Molecular modification of anticholinergics as probes for muscarinic receptors. 2. Amino esters of alpha-methyltropic acid

As a continuation of our goals to study molecular probes for muscarinic cholinergic receptors, a series of 3-substituted 2-methyl-2-phenylpropanoates with the general structure of C6H5C(CH2X)(CH3)COOCH2CH2NEt2 where X = OH, OTs, F, Cl, Br, I, and OAc were prepared and their antispasmodic activities examined on isolated rat ileum preparations. Structure-activity relationship studies with these compounds provide further evidence suggesting that binding of an aromatic moiety in a specific location within the hydrophobic region of the receptor is important for anticholinergic potency. A nucleophilic displacement of chloride by "naked" fluoride under mild conditions is also reported.     

Long-term mortality of living kidney donors: a systematic review and meta-analysis

International Urology and Nephrology - To date, several studies have reported inconsistent findings regarding the mortality risk faced by living kidney donors and controls. Our study assessed the...     

Efficacy of testosterone replacement therapy for treating metabolic disturbances in late-onset hypogonadism: a systematic review and meta-analysis

International Urology and Nephrology - Late onset hypogonadism (LOH) is an age-dependent reduction of testosterone associated with alterations of metabolic profile, including glucose control,...     

Central Regulation of Branched-Chain Amino Acids Is Mediated by AgRP Neurons

Circulating branched-chain amino acids (BCAAs) are elevated in obesity and diabetes, and recent studies support a causal role for BCAAs in insulin resistance and defective glycemic control. The physiological mechanisms underlying BCAA regulation are poorly understood. Here we show that insulin signaling in the mediobasal hypothalamus (MBH) of rats is mandatory for lowering plasma BCAAs, most probably by inducing hepatic BCAA catabolism. Insulin receptor deletion only in agouti-related protein (AgRP)–expressing neurons (AgRP neurons) in the MBH impaired hepatic BCAA breakdown and suppression of plasma BCAAs during hyperinsulinemic clamps in mice. In support of this, chemogenetic stimulation of AgRP neurons in the absence of food significantly raised plasma BCAAs and impaired hepatic BCAA degradation. A prolonged fasting or ghrelin treatment recapitulated designer receptors exclusively activated by designer drugs–induced activation of AgRP neurons and increased plasma BCAAs. Acute stimulation of vagal motor neurons in the dorsal motor nucleus was sufficient to decrease plasma BCAAs. Notably, elevated plasma BCAAs were associated with impaired glucose homeostasis. These findings suggest a critical role of insulin signaling in AgRP neurons for BCAA regulation and raise the possibility that this control may be mediated primarily via vagal outflow. Furthermore, our results provide an opportunity to closely examine the potential mechanistic link between central nervous system–driven BCAA control and glucose homeostasis.     

Learning curve could affect oncologic outcome of minimally invasive radical hysterectomy for cervical cancer

Background/ObjectiveRecent prospective studies have shown poorer oncologic outcomes following minimally invasive surgery, which has led many surgeons to deeply inspect their practices. We reviewed our experience and evaluated the results of radical hysterectomy in patients with early stage cervical cancer.MethodsThis retrospective study included patients with early stage cervical cancer (Ia1 - IIa1) who were treated with radical hysterectomy from May 2006 to Dec 2016. Patients were divided into three groups according to the surgical approach: radical abdominal hysterectomy (RAH), laparoscopic radical hysterectomy (LRH), and robot-assisted radical hysterectomy (RRH).ResultsLearning curves of each type of surgery were obtained using the cumulative sum method. Survival rates were compared using Kaplan–Meier curves. To analyze the learning curve of a single surgeon, 89 patients were selected from the whole population. Learning curves of each group showed two distinct phases. The minimum number of cases required to achieve surgical improvement were 16 in RAH, 13 in LRH, and 21 in RRH. Progression-free survival (PFS) and overall survival did not vary between RAH and minimally invasive surgery (MIS) (p = .828 and p = .757, respectively). However, when stratified by the phases of the learning curves, patients included in the early phase of MIS showed a poorer PFS (p = .014).ConclusionsSurgical proficiency could significantly affect the oncologic outcome in MIS. A prospective study regarding sufficient surgical competence is necessary for elaborate analysis of the feasibility of minimally invasive radical hysterectomy.     

