Acute,sub-acute and general pharmacological evaluation of 5-(3,4-methylenedioxyphenyl)-4-ethyl-2E,4E-pentadienoic acid piperidide (SK-20): A novel drug bioavailability enhancer

An efflux pump inhibitor, SK-20 (5-(3,4-methylenedioxyphenyle)-4 ethyl-2E,4E-pentadienoic acid piperidide), was assessed for its toxicity at three different pharmacological profiles: acute, sub-acute and general pharmacology with pharmacokinetics. In acute study, the SK-20 was found safe up to a dose of 2000 mg/kg (b.wt.); and at sub-acute, dosages of 50 and 100 mg/kg (b.wt.) were found to be safe. However, dosages of 200 mg or above per kg (b.wt.) showed some morphological alterations in cellular architecture of both liver and kidneys in both sexes, viz., mild vascular congestion along with sporadic hemorrhages and infiltration into renal and hepatic parenchyma by mononucleate cell. General pharmacological studies did not result into any alterations in analgesic, convulsions, rectal temperatures and in the rhythm or the rate of the intestinal motility or the secretion of the bile. While the respiratory and the cardiac rate remained normal, the only parameter to show was the blood pressure, which at all the doses tested, showed a tendency toward reduction. Characteristically, the SK-20 at all doses influenced pentobarbital-induced hypnosis positively and negatively to spontaneous motor activity in a dose dependent manner. Pharmacokinetics of SK-20 revealed it to have retention time at 10.2 min and half life 2.47 h.     

Feasibility of intravascular ultrasound studies: Predictors of imaging success before coronary interventions

Background: Intravascular ultrasound (IVUS) is currently used to study lesions during transcatheter coronary therapy. However, before dilation some lesions cannot be reached or crossed with the imaging catheter. Hypothesis: This study seeks to elucidate which factors determine the feasibility of IVUS examination before coronary interventions. Methods: Accordingly, 100 consecutive patients undergoing IVUS examination before coronary angioplasty were prospectively studied. The clinical and angiographic characteristics of 77 patients with a successful IVUS study (Group A) were compared with those of 23 patients in whom IVUS was attempted but the target lesion could not be interrogated (Group B). The echogenic characteristics of the target lesion [before (n = 77) or after intervention (in 18 patients in Group B)] were also studied. Results: Patients in Group B were significantly older (62 ± 7 vs. 57 ± 10 years, p < 0.05) and more frequently had stable angina [8 (35%) vs. 9 (11%), p < 0.05]. The distribution of lesions within the coronary tree and angiographic lesion characteristics including length, eccentricity, calcification, bend location, and the American College of Cardiology/American Heart Association classification were similar in both groups. However, proximal tortuosities (>45° at end diastole) were more frequently found in Group B [20 (87%) vs. 47 (61%), p < 0.05]. In addition, by quantitative angiography, patients in Group B had smaller arteries (reference diameter 2.8 ± 0.4 vs. 3.1 ± 0.4 mm, p < 0.05) and more severe lesions (minimal lumen diameter 0.46 ± 0.24 vs. 0.65 ± 0.34 mm, p < 0.05). On IVUS, calcified lesions were more frequently visualized in Group B (61 vs. 38%, p < 0.05). On multivariate analysis, catheter size, baseline minimal lumen diameter, angiographic proximal tortuosities, and lesion calcification on imaging were independent predictors of the feasibility of IVUS studies. Conclusions: Unsuccessful IVUS studies before intervention occur more frequently (1) in vessels with proximal tortuosities or severe lumen narrowing, (2) in lesions that are calcified on IVUS, and (3) when large imaging catheters are used.     

Complete genome sequence of an M1 strain of Streptococcus pyogenes

The 1,852,442-bp sequence of an M1 strain of Streptococcus pyogenes, a Gram-positive pathogen, has been determined and contains 1,752 predicted protein-encoding genes. Approximately one-third of these genes have no identifiable function, with the remainder falling into previously characterized categories of known microbial function. Consistent with the observation that S. pyogenes is responsible for a wider variety of human disease than any other bacterial species, more than 40 putative virulence-associated genes have been identified. Additional genes have been identified that encode proteins likely associated with microbial "molecular mimicry" of host characteristics and involved in rheumatic fever or acute glomerulonephritis. The complete or partial sequence of four different bacteriophage genomes is also present, with each containing genes for one or more previously undiscovered superantigen-like proteins. These prophage-associated genes encode at least six potential virulence factors, emphasizing the importance of bacteriophages in horizontal gene transfer and a possible mechanism for generating new strains with increased pathogenic potential.     

Timescales of developmental toxicity impacting on research and needs for intervention

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision‐making must be weighed against the costs and necessary duration of research, as well as the long‐term costs to human health because of delayed protection of vulnerable early‐life stages of human development and, possibly, future generations. Although two‐generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY‐BPA‐type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.     

Virtual implantations to transition from porcine to bovine animal models for a total artificial heart

Realheart total artificial heart (TAH) is a novel, pulsatile, four-chamber total artificial heart which had been successfully tested acutely in a porcine animal model. However, the bovine model is better suited for long-term testing and thus an evaluation of how the design would fit the bovine anatomy was required. Virtual implantation is a method that enables a computer simulated implantation based on anatomical 3D-models created from computer tomography images. This method is used clinically, but not yet adopted for animal studies. Herein, we evaluated its suitability in the redesign of the outer dimensions and vessel connections of Realheart TAH to transition from the porcine to the bovine animal model. Virtual implantations in combination with bovine cadaver studies enabled a series of successful acute bovine implantations. Virtual implantations are a useful tool to replace the use of animals in early device development and refine subsequent necessary in vivo experiments. The next steps are to carry out human virtual implantations and cadaver studies to ensure the design is optimized for all stages of testing as well as the final recipient.     

Neutrophil/platelet to lymphocyte ratio in monitoring of response to TNF‐α inhibitors in psoriatic patients

Neutrophil or platelet to lymphocyte ratio (NLR and PLR) has been proposed to be used as prognostic purposes in a variety of diseases. The aim of this study was to evaluate the usefulness of these ratios in monitoring of response to TNF‐α‐inhibitors in psoriatic patients. Eighty psoriatic patients were included and treated with TNF‐α‐inhibitors for 12 months based on drug protocol. Hematologic indices, including NLR and PLR values were assessed before and after treatment. Data on psoriasis area and severity index (PASI), smoking behavior, alcohol intake habit, nail abnormality, body mass index (BMI), joint involvement, and disease duration were also recorded. PASI scores were improved significantly after one‐year treatment (P = .000). Furthermore, this type of treatment significantly reduced the NLR and PLR (P = .000). These changes were in accordance with PASI scores. Patients with BMI greater than 24.9 had higher, but non‐significant NLR and PLR than normal or lean individuals. Cigarette smokers and alcohol consumers had lower NLR and PLR values than other individuals (P < .05). There was no significant association between NLR and PLR and joint or nail involvement. Although NLR and PLR will not be helpful in primary diagnosis of inflammatory diseases, they could be accounted as monitoring tools in management of psoriasis or globally indicators of inflammation.     

Effects of topical allicin on second-intention wound healing in dogs (histological aspects)

Alllicin is one of the pharmacologically active garlic sulfur compounds that have antimicrobial (antibacterial, antiviral, antifungal and antiparasitic) and vasodilating effects. Five normal, male, mixed-breed dogs were selected to investigate the effects of allicin (5 mg/ml in methyl cellulose gel) as a topical treatment for full-thickness, excisional wounds. The dogs were approximately 3 years old. The histological aspects of second-intention wound healing were studied. Eight full-thickness skin wounds (20×20 mm) were created on the back of each dog. On days 0, 7, 14 and 21, each dog received two wounds, symmetrically, and were assigned to one of two groups: control (methyl cellulose gel) or test (allicin 5 mg/ml methyl cellulose gel). Wounds were treated once daily for a week. Left-side wounds were treated with allicfin (test group) and right-side wounds were treated with methylcellulose gel (control group). At day 28 (4 weeks) after initial wounding, biopsies were taken from wounds for histological examination. The density of inflammatory cells in the center of the day 7 wounds was significantly lower in test group (P=0.041), but the density of fibrocytes and fibroblasts in the center of day 7 wounds was significantly higher in the test group (P=0.042). No significant differences were observed in the amount of collagen and fibrin between the test and control wounds (P>0.05).