Mechanisms of HIV-1 Nucleocapsid Protein Inhibition by Lysyl-Peptidyl-Anthraquinone Conjugates

The Nucleocapsid protein NCp7 (NC) is a nucleic acid chaperone responsible for essential steps of the HIV-1 life cycle and an attractive candidate for drug development. NC destabilizes nucleic acid structures and promotes the formation of annealed substrates for HIV-1 reverse transcription elongation. Short helical nucleic acid segments bordered by bulges and loops, such as the Trans-Activation Response element (TAR) of HIV-1 and its complementary sequence (cTAR), are nucleation elements for helix destabilization by NC and also preferred recognition sites for threading intercalators. Inspired by these observations, we have recently demonstrated that 2,6-disubstituted peptidylanthraquinone-conjugates inhibit the chaperone activities of recombinant NC in vitro, and that inhibition correlates with the stabilization of TAR and cTAR stem-loop structures. We describe here enhanced NC inhibitory activity by novel conjugates that exhibit longer peptidyl chains ending with a conserved Nterminal lysine. Their efficient inhibition of TAR/cTAR annealing mediated by NC originates from the combination of at least three different mechanisms, namely, their stabilizing effects on nucleic acids dynamics by threading intercalation, their ability to target TAR RNA substrate leading to a direct competition with the protein for the same binding sites on TAR, and, finally, their effective binding to the NC protein. Our results suggest that these molecules may represent the stepping-stone for the future development of NC-inhibitors capable of targeting the protein itself and its recognition site in RNA

Frailty and Sarcopenia in Older Patients Receiving Kidney Transplantation

Kidney transplantation is the treatment of choice for most of the patients with end-stage renal disease (ESRD). It improves quality of life, life expectancy, and has a lower financial burden to the healthcare system in comparison to dialysis. Every year more and more older patients are included in the kidney transplant waitlist. Within this patient population, transplanted subjects have better survival and quality of life as compared to those on dialysis. It is therefore crucial to select older patients who may benefit from renal transplantation, as well as those particularly at risk for post-transplant complications. Sarcopenia and frailty are frequently neglected in the evaluation of kidney transplant candidates. Both conditions are interrelated complex geriatric syndromes that are linked to disability, aging, comorbidities, increased mortality, and graft failure post-transplantation. Chronic kidney disease (CKD) and more importantly ESRD are characterized by multiple metabolic complications that contribute for the development of sarcopenia and frailty. In particular, anorexia, metabolic acidosis and chronic low-grade inflammation are the main contributors to the development of sarcopenia, a key component in frail transplant candidates and recipients. Both frailty and sarcopenia are considered to be reversible. Frail patients respond well to multiprofessional interventions that focus on the patients' positive frailty criteria, while physical rehabilitation and oral supplementation may improve sarcopenia. Prospective studies are still needed to evaluate the utility of formally measuring frailty and sarcopenia in the older candidates to renal transplantation as part of the transplant evaluation process

Barriers to Physical Activity in Chronic Hemodialysis Patients: A Single-Center Pilot Study in an Italian Dialysis Facility

Background/Aims: In patients on chronic dialysis a sedentary lifestyle is a strong, yet potentially modifiable, predictor of mortality. The present single-center pilot study evaluated social, psychological and clinical barriers that may hinder physical activity in this population. Methods: We explored the association between barriers to physical activity and sedentarism in adult patients at a chronic dialysis facility in Parma, Italy. We used different questionnaries exploring participation in physical activity, physical functioning, patient attitudes and preferences, and barriers to physical activity perceived by either patients or dialysis doctors and nurses. Results: We enrolled 104 patients, (67 males, 65%), mean age 69 years (79% of patients older than 60 years); median dialysis vintage 60 months (range 8-440); mean Charlson score 5.55, ADL (Activities of Daily Living) score 5.5. Ninety-two participants (88.5%) reported at least one barrier to physical activity. At multivariable analysis, after adjusting for age and sex, feeling to have too many medical problems (OR 2.99, 95% CI 1.27 to 7.07; P=0.012), chest pain (OR 10.78, 95% CI 1.28 to 90.28; P=0.029) and sadness (OR 2.59, 95% CI 1.10 to 6.09; P=0.030) were independently associated with physical inactivity. Lack of time for exercise counseling and the firm belief about low compliance/interest by the patients toward exercise were the most frequent barriers reported by doctors and nurses. Conclusion: We identified a number of patient-related and health personnel-related barriers to physical activity in patients on chronic dialysis. Solutions for these barriers should be addressed in future studies aimed at increasing the level of physical activity in this population

[Disglycemia in patients with acute kidney injury in the ICU]

