposed intermolecular potential becomes the most effective in promoting vibrational energy exchange near threshold temperatures and has a behavior opposite to the previously proposed one when varying the coupling of vibration with the other degrees of freedom. © 2014 Wiley Periodicals, Inc., Contract grant sponsor: Spanish MEC;Contract grant number : CTQ2008-02578, CTQ2009-07647, 2009S GR104,CTQ2012-37404, FIS2010-22064-C02-02 and CSD2009-00038

Metal-ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a novel derivative of glutathione, GS(HQ)H, endowed with an 8-hydroxyquinoline group as a metal-chelating moiety. In vitro results showed that GS(HQ)H may be stable enough to be absorbed unmodified and arrive intact to the blood-brain barrier, that it may be able to remove Cu(II) and Zn(II) from the Aβ peptide without causing any copper or zinc depletion in vivo, and that it protects SHSY-5Y human neuroblastoma cells against H2 O2 - and 6-OHDA-induced damage. Together, these findings suggest that GS(HQ)H could be a potential neuroprotective agent for the treatment of neurodegenerative diseases in which a lack of metal homeostasis has been reported as a key factor.

Aim The role of atenolol, a non-vasodilating beta-blocker drug, on long-term mortality in hypertensive older adults is still unclear. The aim of the present study was to evaluate long-term mortality in community-dwelling hypertensive older adults taking atenolol. Methods Long-term mortality after 12-year follow up in isolated hypertensive older adults (n = 972) was analyzed. The patients were stratified in the presence and absence of atenolol use. Systolic, diastolic and pulse arterial pressure were measured. Results Older adults taking atenolol showed a greater mortality and higher pulse arterial pressure values than those not taking atenolol (73.9% vs 55.0%; P = 0.047 and 74.7 ± 14.1 vs 63.0 ± 14.2 mmHg, P

Worldwide efforts are underway to develop new antimicrobial agents against bacterial resistance. To identify new compounds with a good antimicrobial profile, we designed and synthesized two series of small cationic antimicrobial peptidomimetics (1–8) containing unusual arginine mimetics (to introduce cationic charges) and several aromatic amino acids (bulky moieties to improve lipophilicity). Both series were screened for in vitro antibacterial activity against a representative panel of Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacterial strains, and Candida albicans. The biological screening showed that peptidomimetics containing tryptophan residues are endowed with the best antimicrobial activity against S. aureus and S. epidermidis in respect to the other synthesized derivatives (MIC values range 7.5–50 µg/ml). Moreover, small antimicrobial peptidomimetics derivatives 2 and 5 showed an appreciable activity against the tested Gram-negative bacteria and C. albicans. The most active compounds (1–2 and 5–6) have been tested against Gram-positive established biofilm, too. Results showed that the biofilm inhibitory concentration values of these compounds were never up to 200 µg/ml. The replacement of tryptophan with phenylalanine or tyrosine resulted in considerable loss of the antibacterial action (compounds 3–4 and 7–8) against both Gram-positive and Gram-negative bacterial strains. Furthermore, by evaluating hemolytic activity, the synthesized compounds did not reveal cytotoxic activities, except for compound 5. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

Letter to Editor

In the 1960s, trichloroethene (TCE) was used at what is now designated as Installation Restoration Program Site 32 Cluster at Vandenberg Air Force Base to flush missile engines prior to launch and perhaps for other degreasing activities, resulting in releases of TCE to groundwater. The TCE plume extends approximately 1 kilometer from the previous launch facilities beyond the southwestern end of the site. To limit further migration of TCE and chlorinated degradation by-products, an in situ, permeable, reactive bioremediation barrier (biobarrier) was designed as a cost-effective treatment technology to address the TCE plume emanating from the source area. The biobarrier treatment would involve injecting carbon-based substrate and microbes to achieve reductive dechlorination of volatile organic compounds, such as TCE. Under reducing conditions and in the presence of certain dechlorinating microorganisms, TCE degrades to nontoxic ethene in groundwater. To support the design of the full-scale biobarrier, a pilot test was conducted to evaluate site conditions and collect pertinent design data. The pilot test results indicated possible substrate delivery difficulties and a smaller radius of influence than had been estimated, which would be used to determine the final biobarrier well spacing. Based on these results, the full-scale biobarrier design was modified. In January 2010, the biobarrier was implemented at the toe of the source area by adding a fermentable substrate and a dechlorinating microbial culture to the subsurface via an injection well array that spanned the width of the TCE plume. After the injections, the groundwater pH in the injection wells continued to decrease to a level that could be detrimental to the population of Dehalococcoides in the SDC-9TM culture. In addition, 7 months postinjection, the injection wells could not be sampled due to fouling. Cleaning was required to restore their functions. Bioassay and polymerase chain reaction analyses were conducted, as well as titration tests, to assess the need for biobarrier amendments in response to the fouling issues and low pH. Additionally, slug tests were performed on three wells to evaluate possible localized differences in hydraulic conductivity within the biobarrier. Based on the test results, the biobarrier was amended with sodium carbonate and inoculated a second time with SDC-9TM. The aquifer pH was restored, and reductive dechlorination resumed in the treatment zone, evidenced by the reduction in TCE and the increase in degradation products, including ethene. © 2011 Wiley Periodicals, Inc.

