Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide

Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.     

Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population

ObjectivesPrevious work on high-sensitivity troponin I (hs-cTnI) has demonstrated that it may identify patients with stable cardiovascular disease (CVD) at risk for future myocardial infarction (MI). In this study, we assessed if hs-cTnT concentrations could also identify those stable CVD patients at high risk for future MI and other ischemic cardiac outcomes.Methodshs-cTnT (lot:153-401) was measured in specimens obtained at randomisation in the Heart Outcomes Prevention Evaluation (HOPE) study (n = 2941 stable CVD patients, 4.5 years follow-up). The primary outcome for the HOPE study (MI, stroke, or cardiovascular death) was used to identify cutoffs by receiver operating characteristic (ROC) curve analysis and was used in conjunction with the 95th and 99th percentile upper limits to construct different concentration ranges, which were assessed using log-rank tests and multivariable Cox proportional hazard models. These different concentration ranges were then assessed for the components of the primary outcome and for heart failure (HF).ResultsThe ROC derived hs-cTnT cutoff was 8 ng/L for the primary outcome. Subjects with hs-cTnT either below (8 to < 14 ng/L) or slightly above the published 99th from a healthy population (14 to 21 ng/L) had similar probability for the primary outcome. Those with hs-cTnT concentrations > 31 ng/L had the highest probability and greatest risk for future MI, HF, and cardiovascular death as compared to those with hs-cTnT concentrations < 8 ng/L.ConclusionIn patients with stable CVD disease hs-cTnT measurement identifies those at risk for MI as well as HF and cardiovascular death.     

Comparison of paper-patch, fat, and perichondrium myringoplasty in repair of small tympanic membrane perforations.

OBJECTIVE: To compare the effectiveness of paper-patch, fat, and perichondrium myringoplasty in the treatment of chronic tympanic membrane perforations smaller than 3 mm. SUBJECTS AND METHODS: This investigation included 45 patients with chronic tympanic membrane perforations smaller than 3 mm. The patients were equally divided into 3 main groups according to surgical procedures. Each group consisted of 3 subgroups, which had 1-mm, 2-mm, and 3-mm perforations. The patients underwent paper-patch, fat, or perichondrium myringoplasty via transcanal approach under local anesthesia. Healing of perforation, hearing improvement, and complications were investigated. RESULTS: Closure rates of the perforations in the paper-patch, fat, and perichondrium myringoplasty groups were 66.7%, 86.7%, and 86.7%, respectively. There were no statistically significant differences in tympanic membrane closure rates between techniques with regard to size. CONCLUSION: Three techniques were found to be feasible for tympanic membrane perforations smaller than 3 mm.     

Subclinical cardiovascular disease and its association with risk factors in children with steroid-resistant nephrotic syndrome

Background

The aim of this study was to evaluate the presence of subclinical cardiovascular disease (CVD) and its relation to risk factors in pediatric patients with steroid-resistant nephrotic syndrome (NS).

Methods

Thirty-seven patients with normal renal function were compared with 22 healthy controls regarding the presence of subclinical CVD. Measurements included aortic pulse wave velocity (PWV), carotid intima media thickness (IMT), and left ventricular mass (LVM). Patients were additionally assessed for blood pressure (BP) pattern and the presence of hypertension by 24-h ambulatory blood pressure monitoring.

Results

Compared with the controls, patients had significantly higher mean aortic PWV-standard deviation scores (SDS), mean carotid IMT-SDS, and LVM index (p?<?0.001 for all). Increased aortic PWV was noted in 5 % of patients, increased carotid IMT in 22 %, and increased LVM index in 19 %. Five patients (14 %) were hypertensive, and mean BP indexes, SDS, and BP loads during nighttime were significantly higher than those during daytime (p?<?0.001 for all). Multivariate analysis revealed a significant relationship between PWV-SDS and ferritin (R ²?=?0.269, p?=?0.006) and between carotid IMT-SDS and proteinuria (R ²?=?0.141, p?=?0.022). The LVM index was independently associated only with higher body mass index SDS (R ²?=?0.317, p?<?0.001). In addition, six patients (16 %) had multiple abnormal subclinical CVD markers, and increased subclinical CVD risk was independently associated only with higher low-density lipoprotein cholesterol (R ²?=?0.292, p?=?0.044).

Conclusions

Based on these results, steroid-resistant NS children generally are at high risk of cardiovascular complications, but the increased risk is likely to be multifactorial.     