Derangements of glucose metabolism are common among critically ill patients. Critical illness- associated hyperglycemia (CIAH) is characterized by raised blood glucose levels in association with an acute event that is reversible after resolution of the underlying disease. CIAH has many causes, such as changes in counter-regulatory hormone status, release of sepsis mediators, insulin resistance, drugs and nutritional factors. It is associated with increased mortality risk. This association appears to be strongly influenced by diabetes mellitus as a comorbidity, suggesting the need for an accurate individualization of glycemic targets according to baseline glycemic status. Hypoglycemia is also very common in this clinical context and it has a negative prognostic impact. Many studies based on intensive insulin treatment protocols targeting normal blood glucose values have in fact documented both an increased incidence of hypoglycemia and an increased mortality risk. Finally, glycemic control in the ICU is made even more complex in the presence of acute kidney injury. On one hand, there is in fact a reduction of both the renal clearance of insulin and of gluconeogenesis by the kidney. On the other hand, the frequent need for renal replacement therapy (dialysis / hemofiltration) may result in an energy intake excess, under the form of citrate, lactate and glucose in the dialysate/reinfusion fluids. With regard to the possible renal protective effects afforded by intensive glycemic control protocols, the presently available evidence does not support a reduction in the incidence of AKI and/or the need for RRT with this approach, when compared with standard glucose control. Thus, the most recent guidelines now suggest higher blood glucose targets (<180 mg/dl or 140-180 mg/dl) than in the past (80-110 mg/dl). Albeit with limited evidence, it seems reasonable to extend these indications also to patients with AKI in the intensive care unit. Further studies are needed in order to better ascertain the effects of dysglycemia on the outcome of patients with AKI

Survey on carbapenem-resistant bacteria in pigs at slaughter and comparison with human clinical isolates in Italy

This study is focused on resistance to carbapenems and third-generation cephalosporins in Gram-negative microorganisms isolated from swine, whose transmission to humans via pork consumption cannot be excluded. In addition, the common carriage of carbapenem-resistant (CR) bacteria between humans and pigs was evaluated. Sampling involved 300 faecal samples collected from slaughtered pigs and 300 urine samples collected from 187 hospitalised patients in Parma Province (Italy). In swine, MIC testing confirmed resistance to meropenem for isolates of Pseudomonas aeruginosa and Pseudomonas oryzihabitans and resistance to cefotaxime and ceftazidime for Escherichia coli, Ewingella americana, Enterobacter agglomerans, and Citrobacter freundii. For Acinetobacter lwoffii, Aeromonas hydrofila, Burkolderia cepacia, Corynebacterium indologenes, Flavobacterium odoratum, and Stenotrophomonas maltophilia, no EUCAST MIC breakpoints were available. However, ESBL genes (blaCTXM-1, blaCTX-M-2, blaTEM-1, and blaSHV) and AmpC genes (blaCIT, blaACC, and blaEBC) were found in 38 and 16 isolates, respectively. P. aeruginosa was the only CR species shared by pigs (4/300 pigs; 1.3%) and patients (2/187; 1.1%). P. aeruginosa ST938 carrying blaPAO and blaOXA396 was detected in one pig as well as an 83-year-old patient. Although no direct epidemiological link was demonstrable, SNP calling and cgMLST showed a genetic relationship of the isolates (86 SNPs and 661 allele difference), thus suggesting possible circulation of CR bacteria between swine and humans

Stem cell transplantation in neuropathic pain

The neuropathic pain is a disabling condition which occurs secondarily to injury of peripheral or central nervous system. To date, the neuronal basis are poorly understood and effective treatments with long lasting relief are not available. Stem cells represent a more innovative and interesting therapeutic approach for tissue damage restoration. This study evaluates the effect of intravenous administration of murine adult neuronal stem cells and the administration in the lateral cerebral ventricle of human mesenchymal stem cells in two animal models of peripheral mononeuropathy: the chronic constriction injury and the spared nerve injury of the sciatic nerve. Pain related behaviour evaluation, morphofunctional alterations and the stem cell localization in brain, spinal cord and sciatic nerve were studied using respectively behavioural tests and immunohistochemical techniques. Stem cells were able to reduce pain-like behaviours, such as mechanical allodynia and thermal hyperalgesia, and to decrease the activation of nociceptive neurons at central level. The stem cells injected intravenously homed in the injured nerve site, while when injected in the cerebral ventricle was localized near the injection site. These data suggest that the stem cells administered intravenously influence directly the damaged area, whereas the cells injected in the cerebral ventricle could modulate the central neuronal pathway, responsible of neuropathic pain. The administration of stem cells in neuropathic pain syndromes may be a more suitable therapy than ‘’classical’’ drugs to decrease the unpleasant related symptoms

Prevalence of major cardiovascular risk factors among oil and gas and energy company workers