Risk factors for sleep disturbance in patients with cervical myelopathy and its clinical significance: a cross-sectional study

BACKGROUND CONTEXTSleep disturbance is highly prevalent in patients with spinal cord injury and is one of the most important clinical issues affecting their quality of life. However, it has not been properly measured or treated in patients with cervical myelopathy (CM), although most typical or atypical symptoms of CM are known to be risk factors for sleep disturbance. In addition, previous studies identified that the presence of sleep disturbance is unintentionally missed under the current evaluation process for degenerative spinal disease without direct investigation using validated tools for sleep. Therefore, studies about sleep disturbances in patients with CM are essential.PURPOSEThe purpose of this study was to investigate the prevalence of sleep disturbance in patients with CM using validated tools and to understand its mechanism by identifying high-risk patients.STUDY DESIGN/SETTINGCross-sectional study.PATIENT SAMPLEConsecutive patients diagnosed with CM.OUTCOME MEASURESPittsburgh sleep quality index.METHODSThis study was performed on patients diagnosed with CM. Sleep disturbance was determined using the Pittsburgh sleep quality index. Variables associated with sleep disturbance including demographics, lifestyle, medical history, and radiologic parameters were investigated. Independent risk factors related to sleep disturbance were identified using multivariate logistic regression analysis.RESULTSA total of 203 patients with CM were included in our study. Among them, 126 patients (62.1%) were men, and the mean age was 63.0 years. Despite male predominance, sleep disturbance was identified in 71.4% of patients (145 of 203). Multivariate analysis identified a worse depression scale score, a lower modified Japanese Orthopedic Association score, chronic shoulder joint pain, smaller spinal cord area, and decreased cervical range of motion as independent risk factors for sleep disturbance.CONCLUSIONSIn patients with CM, sleep disturbance was associated with a more severe type of myelopathy. Further studies including polysomnography and measurement of melatonin will be helpful to identify the mechanisms of the sleep disturbance in patients with CM and to improve their quality of life and clinical outcomes.     

Association between Osteoporotic Vertebral Compression Fractures and Age,Bone Mineral Density,and European Quality of Life-5 Dimensions in Korean Postmenopausal Women: A Nationwide Cross-sectional Observational Study

BackgroudThe purpose of this study was to investigate the characteristics of osteoporotic vertebral compression fractures (OVCFs) in Korean postmenopausal women and the association between OVCFs and clinical factors such as age, bone mineral density (BMD), and quality of life.MethodsAccording to the population distribution in four regions in Korea, 1,281 postmenopausal female patients were recruited from nationwide orthopedic outpatient clinics. Radiologic, asymptomatic, and within 3 months of OVCF groups were analyzed based on age, fracture location, and prevalence according to BMD. In addition, BMD, T-score, body mass index, and European Quality of Life-5 Dimensions (EQ-5D) were investigated in the three groups, and the differences between groups were compared and analyzed.ResultsThe prevalence of radiologic OVCFs at the T11–L1 was 3.7 times higher in the 70s group (44.0%) than in the 50s group (11.9%). Femur and total hip BMD were significantly lower in patients with thoracolumbar junction fractures than in patients with L2–5 fractures, whereas no difference was observed in lumbar spine BMD. Of the three OVCF groups, the within 3 months of OVCF group had the lowest lumbar spine T-score of −2.445. The asymptomatic OVCF group also showed significantly lower lumbar spine T-score than did the group without radiologic OVCFs (p < 0.001). The EQ-5D showed a significant decrease in the radiologic OVCF group (p < 0.001) and within 3 months of OVCF group (p < 0.001).ConclusionsThe prevalence of OVCFs in the thoracolumbar junction rapidly increases with old age and low BMD in Korean postmenopausal women. Femur and total hip BMD are more predictive of thoracolumbar junction fractures than lumbar spine BMD. Patients with radiologic OVCFs had a significantly lower quality of life than no OVCF group. Therefore, this study shows it is important to treat and prevent osteoporosis before an OVCF occurs.     

Diagnostic accuracy of Raman spectroscopy for prostate cancer: a systematic review and meta-analysis

BackgroundAlthough various studies have been conducted to demonstrate the possibility of Raman spectroscopy (RS) as a diagnostic tool for prostate cancer (PC), it is difficult to use it in the real clinical area because of imitations in various research processes. Therefore, we did a systematic review and meta-analysis about the accuracy in diagnostic use of RS for PC.MethodsA literature search was done using PubMed, Embase, and Cochrane library databases in March 2019 to analyze the accuracy of RS for diagnosis of PC. The accuracy of RS for diagnosis of PC was evaluated by means of pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC).ResultsFive studies were included for qualitative analysis by screening the remaining articles according to the inclusion and exclusion criteria by means of a systematic review. The pooled sensitivity and specificity of RS were 0.89 (95% CI: 0.87–0.91) and 0.91 (95% CI: 0.89–0.93), respectively. The overall PLR and NLR were 9.12 (95% CI: 4.15–20.08) and 0.14 (95% CI: 0.07–0.29), respectively. The DOR of RS demonstrated high accuracy (73.32; 95% CI: 18.43–291.73). The area under the curves (AUCs) of SROC curves was 0.93.ConclusionsRS is an optical diagnostic method with high potential for diagnosis and grading of PC and has advantages of real-time and convenient use. In order to consider real-time use of RS in an actual clinical setting, more studies for standardization and generalization of RS performance and analytical method must be conducted.