The use of diffusion‐weighted MR imaging in the functional assessment of the testes of patients with clinical varicocele

We aimed to evaluate the use of diffusion‐weighted imaging (DWI) in the assessment of the varicocele effect on testicular parenchyma and spermatogenesis, with estimation of apparent diffusion coefficient (ADC) value changes in the testicular parenchyma. We prospectively evaluated 30 consecutive patients (18 patients with bilateral varicocele and 12 patients with unilateral varicocele) and 10 healthy controls. US and DWI were performed to all patients. A total of 80 testes were included, which divided into three groups: group A: testes ipsilateral to the varicocele (n = 48, 60%); group B: testes contralateral to the varicocele (n = 12, 15%); and group C: normal testes of the control (n = 20, 25%). There was a statistically significant difference in mean ADC value between all groups (p‐value < 0.001). In groups A and B, there was a negative correlation between mean ADC values and varicocele grade as well as pampiniformis venous diameter. In group A, there was a significant positive correlation between mean ADC value and sperm count (p‐value = 0.01, r‐value = 0.48) as well as sperm motility (p‐value = 0.04, r‐value = 0.33). DWI sequence can be used to evaluate the sequel of varicocele, with decreased ADC values that are significantly correlated with abnormal semen parameters. Thus, ADC values may be considered as an ancillary indicator of testicular parenchyma changes.     

Differences in Characteristics and Outcome of Patients with Penetrating Injuries in the USA and the Netherlands: A Multi-institutional Comparison

Introduction

The incidence and nature of penetrating injuries differ between countries. The aim of this study was to analyze characteristics and clinical outcomes of patients with penetrating injuries treated at urban Level-1 trauma centers in the USA (USTC) and the Netherlands (NLTC).

Methods

In this retrospective cohort study, 1331 adult patients (470 from five NLTC and 861 from three USTC) with truncal penetrating injuries admitted between July 2011 and December 2014 were included. In-hospital mortality was the primary outcome. Outcome comparisons were adjusted for differences in population characteristics in multivariable analyses.

Results

In USTC, gunshot wound injuries (36.1 vs. 17.4%, p?<?0.001) and assaults were more frequent (91.2 vs. 77.7%, p?<?0.001). ISS was higher in USTC, but the Revised Trauma Score (RTS) was comparable. In-hospital mortality was similar (5.0 vs. 3.6% in NLTC, p?=?0.25). The adjusted odds ratio for mortality in USTC compared to NLTC was 0.95 (95% confidence interval 0.35–2.54). Hospital stay length of stay was shorter in USTC (difference 0.17 days, 95% CI ?0.29 to ?0.05, p?=?0.005), ICU admission rate was comparable (OR 0.96, 95% CI 0.71–1.31, p?=?0.80), and ICU length of stay was longer in USTC (difference of 0.39 days, 95% CI 0.18–0.60, p?<?0.0001). More USTC patients were discharged to home (86.9 vs. 80.6%, p?<?0.001). Readmission rates were similar (5.6 vs. 3.8%, p?=?0.17).

Conclusion

Despite the higher incidence of penetrating trauma, particularly firearm-related injuries, and higher hospital volumes in the USTC compared to the NLTC, the in-hospital mortality was similar. In this study, outcome of care was not significantly influenced by differences in incidence of firearm-related injuries.

     

Relation between serum anti-p53 antibodies and microvessel density in bladder cancer patients

INTRODUCTION: Etiology of serum anti-p53 antibodies in bladder cancer patients is still unknown. In this study we evaluated the relationship between serum anti-p53 antibodies and microvessel density in bladder cancer patients. MATERIALS AND METHODS: Seventy-six patients with transitional cell carcinoma of the urinary bladder were assessed prospectively (18 Ta, 30 T1, 28 T2>or =). Serum anti-p53 antibodies were detected by enzyme-linked immunosorbent assay. Tumor p53 overexpression was assessed by immunohistochemical staining. Vessels were stained immunohistochemically using an antibody against platelet endothelial cell-adhesion molecule CD31. Spearman correlation test and t test were used for statistical analysis. RESULTS: Serum anti-p53 antibodies were positive in 25 (60%) of 41 tumor p53-positive patients. While the mean (SD, range) microvessel density was found to be 43 (7.59, 8-99) in patients who had positive serum anti-p53 antibodies, it was found to be 23 (4.53, 6-98) in patients who had negative serum anti-p53 antibodies. There was a good correlation between serum anti-p53 antibodies and microvessel density (p<0.05). No correlation was found between tumor p53 expression and microvessel density (p>0.05). CONCLUSIONS: We found that there is a significant correlation between the microvessel density and serum anti-p53 antibodies. This result may show the role of angiogenesis in the etiology of serum anti-p53 antibodies in bladder cancer patients.