Uptake and intracellular distribution of idarubicin in secondary cultures of normal and neoplastic urothelium

This study analyzes the uptake and endocellular distribution of idarubicin (IDA) in normal and neoplastic urothelial secondary cultures in relation to the changes in concentration and time of exposure. The urothelial lines were isolated by Freshney's method from biopsy fragments taken from five patients with superficial bladder cancer. Pharmacological experiments were carried out on subcultures previously immunophenotypically characterized and did not exceed ten passages. The uptake and endocellular distribution of IDA was analyzed by densitometric image analysis on cells treated for 10, 20, 30 and 60 min and 2 h with scalar dosages from 10 ng/ml to 2430 ng/ml. Microscopic observations and densitometric analyzes revealed that in the cells treated with IDA, fluorescence was higher in the cytoplasm compared to the nucleus and increased with the change in dosage. Moreover, densitometric data showed that IDA uptake in the first 20 min was higher in the neoplastic cells, but after that period its behavior became heterogeneous at 30 and 60 min, while at 2 h there was an inversion of the trend. These results suggest that the in vitro cytotoxicity should be evaluated in order to verify whether the elevated uptake of IDA in the first 20 min of treatment is really correlated to a more elevated toxicity in the neoplastic cells with respect to the normal cells. This is presently under investigation.     

Prognostic value of galactose elimination capacity,aminopyrine breath test,and ICG clearance in patients with cirrhosis

Seventy-eight patients with cirrhosis were prospectively followed for up to 20 months, on the average. At entry into the study, galactose elimination capacity, aminopyrine breath test, and ICG clearance were measured. At the end of the study, 27 patients had died. Univariate analysis using the Kaplan-Meier method showed that both quantitative liver function tests (galactose elimination capacity:P<0.025; aminopyrine breath test:P<0.001; ICG clearance:P<0.005) and common clinical and biochemical data (encephalopathy:P<0.001; ascites:P<0.001; serum bilirubin:P<0.005; serum albumin:P<0.001; prothrombin index:P<0.05) were significant predictors of survival. To investigate whether quantitative liver function tests could contribute to a better definition of the prognosis, once Pugh score had already been taken into account, a multiple regression analysis according to the Cox model was performed. Pugh score and galactose elimination capacity resulted in the only independent prognostic covariates. From them a prognostic index was calculated, and the model was validated in an additional sample of 70 patients investigated according to the same protocol. The contribution GEC gave to the assessment of overall prognosis over that obtained using the Pugh score was slight, as estimated by the statistical parameters of the Cox's model, but was significant as assessed by a ROC curve analysis (P=0.05). These data show that all quantitative liver function tests were predictors of survival in cirrhosis, and that the galactose elimination capacity added some new prognostic information to those already available using the Child-Turcotte-Pugh classification.This study was supported in part by a grant from the Italian Ministry of Education (National Project Liver Cirrhosis). Part of this study was presented at the 22nd Meeting of the European Society for Clinical Investigation, Graz, Austria, April 20–23, 1988.     

Synthesis and Antimuscarinic Activity of Derivatives of 2-Substituted-1,3-Dioxolanes

Geometric cis, trans isomers, derivatives of 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabbit vas deferens (putative M₁), guinea-pig heart (M₂) and guinea-pig ileum (M₃). The effect of the replacement of a trimethylammonium group with a dimethysulfonium in the two rings was also evaluated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors.     

Susceptibility to Resurgent COVID-19 Outbreaks Following Vaccine Rollouts: A Modeling Study

Using the recently proposed Susceptible–Asymptomatic–Infected–Vaccinated–Removed (SAIVR) model, we study the impact of key factors affecting COVID-19 vaccine rollout effectiveness and the susceptibility to resurgent epidemics. The SAIVR model expands the widely used Susceptible–Infectious–Removed (SIR) model for describing epidemics by adding compartments to include the asymptomatic infected (A) and the vaccinated (V) populations. We solve the model numerically to make predictions on the susceptibility to resurgent COVID-19 epidemics depending on initial vaccination coverage, importation loads, continuing vaccination, and more contagious SARS-CoV-2 variants, under persistent immunity and immunity waning conditions. The parameters of the model represent reported epidemiological characteristics of the SARS-CoV-2 virus such as the disease spread in countries with high levels of vaccination coverage. Our findings help explain how the combined effects of different vaccination coverage levels and waning immunity lead to distinct patterns of resurgent COVID-19 epidemics (either surges or endemic), which are observed in countries that implemented different COVID-19 health policies and achieved different vaccinated population plateaus after the vaccine rollouts in the first half of 2021.     

Coenzyme Q-10 treatment of patients with a 7445A--->G mitochondrial DNA mutation stops the progression of hearing loss

CONCLUSION: CoQ 10 may be helpful in delaying the progression of hearing loss in patients with the 7445A-->G mitochondrial mutation. Objective. To assess the effect of an antioxidant drug (Coenzyme Q-10) on the hearing level of patients with the mitochondrial DNA 7445A-->G mutation and associated sensorineural hearing loss (SNHL). Material and methods. We identified three patients with bilateral non-syndromic SNHL harboring the mitochondrial 7445A-->G mutation. Two patients had a family history of hearing loss with a strong matrilineal inheritance. The other patient did not have a family history of hearing loss. Two patients (1 with familial and 1 with sporadic SNHL) received treatment with 75 mg of Coenzyme Q-10 (CoQ10) twice a day for 1 year. The remaining patient with a familial form of hearing loss did not agree to take the treatment. Average bone conduction pure-tone thresholds for 0.5, 1, 2 and 4 kHz were obtained before and after diagnosis of mitochondrial hearing loss, and before and after treatment with CoQ10. Results. CoQ10-treated patients did not show any additional deterioration of their SNHL after 12 (familial case) and 13 months (sporadic case). The progression rate of SNHL was 6 dB/year in the 2 years prior to initiation of treatment in the familial case who received CoQ10 treatment. One year after being diagnosed with mitochondrial hearing loss, the patient who refused CoQ10 treatment exhibited an 11-dB deterioration of his hearing thresholds. There were no side-effects related to treatment with CoQ10.     

A lack of an association between COVID-19 vaccination and corneal graft rejection: results of a large multi-country population based study

PurposeThe aim of the study was to present the rates of corneal transplant rejection from 2018 to 2022 at both Moorfields Eye Hospital UK, and Ospedali Privati Forli (OPF) “Villa Igea”, Italy and evaluate the purported association between COVID-19 vaccination and rejection.MethodsWe performed a retrospective review of rejection cases presenting to the two units. Monthly rates were correlated against regional vaccination programme rates. At OPF, conditional Poisson regression model was employed to estimate the incidence risk ratio (IRR) of graft rejection following COVID-19 vaccination risk period compared with the control period.ResultsBetween January 2018 and March 2022, there were 471 (Moorfields), 95 (OPF) episodes of rejection. From the start of vaccination programme in the UK in late January 2021, the median number of graft rejections per month at Moorfields was 6 (range: 5–9), which was not significantly different to post-lockdown, pre-vaccination programme (March 2020–January 2021), p = 0.367. At OPF, the median rates of rejection before and after initiation of the vaccination programme were not significantly different (p = 0.124). No significant increase in incidence rate of rejection in the risk period following COVID-19 vaccination was found (IRR = 0.53, p = 0.71).ConclusionNo notable increase in rates of transplant rejection was noted in year 2021 when COVID-19 vaccination was broadly implemented. The apparent temporal relationship between COVID-19 vaccination and corneal graft rejection highlighted in several case reports may not represent a causative association.Subject terms: Corneal diseases, Risk factors     

SARS-CoV-2 Specific Immune Response and Inflammatory Profile in Advanced HIV-Infected Persons during a COVID-19 Outbreak

