Antinociceptive activity of sildenafil and adrenergic agents in the writhing test in mice

The authors investigated the antinociceptive activity of sildenafil and adrenergic agents co-administered in the writhing test in mice. The intensity of nociception was quantified by the number of writhes occurring between 0 and 30 min after stimulus injection. Nontreated groups (NT) received acid intraperitoneally (ip) followed by sterile saline (ip). Animals received (ip) sildenafil (2.5 or 5 mg/kg), propranolol (0.5 or 2 mg/kg), atenolol (0.05 or 2 mg/kg), prazosin (0.05 or 0.25 mg/kg) or clonidine (0.01 or 0.1 mg/kg) 30 min before acid injection. It was observed that only the largest doses of every drug inhibited the number of writhes in mice. In another series of experiments, animals were pretreated with the lower ineffective doses of propranolol, atenolol, prazosin or clonidine. After 30 min, mice also received the lower ineffective dose of sildenafil followed by acid injection. The combination of ineffective doses of propranolol, atenolol, prazosin or clonidine with sildenafil significantly inhibited the nociceptive response induced by acetic acid injection. Data obtained from these experiments showed that ineffective doses of sildenafil associated with ineffective doses of adrenergic agents provided analgesic effects in the writhing test.     

Tumor necrosis factor alpha—an underestimated risk predictor in patients undergoing transcatheter aortic valve replacement (TAVR)?

BackgroundSystemic inflammation has been identified as a major cardiovascular risk factor in patients undergoing transcatheter aortic valve replacement (TAVR), yet currently, it is not adequately portrayed in scores for pre‐interventional risk assessment. The aim of this study was to investigate the predictive ability of TNF‐α in TAVR.MethodsA total of 431 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were drawn prior to intervention, 24 h post‐intervention, 4, 5, and 7 days post‐intervention, and 1, 3, and 6 months post‐TAVR.ResultsIn a univariate Cox proportional hazard analysis, plasma concentrations of TNF‐α after 24 h and after 5 days were associated with mortality after 12 months (after 24 h: HR 1.002 (1.000–1.004), p = 0.028; after 5d: HR 1.003 (1.001–1.005), p = 0.013). This association remained significant even after correction for confounders in a multivariate Cox regression analysis. Additionally, cut‐offs were calculated. Patients above the cut‐off for TNF‐α after 5d had a significantly worse 12‐month mortality than patients below the cut‐off (18.8% vs. 2.8%, p = 0.046).ConclusionPlasma levels of TNF‐α after 24 h and 5 days were independently associated with 12‐month mortality in patients undergoing TAVR. Thus, TNF‐α could represent a novel biomarker for enhanced risk stratification in these patients.     

Use of experimental design for the optimization of the production of new secondary metabolites by two Penicillium species

A fractional factorial design approach has been used to enhance secondary metabolite production by two Penicillium strains. The method was initially used to improve the production of bioactive extracts as a whole and subsequently to optimize the production of particular bioactive metabolites. Enhancements of over 500% in secondary metabolite production were observed for both P. oxalicum and P. citrinum. Two new alkaloids, citrinalins A (5) and B (6), were isolated and identified from P. citrinum cultures optimized for production of minor metabolites.     

Styling without shedding: Novel topical formula reduces hair shedding by contracting the arrector pili muscle

Approximately 40% of women experience excessive hair shedding during styling (e.g., hair brushing). Previously, we demonstrated that topically applied phenylephrine, a potent α₁ adrenergic receptor agonist, can be used to contract the arrector pili muscle of the follicular unit; thus, increasing the force required to pluck hair and reducing shedding during brushing. While demonstrating efficacy, phenylephrine has several drawbacks when applied to the scalp, including the possibility cardiovascular events. We hypothesized that a high concentration of a weak α₁ agonist would allow for: (a) rapid penetration through the stratum corneum eliciting a quick response; (b) a low probability of cardiac adverse events owing to the low receptor binding affinity; and (c) an efficacy of the weak α₁ agonist similar to that of phenylephrine at the local site of application. Accordingly, we developed a novel topical solution, AB‐102, containing a high concentration of a weak α₁ agonist. Several studies were conducted to test the safety and efficacy of AB‐102. In a dose escalating safety study, utilizing a wearable holter monitor, we observed no cardiac or hemodynamic adverse events. In addition, in a controlled efficacy study, AB‐102 reduced the number of hairs shed during brushing by up to 77% (average of 38%).     

Challenges and strategies in dermatologic therapy—Personalized medicine,patient safety,and pharmacoeconomics

Skin conditions are among the most prevalent and disabling diseases affecting millions of people worldwide. Recently, there have been significant changes in dermatologic clinical practice. Advances in knowledge of disease pathophysiology have led to significant breakthroughs in diagnostics and therapy, as well as discovery of new treatment modalities. Additionally, research focusing on differences between individual patients has resulted in the growth of personalized medicine. Health care professionals are focusing on tailoring therapy to the individual characteristics of each patient, which in turn leads to improved quality of care and management of each individual. Of note, patient safety may be compromised when applying or taking dermatologic therapy as a result of medical error, patient noncompliance, adverse effects, or drug interactions. It is therefore of great importance to minimize, and if possible prevent these risks. Finally, the appraisal of health care goods and services currently does not only analyze the safety and efficacy of treatment, but also considers the economic impact on the cost of health care. Consequently, pharmacoeconomic evaluation has become an essential step in the introduction of new dermatologic treatments and the rational use of pharmaceuticals.     

Validation of modified albumin-bilirubin-TNM score as a prognostic model to evaluate patients with hepatocellular carcinoma

BACKGROUND An ideal staging system for hepatocellular carcinoma(HCC) should rely on the hepatic reserve function and tumor burden. With the improvement in diagnostic and treatment strategies for HCC, in addition to recent treatment of viral hepatitis, finding a suitable assessment tool for hepatic reserve has become mandatory.AIM To validate a recently proposed modified albumin-bilirubin-TNM(mALBI-T)grade as a prognostic model for patients with HCC in Egypt.METHODS For patients diagnosed with HCC, Child-Turcotte-Pugh(CTP) score, Barcelona Clinic Liver Cancer(BCLC) stage, albumin-bilirubin(ALBI), plateltetalbumin–bilirubin(PALBI), ALBI-based BCLC, ALBI-T and mALBI-T grades were estimated. Patients were followed from time of diagnosis to date of death or date of data collection if they remained alive. Overall survival and received treatments were determined. Survival data were analyzed.RESULTS A total of 1910 patients were included(mean age, 57 years; 1575 males). At presentation, 50.6% had CTP A, 36.1% had CTP B and 13.4 % had CTP C; 12%had ALBI grade 1, 62.3% had ALBI grade 2 and 24.7% had ALBI grade 3. Overall median survival was 13 mo; survival was better in patients with ALBI 1 than in those with ALBI 2 and 3(28.6 vs 14 and 5.8 mo, respectively, P 0.001). Patients with ALBI-T grades 0 and 1 had better survival than those with ALBI-T grades 2,3, 4 and 5(P 0.001). The modified ALBI-T showed better stratification and significant improvement in prediction of survival.CONCLUSION ALBI-T grade is a superior prognostic tool that selects patients with HCC who have better liver reservoir and tumor stage. mALBI-T is a better prognostic model in patients with HCC.     

The Emergence of SARS-CoV-2 within the Dog Population in Croatia: Host Factors and Clinical Outcome

Over a year into the COVID-19 pandemic, there is growing evidence that SARS-CoV-2 infections among dogs are more common than previously thought. In this study, the prevalence of SARS-CoV-2 antibodies was investigated in two dog populations. The first group was comprised of 1069 dogs admitted to the Veterinary Teaching Hospital for any given reason. The second group included dogs that shared households with confirmed COVID-19 cases in humans. This study group numbered 78 dogs. In COVID-19 infected households, 43.9% tested ELISA positive, and neutralising antibodies were detected in 25.64% of dogs. Those data are comparable with the secondary attack rate in the human population. With 14.69% of dogs in the general population testing ELISA positive, there was a surge of SARS-CoV-2 infections within the dog population amid the second wave of the pandemic. Noticeably seroprevalence of SARS-CoV-2 in the dog and the human population did not differ at the end of the study period. Male sex, breed and age were identified as significant risk factors. This study gives strong evidence that while acute dog infections are mostly asymptomatic, they can pose a significant risk to dog health. Due to the retrospective nature of this study, samples for viral isolation and PCR were unavailable. Still, seropositive dogs had a 1.97 times greater risk for developing central nervous symptoms.     

Heme oxygenase/carbon monoxide-biliverdin pathway may be involved in the antinociceptive activity of etoricoxib, a selective COX-2 inhibitor

The aim of this study was to assess the interaction between the heme oxygenase-1/ biliverdin/carbon monoxide (HO-1/BVD/CO) and cyclooxygenase-2 (COX-2) pathways in the writhing test. Mice were pretreated with 0.1, 1 or 10 mg/kg, ip etoricoxib, a selective COX-2 inhibitor, or with one of the following HO-1/BVD/CO pathway modulators: 1, 3 or 9 mg/kg, sc ZnPP IX, a specific HO-1 inhibitor, 0.3, 1 or 3 mg/kg, sc hemin, a substrate of the HO-1/BVD/CO pathway; or 0.00025, 0.025 or 2.5 μmol/kg, sc DMDC, a CO donor. Mice pretreated with etoricoxib or one of the HO-1/BVD/CO pathway modulators received an injection of acetic acid (ip) after 30 and 60 min, respectively. Next, the number of writhes was quantified between 0 and 30 min after stimulus injection. In another series of experiments, ineffective doses of etoricoxib were co-administered with hemin or DMDC and an effective dose of etoricoxib with ZnPP IX, followed by an acetic acid injection. Four hours after the acetic acid injection, levels of bilirubin, which is a product of BVD conversion by the BVD reductase enzyme, in the peritoneal lavage were determined. Hemin or DMDC reduced (p<0.05) the number of writhes, but ZnPP IX potentiated (p<0.05) the effect of acetic acid by increasing (p < 0.05) the number of writhes. The co-administration of etoricoxib with hemin or DMDC reduced (p<0.05) the number of writhes. However, the analgesic effect of etoricoxib was not observed in the presence of ZnPP IX. Pretreatment with ZnPP IX reduced bilirubin levels, but etoricoxib pretreatment significantly increased the bilirubin concentration in peritoneal exudates. The data obtained from these experiments showed that the HO-1/BVD/CO pathway was activated in the acetic acid-induced abdominal writhing model. The analgesic effect of etoricoxib was at least partially dependent on the participation of the HO-1/BVD/CO pathway.     

Clustering and switching strategies during verbal fluency performance differentiate Alzheimer's disease and healthy aging

Clustering and switching strategies during phonemic and semantic verbal fluency tasks as defined by Troyer et al. (1997), Abwender et al. (2001), and Lanting et al. (2009) were compared using archival data to determine which scoring procedures best differentiate healthy older adults (n = 26) from individuals with early-stage Alzheimer's disease (AD, n = 26). Total word production showed the largest group difference, especially for semantic fluency. The AD group produced fewer switches when compared to the healthy control group, whereas the groups did not differ in cluster size. The AD group also accessed fewer novel semantic subcategories, presumably due to reduced access to semantic memory storage rather than lower processing speed. Clustering and switching scores on the phonemic task did not add information above total words produced, consistent with previous research indicating these variables are most informative in relation to semantic fluency.