Introduction. Cardiovascular diseases (CVD) remain the biggest cause of disability and premature death throughout the world. Aim. The aim of this study was to describe and determine the prevalence of major cardiovascular risk factors emerged at the first medical examination carried out by a group of an oil and gas contractor company workers in the observation period 2000-2010. Methods. An observational cross-sectional study was conducted on 1073 workers (mean age 41 years, SD = 9.5) presenting overweight BMI (body mass index) values, hypertension and cholesterol problems. Results. In particular, we found that workers > 45 years had significant higher risk to have obesity (OR = 3.8, CI 95% = 2.5-5.7), hypertension (OR = 2.7, CI 95% = 2.1-3.6), high blood fasting glucose (OR = 2.6, CI 95% = 1.2-5.5), high cholesterol (OR = 2.7, CI 95% = 2.0-3.6), high triglycerides (OR = 1.8, CI 95% = 1.4-2.4) compared to younger (< 45 years)

Ultrasonography of Quadriceps Femoris Muscle and Subcutaneous Fat Tissue and Body Composition by BIVA in Chronic Dialysis Patients

Protein Energy Wasting (PEW) in hemodialysis (HD) patients is a multifactorial condition due to specific pathology-related pathogenetic mechanisms, leading to loss of skeletal muscle mass in HD patients. Computed Tomography and Magnetic Resonance Imaging still represent the gold standard techniques for body composition assessment. However, their widespread application in clinical practice is difficult and body composition evaluation in HD patients is mainly based on conventional anthropometric nutritional indexes and bioelectrical impedance vector analysis (BIVA). Little data is currently available on ultrasound (US)-based measurements of muscle mass and fat tissue in this clinical setting. The purpose of our study is to ascertain: (1) if there are differences between quadriceps rectus femoris muscle (QRFM) thickness and abdominal/thigh subcutaneous fat tissue (SFT) measured by US between HD patients and healthy subjects; (2) if there is any correlation between QRFM and abdominal/thigh SFT thickness by US, and BIVA/conventional nutritional indexes in HD patients. We enrolled 65 consecutive HD patients and 33 healthy subjects. Demographic and laboratory were collected. The malnutrition inflammation score (MIS) was calculated. Using B-mode US system, the QRFM and SFT thicknesses were measured at the level of three landmarks in both thighs (superior anterior iliac spine, upper pole of the patella, the midpoint of the tract included between the previous points). SFT was also measured at the level of the periumbilical point. The mono frequency (50 KHz) BIVA was conducted using bioelectrical measurements (Rz, resistance; Xc, reactance; adjusted for height, Rz/H and Xc/H; PA, phase angle). 58.5% were men and the mean age was 69 (SD 13.7) years. QRFM and thigh SFT thicknesses were reduced in HD patients as compared to healthy subjects (p &lt; 0.01). Similarly, also BIVA parameters, expression of lean body mass, were lower (p &lt; 0.001), except for Rz and Rz/H in HD patients. The average QRFM thickness of both thighs at top, mid, lower landmarks were positively correlated with PA and body cell mass (BCM) by BIVA, while negatively correlated with Rz/H (p &lt; 0.05). Abdominal SFT was positively correlated with PA, BCM and basal metabolic rate (BMR) (p &lt; 0.05). Our study shows that ultrasound QRFM and thigh SFT thicknesses were reduced in HD patients and that muscle ultrasound measurements were significantly correlated with BIVA parameters

Efficacy of nutritional interventions on inflammatory markers in haemodialysis patients: a systematic review and limited meta-analysis

Low-grade chronic inflammation is prevalent in patients undergoing haemodialysis (HD) treatment and is linked to the development of premature atherosclerosis and mortality. The non-pharmacological approach to treat inflammation in HD patients through nutritional intervention is well cited. We aimed to assess the efficacy of different nutritional interventions at improving inflammatory outcomes in HD patients, based on markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). We searched PubMed, Cochrane Library, and Embase for randomized controlled trials (RCT) published before June 2017. Inclusion criteria included RCTs on adult patients on maintenance HD treatment with duration of nutritional interventions for a minimum 4 weeks. Risk of bias was assessed using the Jadad score. In total, 46 RCTs experimenting different nutritional interventions were included in the review and categorized into polyphenols rich foods, omega-3 fatty acids, antioxidants, vitamin D, fibres, and probiotics. Meta-analyses indicated significant reduction in CRP levels by omega-3 fatty acids (Random model effect: −0.667 mg/L, p < 0.001) and vitamin E (fixed model effect: −0.257 mg/L, p = 0.005). Evidence for other groups of nutritional interventions was inconclusive. In conclusion, our meta-analysis provided evidence that omega-3 fatty acids and vitamin E could improve inflammatory outcomes in HD patients

SARS-CoV-2 vaccination and multiple sclerosis: a large multicentric study on relapse risk after the third booster dose

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce. Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS. Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60&nbsp;days prior to and after the third booster dose. Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60&nbsp;days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60&nbsp;days prior to vaccination, which was 1.9%. Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS