Multicentre, randomised, double-blind, placebo-controlled, proof of concept study of LSALT peptide as prevention of acute respiratory distress syndrome and acute kidney injury in patients infected with SARS-CoV-2 (COVID-19).

OBJECTIVE: Dipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19. DESIGN: Phase 2a randomised, placebo-controlled, double-blinded, trial. SETTING: Hospitals in Canada, Turkey and the USA. PARTICIPANTS: A total of 61 subjects with moderate-to-severe COVID-19. INTERVENTIONS: Randomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers. RESULTS: At 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups. CONCLUSION: In a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19. TRIAL REGISTRATION NUMBER: NCT04402957.

The association of vascular endothelial growth factor, metalloproteinases and their tissue inhibitors with cardiovascular risk factors in the metabolic syndrome.

OBJECTIVE: The present study was proposed to examine the matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and vascular endothelial growth factor (VEGF) in patients with metabolic syndrome (MetS), and to compare these parameters with healthy controls. We also compared the possible association of the circulating levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF with cardiovascular risk factors in patients with MetS. We also compared the possible association of the circulating levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF with cardiovascular risk factors in patients with MetS. PATIENTS AND METHODS: A total of 45 patients with MetS and 17 healthy controls with a body mass index (BMI) less than 25 kg/m2 were enrolled in the study. Plasma MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF levels were determined using ELISA. RESULTS: TIMP-1,-2, MMP-2,-9 levels were significantly higher in patients with MetS compared with healthy controls (p < 0.001). Carotid intima-media thickness and serum VEGF levels were found to be significantly increased (p < 0.01, p < 0.05 respectively) in MetS compared with healthy controls. According to the ROC curves, TIMP-1 levels were both sensitive (93.3%) and specific (81.2%). CONCLUSIONS: We observed that the patients with MetS have increased circulating concentrations of MMP-9, MMP-2, and TIMP-1, TIMP-2 that are associated with increased concentrations of VEGF. These findings suggest that MMP-2 may have a role in the increased cardiovascular risk of MetS patients.

Plasma ghrelin, leptin, and orexin-A levels and insulin resistance after laparoscopic gastric band applications in morbidly obese patients.

AIM: The main cause of obesity is a change in the energy balance in favor of intake. Communication between the hypothalamus and other organs occurs through special peptides, such as ghrelin, leptin, and orexin-A, to provide energy balance. The purpose of this study was to investigate the effects of a laparoscopic gastric band application on insulin resistance and the peptides involved in appetite in morbidly obese patients. METHODS: The study group consisted of 20 patients who were operated on for morbid obesity (body mass index [BMI], 48.3±6.7 kg/m2) and the control group contained 20 healthy, normal-weight subjects (BMI, 22.6±2 kg/m2). We obtained blood samples from the study subjects before surgery and one month after surgery, and once from the control group. We measured plasma levels of ghrelin, leptin, orexin-A, and plasma glucose. RESULTS: Significant weight loss was achieved after surgery (P<0.05). Plasma ghrelin levels were lower in morbidly obese patients (P=0.033), but increased postoperatively (P=0.014), compared with those in the control subjects. Leptin levels were higher in the morbidly obese group (P=0.000), but decreased after the operation (P=0.01). Orexin-A levels were higher in the morbidly obese group (P=0.000), but decreased after the operation (P=0.000). Insulin resistance values also decreased in a manner similar to leptin and orexin-A levels (P=0.000 and P=0.008, respectively). CONCLUSION: Laparoscopic gastric band application results in significant weight loss in morbidly obesity patients, even after one month. We found a decrease in patient BMI, increased ghrelin levels, and decreased leptin and orexin-A levels and insulin resistance.

Effects of peritoneal-and hemodialysis on levels of plasma protein and lipid oxidation markers in diabetic patients.

AIM: The aim of this paper was to evaluate the effects of dialysis procedures on oxidative stress in diabetic patients. METHODS: The study was performed on 15 non-diabetic hemodialysis (HD) patients, 30 non-diabetic perinoteal dialysis (PD) patients, 18 diabetic HD patients (DHD), 15 diabetic PD patients (DPD), and 20 healthy controls. Plasma thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCO), and oxidized LDL (oxLDL) were determined as oxidative stress markers. Plasma thiol (P-SH), erythrocyte glutathione (GSH) levels, and serum paraoxonase (PON1) activities were measured as antioxidants. RESULTS: HD patients have significantly higher oxLDL, TBARS and PCO levels and significantly lower P-SH levels than PD patients. DHD patients have significantly higher PCO levels and PON1 activities and significantly lower GSH levels than non-diabetic HD patients. There was no any difference in oxidative stress parameters between DPD and non-diabetic PD patients. CONCLUSION: Oxidative stress is exacerbated by HD in diabetic patients. Treatment strategy with antioxidants in dialysis patients may be associated with a worsened survival.

Evaluation of serum paraoxonase and arylesterase activities in subjects with asthma and chronic obstructive lung disease.

BACKGROUND: Asthma and chronic obstructive lung disease (COPD) are characterised by airway inflammation. Paraoxonasel (PON1) and arylesterase (AE) enzymes have the ability to protect HDL from oxidation and may have antiatherogenic, antioxidant, and antiinflammatory features. We carried out a study to assess if there is a difference between PON1 and AE activities and biochemical values between asthmatics and COPD patients and if there is a difference between comorbid or pure COPD patients. METHODS: 40 asthmatics, 20 pure COPD, 20 comorbid COPD patients, and 20 healthy controls were included. We excluded patients with hypertension, metabolic syndrome, diabetes mellitus, thyroid, renal, hepatic, rheumatic, cardiac, cerebrovascular, malignant, and infectious diseases to establish the asthma and pure COPD groups. Patients using drugs which could affect PON1 and AE were excluded in these groups. There were 11 hypertensive, 5 diabetic, and 4 cardiac patients in the comorbid COPD group. PON1 and AE activities were measured spectrophotometrically. RESULTS: Mean age was higher and male gender was more prevalant in COPD than other groups. Fasting blood glucose, LDL-cholesterol, triglyceride, leucocyte counts, erythrocyte sedimentation rate, and hs-CRP levels were higher in COPD patients. Although PON1 and AE were lower in patients than controls, no difference was found between the asthma and COPD groups, nor between pure and comorbid COPD patients. CONCLUSIONS: Although asthma and COPD are two different conditions PON1 and AE activities cannot be markers of differantial diagnosis as they overlap. Comorbid COPD patients may have similar enzyme levels because of the drugs such as statins and aspirin.

Circulating levels of adiponectin, orexin-A, ghrelin and the antioxidant paraoxonase-1 in metabolic syndrome.

AIM: Metabolic syndrome (MS) is a disorder consisting of various abnormalities such as dyslipidemia, obesity, hypertension and hyperglycemia. Over the past two decades, the prevalence of MS has greatly increased, and it has become a global health problem. We measured and compared plasma concentrations of adiponectin, orexin-A, ghrelin and the antioxidant paraoxonase-1 (PON1) between patients with metabolic syndrome (MS) and healthy controls. METHODS: A total of 87 patients (46 women, 41 men) with MS and 40 healthy controls (21 women, 19 men) with a BMI less than 25 kg/m2 were enrolled in the study. The plasma concentrations of the adiponectin, orexin-A, ghrelin and PON1 were measured by ELISA. RESULTS: Plasma concentrations of Orexin-A were significantly higher in patients with MS than controls (P<0.001). However, plasma concentrations of adiponectin, ghrelin and PON1 were significantly lower in patients with MS compared to controls (P<0.001, P<0.001 and P<0.001, respectively). CONCLUSION: Our data confirmed the previous findings that plasma concentrations of orexin-A is higher than controls, however plasma concentrations of PON1, ghrelin and adiponectin are lower compared to controls.

Hypertension and hemostatic/fibrinolytic balance disorders.

BACKGROUND: Hypertension is one of the principal risk factors for cardiovascular disease. We aimed to evaluate the impact of hypertension on fibrinolytic balance and endothelial function by measuring plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen (tPA), tPA/PAI-1 complex and fibrinogen. METHODS: Patients enrolled into the study were divided into four groups: 22 essential hypertensive (EH), 22 white coat hypertensive (WCH), 22 renovascular hypertensive (RH) and 22 normotensive control subjects. Plasma PAI-1, tPA, tPA/PAI-1 complex levels were measured by enzyme linked immunosorbent assays. RESULTS: There was no difference in the systolic and diastolic blood pressure measurements of the EH and RH groups. The four groups were comparable for age, gender, smoking habits and BMI. Patients with EH, RH and WCH had increased plasma levels of PAI-1, tPA, tPA/PAI-1 complex and fibrinogen compared with controls. No fibrinolytic parameter was associated with blood pressure in hypretensive subjects. CONCLUSION: This prospective study showed that fibrinolytic markers such as PAI-1, tPA, tPA/PAI-1 complex are independently associated with the development of hypertension. This supports the hypothesis that disturbances in fibrinolysis precede a cardiovascular event. Therefore, hypertension may be associated with impaired fibrinolysis.

Retroviral coinfections at a New Orleans HIV outpatient clinic.

The purpose of the study was to determine the seroprevalence of human T-lymphotropic virus types I and II (HTLV-I and HTLV-II) infections in an outpatient clinic population of human immunodeficiency virus (HIV)-1 infected persons as well as to identify the demographic and clinical characteristics and laboratory results associated with HTLV-I/II infections. During 1993-1995, 854 patients were tested for HTLV-I/II infection on entry into the clinic, of whom 25 were infected with HTLV-I and 35 with HTLV-II. Multivariate analysis revealed that patients with coinfections were more likely to be black, aged over 35 years, and have a history of injection drug use. HIV-1/HTLV-I coinfections were associated with higher median CD8 counts on entry (p < 0.05), and HIV-1/HTLV-II coinfections were associated with higher median percent CD4 counts (p < 0.05) compared with patients infected with HIV only. Coinfection was not associated with an increased diagnosis of AIDS. These findings indicate that HIV-1/HTLV-I/II coinfections are frequently diagnosed and are associated with unique immune phenotypes. Given the lack of information regarding the influence of dual infection on clinical status, differentiation of HTLV-I from HTLV-II infections may be important in understanding the clinical significance of retroviral coinfections.

Nosocomial central venous catheter-related infections in intensive care units.

To examine the recent microbiology of catheter-related infections (CRIs) in the intensive care unit (ICU) setting and to determine the association between selected factors and mortality among ICU patients diagnosed with a CRI, a retrospective review of all ICU patients determined to have a CRI between January 1992 and December 1994 was undertaken. A total of 108 patients with 111 episodes of CRIs were identified. The most common isolate was coagulase negative staphylococcus (37.9%), followed by Staphylococcus aureus (20.9%). Methicillin resistance was common in both CNS (93%), and S aureus (42%) isolates. Factors predictive for death in a multivariate analysis were as follows: male sex (relative risk (RR) 2.43, 95% confidence interval (CI) 1.0, 6.07), hypotension (RR 6.90, 95% CI 1.56, 12.2), American Society of Anesthesiologist physical status score greater than 3 (RR 4.36, 95% CI 1.56, 12.2), and underlying medical condition (RR 3.50, 95% CI 1.17, 10.5). This study demonstrated the increasing proportion of CRIs due to methicillin-resistant organisms in the ICU. Functional status and degree of illness were the strongest predictors for survival in this population.