The main aim of this study was to describe the clinical and immunological outcomes, as well as the inflammatory profile, of patients with advanced HIV in an assisted-living facility in which an outbreak of SARS-CoV-2 occurred. SARS-CoV-2 humoral and specific T-cell response were analyzed in patients with HIV infection and COVID-19; as a secondary objective of the analysis, levels of the inflammatory markers (IL-1β, IL-6, IL-8, and TNFα) were tested in the HIV/COVID-19 group, in HIV-positive patients without COVID-19, and in HIV-negative patients with mild/moderate COVID-19. Antibody kinetics and ability to neutralize SARS-CoV-2 were evaluated by ELISA assay, as well as the inflammatory cytokines; SARS-CoV-2 specific T-cell response was quantified by ELISpot assay. Mann–Whitney or Kruskal–Wallis tests were used for comparisons. Thirty patients were included with the following demographics: age, 57 years old (IQR, 53–62); 76% male; median HIV duration of infection, 18 years (15–29); nadir of CD4, 57/mmc (23–100) current CD4 count, 348/mmc (186–565). Furthermore, 83% had at least one comorbidity. The severity of COVID-19 was mild/moderate, and the overall mortality rate was 10% (3/30). Additionally, 90% of patients showed positive antibody titers and neutralizing activity, with a 100% positive SARS-CoV-2 specific T-cell response over time, suggesting the ability to induce an effective specific immunity. Significantly higher levels of IL-6, IL-8, and TNF-α in COVID-19 without HIV vs. HIV/COVID-19 patients (p < 0.05) were observed. HIV infection did not seem to negatively impact COVID-19-related inflammatory state and immunity. Further data are mandatory to evaluate the persistence of these immunity and its ability to expand after exposure and/or vaccination.     

Patent foramen ovale with paradoxical embolism: mid-term results of transcatheter closure in 256 patients

The purpose of this study was to assess the safety and feasibility of percutaneous interventional closure of patent foramen ovale (PFO) with or without atrial septal aneurysm (ASA) in symptomatic patients. Between June 1999 and June 2002, we performed transcatheter closure of PFO in 256 consecutive symptomatic patients (female/male = 1.45; mean age 48 +/- 16 years; range 14-75): ischemic stroke (n = 101), transient ischemic attack (n = 144), peripheral and coronary arterial embolism (n = 17); multiple events (n = 23); platypnea-orthodeoxia syndrome (n = 2); refractory hypoxemia (n = 1); and migraine aura (n = 27). The implanted devices were an Amplatzer PFO Occluder (n = 248), a Gore-HELEX Septal Occluder (n = 4), and PFO STAR (n = 4). Most procedures (n = 176.69%) were done under two-dimensional intracardiac echocardiography (ICE) guidance alone; in the last 30 patients, 3D/4D ICE reconstruction (TomTec Imaging Systems) 6mbH was obtained. In 30 cases, ICE and contrast enhanced-TCD have been used simultaneously in the catheterization laboratory. The devices were placed correctly in all patients. Mean fluoroscopy time was 9.45 +/- 5 minutes (range = 2.5-35 minutes); mean procedural time was 57 +/- 21 minutes (range = 15-135 minutes). Total occlusion rate at follow-up (mean 19 months, range 1-33) was 98.1%. No significant recurrent neurological events were observed. Transcatheter closure of PFO with or without ASA is a safe and effective, minimally invasive procedure that ensures high closure rate and avoids life-long anticoagulation. Mid-term follow-up results appear favorable with respect to recurrent thromboembolic events.     

The evolution and refinement of traditional risk factors for cardiovascular disease

Traditional risk factors for cardiovascular disease such as systemic hypertension and hypercholesterolemia, all described more than half a century ago, are relatively few in number. Efforts to expand the epidemiologic canon have met with limited success because of the high hurdle of causality. Fortunately, another solution to current deficiencies in risk assessment-in particular, the underestimation of risk both before and after initiation of pharmacotherapy-may exist. Parallel to the investigation of novel biomarkers, such as high-sensitivity C-reactive protein, ongoing research has yielded improved metrics of known causative conditions. This evolution of traditional risk factors, heralded by measures such as ambulatory blood pressure, central hemodynamics, low density lipoprotein particle concentration, genetic testing, and "vascular age," may better address the detection gap in cardiovascular disease.