Thiophene-Pyrazolourea Derivatives as Potent,Orally Bioavailable,and Isoform-Selective JNK3 Inhibitors

Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC₅₀ = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t_1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.     

Multiple Subepidermal Calcified Nodules on the Thigh Mimicking Molluscum Contagiosum

Abstract: Subepidermal calcified nodule (SCN) is a rare form of calcinosis cutis that presents as a solitary verrucous nodule on the face. Here, we report an unusual case of SCN. A healthy 2‐year‐old boy presented with multiple, round, hard, yellow‐white to erythematous lesions on his right thigh. Histopathologic examination of a punch biopsy specimen revealed deposition of calcium in the dermis.     

Evaluation of technical quality and periapical health of root-filled teeth by using cone-beam CT

Objective

This study aimed to assess the quality of root fillings, coronal restorations, complications of all root-filled teeth and their association with apical periodontitis (AP) detected by cone-beam computed tomography (CBCT) images from an adult Turkish subpopulation.

Material and Methods

The sample for this study consisted of 242 patients (aging from 15 to 72 years) with 522 endodontically treated teeth that were assessed for technical quality of the root canal filling and periapical status of the teeth. Additionally, the apical status of each root-filled tooth was assessed according to the gender, dental arch, tooth type and age classification, undetected canals, instrument fracture, root fracture, apical resorption, apical lesion, furcation lesion and type and quality of the coronal structure. Statistical analysis was performed using percentages and chi-square test.

Results

The success rate of the root canal treatment was of 54.4%. The success rates of adequate and inadequate root canal treatment were not significantly different (p>0.05). Apical periodontitis was found in 228 (45.6%) teeth treated for root canals. Higher prevalence of AP was found in patients aging from 20 to 29 years [64 (27%) teeth] and in anterior (canines and incisors) teeth [97 (41%) teeth].

Conclusions

The technical quality of root canal filling performed by dental practitioners in a Turkish subpopulation was consistent with a high prevalence of AP. The probable reasons for this failure are multifactorial, and there may be a need for improved undergraduate education and postgraduate courses to improve the clinical skills of dental practitioners in endodontics.     

Impact of prehypertension on left ventricular mass and QT dispersion in adult black Nigerians

The heterogeneity of individuals with blood pressure (BP) < 140/90 mmHg in terms of cardiovascular (CV) risk was reported as early as 1939 by Robinson and Brucer.1 BP in the range of 120–139/80–89 mmHg (labelled then as prehypertension) was observed to be associated with high risk of progression to hypertension (HT) and cardiovascular disease (CVD) later in life when compared with BP < 120/80 mm Hg.1The term prehypertension was adopted in May 2003 by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High blood Pressure (JNC-7) to describe BP range of 120–139/80–89 mmHg.2 The resuscitation of this terminology/concept in JNC-7 was a sequel to the documentation of a higher morbidity in individuals with prehypertension in landmark publications.3-5 Prehypertension (PHT) was defined in JNC-7 not only to emphasise the excess risk associated with BP in this range, but also to focus increased clinical and public health attention on prevention.2,6,7Prevalence rates of PHT among adults in the United States, Ghana and northern Nigeria have been reported to be 31, 40 and 58.7%, respectively.7-9 In most studies, including the ones above, PHT was more prevalent than hypertension.7-9 Though PHT is associated with increased risk of major CV events independently of other CV risk factors,10 most individuals (90%) with PHT have at least one cardiovascular risk factor such as dyslipidaemia, abdominal obesity, hyperinsulinaemia, impaired fasting glucose levels, insulin resistance, a prothrombotic state, tobacco use, endothelial dysfunction, and impaired vascular distensibility.6,7,9,10QT interval dispersion (QTd) (the difference between the longest and the shortest QT intervals on a surface ECG), when excessive, is associated with increased risk of cardiovascular morbidity and mortality in population studies, and many clinical conditions, including hypertension.11,12 This has been related to ventricular electrical instability, providing the necessary substrate for lethal ventricular arrhythmias.12,13 Greater QTd and left ventricular mass have been demonstrated in hypertensive individuals compared with normal individuals.11,13,14Considering the well-established, linear relationship between BP and the risk of cardiovascular events, the CV risk associated with PHT is intermediate between normotension and hypertension.2,03 Hence, electrocardiographic and echocardiographic indices of target-organ damage in PHT may also be intermediate between normotension and hypertension. The aims of this study were: (1) to compare the QTd and indices of left ventricular hypertrophy in adult black normal and prehypertensive subjects, and (2) to evaluate the relationship of QTd with electrocardiographic and echocardiographic indices in these subjects.     

用NOE差谱和二维核磁共振技术研究3S-取代烷氧基-奎宁环烷的立体化学

用3S-奎宁环醇与环氧化合物反应,得到化合物(Ⅰ)的二个光学异构体(3S-1)和(3S-2)。它们的生物活性有明显差别。本文采用NOE差谱和二维NMR技术指定了各异构体的^{1H和13C信号的归属,确定了它们的溶液态构象,测定了其C-11的绝对构型,并且阐明了立体结构与生物活性间的关系。C-11绝对构型的测定结果经X-射线衍射测定进一步得以肯定。}     

Squamous Cell Carcinoma of the Stomach

Squamous cell carcinoma of the stomach is a rare, unusual lesion which tends to occur at a somewhat earlier age than adenocarcinoma. Grossly and radiologically the tumor is indistinguishable from adenocarcinoma and may involve any portion of the stomach. Although the pathogenesis of this lesion remains unclear, most authors favor the "metaplastic theory" for the development of the tumor. In this case it is felt that the tumor probably arose from gastric squamous mucosa present congenitally in the lesser curvature.     

The effects of intranasal dexmedetomidine premedication in children: a systematic review and meta-analysis

Purpose

Intranasal dexmedetomidine premedication is a newly introduced method for reducing stress and anxiety before general anesthesia in children. We performed a meta-analysis to identify the effects of intranasal dexmedetomidine premedication in children.

Source

We conducted a systematic review to find published randomized-controlled trials using intranasal dexmedetomidine as premedication. We searched databases in EMBASE?, MEDLINE®, and the Cochrane Controlled Trials Register using the Ovid platform. This study was conducted based on the Cochrane Review Methods.

Principal findings

This review included 1,168 participants in 13 studies. Intranasal dexmedetomidine premedication provided more satisfactory sedation at parent separation (relative risk [RR], 1.45; 95% confidence interval [CI], 1.19 to 1.76; P = 0.0002; I² = 80%) than other premedication regimes. In addition, it reduced the need for rescue analgesics (RR, 0.58; 95% CI, 0.40 to 0.83; P = 0.003; I² = 0%). Nevertheless, there were no differences in sedation at mask induction (RR, 1.25; 95% CI, 0.98 to 1.59; P = 0.08; I² =71%) or in the incidence of emergence delirium (RR, 0.52; 95% CI, 0.24 to 1.13; P = 0.10; I² = 67%). Intranasal dexmedetomidine was associated with a significantly lower incidence of nasal irritation (RR, 0.05; 95% CI, 0.01 to 0.36; P = 0.003; I² = 0%) and postoperative nausea and vomiting (RR, 0.63; 95% CI, 0.40 to 0.99; P = 0.04; I² = 0%) than other premedication treatments. It also showed significantly lower systolic blood pressure (weighted mean difference [WMD], ?6.7 mmHg; 95% CI, ?10.5 to ?2.9; P = 0.0006; I² = 96%) and heart rate (WMD, ?6.8 beats·min^?1; 95% CI, ?11.3 to ?2.6; P = 0.002; I² = 98%).

Conclusions

Intranasal dexmedetomidine provided more satisfactory sedation at parent separation and reduced the need for rescue analgesics and the incidence of nasal irritation and postoperative nausea and vomiting when compared with other premedication treatments.