BACKGROUND Chronic heart failure (CHF) is characterized by a high mortality in the elderly. Moreover, depression status is also related to poor prognosis in advancing age. Thus, we sought to determine whether depressive status predicts long-term mortality in subject with or without CHF. METHODS AND RESULTS Long-term mortality after 12-year follow-up in 125 elderly subjects with CHF and 1143 elderly subjects without CHF was studied. Depression was evaluated using the Geriatric Depression Scale (GDS), and all subjects were stratified in tertiles according to GDS score (0-10, 11-20 and 21-30). With increasing GDS score, long-term mortality at the end of follow-up increased from 43·4% to 72·0% in subjects without (P < 0·001) and from 52·6% to 83·9% in subjects with (P < 0·007) CHF. In multivariate analysis, GDS appeared to be predictive of long-term mortality in the absence (Hazard ratio = 1·01; confidence interval 95% 1·00-1·05; P = 0·04) and, even more, in the presence of CHF (Hazard ratio = 1·08; confidence interval 95% 1·01-1·15; P < 0·01). CONCLUSIONS Depression symptoms predict long-term mortality in elderly subjects without and, even more, with CHF. Thus, depression can be considered a strong predictor of death in CHF elderly subjects.

OBJECTIVE: Inducing tolerance to myocardial ischemia by repeated brief episodes of ischemia has been called “ischemic preconditioning.” “Warm-up” phenomenon refers to patients with coronary heart disease improving performance after a first exertion and may represent a clinical counterpart to ischemic preconditioning. The goal of this study was to assess whether the severity of myocardial ischemia would be attenuated by two repeated walking-induced ischemic episodes in adult and older patients. SUBJECTS: Thirty-eight adults (51 ± 5 years) and 39 older patients (76 ± 4 years) with stable angina and angiographic evidence of coronary stenosis. MEASUREMENTS: Holter monitoring was performed in adult and older patients walking on two consecutive occasions, with a 5-minute rest between walks, a distance known to have previously caused myocardial ischemia. RESULTS:Computer-assisted analysis recorded by ambulatory Holter monitoring revealed that the mean maximal ST-segment depression (P < .001) and ischemia duration decreased (P < .001), whereas the ischemic threshold increased (P < .001), from the first to the second walk in the adult but not in the older group. CONCLUSIONS: Myocardial ischemia is attenuated and ischemic threshold is increased between two brief ischemic episodes in adult but not in older patients. These results indicate that the “warm-up” phenomenon, involved in increasing myocardial ischemic tolerance, is absent in the aging heart. J Am Geriatr Soc 47:1114–1117,1999.

OBJECTIVES: To examine whether waist circumference (WC) and body-mass index (BMI) can predict long-term mortality in elderly subjects with and without chronic heart failure (CHF). DESIGN: Longitudinal evaluation with a 12-year follow-up. SETTING: Campania, a region of southern Italy. PARTICIPANTS: One thousand three hundred thirty-two subjects aged 65 and older selected from the electoral rolls of Campania. MEASUREMENTS: The relationship between WC or BMI and mortality during a 12-year follow-up in 125 subjects with and 1,143 subjects without CHF. RESULTS: Mortality increased as WC increased in elderly subjects without CHF (from 47.8% to 56.7%, P=.01), and the increase was even greater in patients with CHF (from 58.1% to 82.0%, P=.01). In contrast, mortality decreased as BMI increased in elderly subjects without CHF (from 53.8% to 46.1%, P0 =.046) but not in those with CHF. According to Cox regression analysis, BMI protected against long-term mortality in the absence but not in the presence of CHF. In the absence of CHF, WC was associated with a 2% increased risk of long-term mortality for each 1-cm greater WC (Hazard Ratio (HR)=1.02, 95% confidence interval (CI)=1.01–1.03; P

OBJECTIVES: To assess the ability of specific early symptoms to predict cardiac and noncardiac syncope in elderly people. DESIGN: Multicenter cross-sectional observational study. SETTING: Inpatient geriatric acute care departments and outpatient clinics. PARTICIPANTS: Two hundred forty-two patients with syncope (mean age 79±8) consecutively referred for evaluation of transient loss of consciousness to any of six clinical centers participating in the Italian Group for the Study of Syncope in the Elderly (GIS Study). MEASUREMENTS: All patients were assessed according to European Society of Cardiology Syncope guidelines and interviewed about symptoms and signs present before syncope. RESULTS: One hundred seventy-four of 242 patients (75.4%) had noncardiac syncope, and 34 (14.7%) had cardiac syncope; 165 patients (71.1%) related symptoms before the loss of consciousness. When elderly patients with syncope were stratified for the presence and absence of symptoms, noncardiac syncope showed the highest prevalence of symptoms (75.3%, P

Some guidelines encourage mothers to see and hold their babies after stillbirth, which might be traumatizing. The study objective was to investigate the effects of women seeing and holding their stillborn baby on the risk of anxiety and depression in a subsequent pregnancy and in the long term.Thirty-seven organizations recruited women who had experienced stillbirth (N = 2,292 of whom 286 reported being pregnant). Anxiety and depressive symptoms were assessed by using the 25-item Hopkins Symptom Check List.Among nonpregnant women, seeing and holding their stillborn baby were associated with lower anxiety symptoms (OR 0.68, 95% CI 0.49-0.95) and a tendency toward fewer symptoms of depression (OR 0.72, 95% CI 0.51-1.02), compared with pregnant women. Participants who were pregnant also had less depressive symptomatology (OR 0.57, 95% CI 0.43-0.75), but more symptoms of anxiety if they had seen and held their baby (OR 3.79, 95% CI 1.42-10.1).Seeing and holding the baby are associated with fewer anxiety and depressive symptoms among mothers of stillborn babies than not doing so, although this beneficial effect may be temporarily reversed during a subsequent pregnancy.