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The development of opioid analgesics with reduced adverse effects is an unmet need. In a previous study, we discovered a unique combination of BPRMU191 and morphinan antagonists that produced potent antinociception with reduced adverse effects after central administration (intrathecal or intracerebroventricular). BPRMU191/naltrexone exhibits notable in vitro and in vivo pharmacological properties. However, the poor blood-brain barrier penetrative ability of BPRMU191 restricts its clinical application. In this study, we utilized a prodrug strategy to deliver sufficient brain concentrations of BPRMU191 and selected compound 2 (DBPR116) with the best physicochemical and pharmacological properties among other in vivo active prodrugs. The in vivo pharmacological studies of compound 2 /naltrexone, including thermally stimulated pain, cancer pain, constipation, sedation, psychological dependence, heart rate, and respiratory frequency measurements, demonstrated that it was a safer opioid analgesic than morphine in pain control.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation., Competing Interests: Declaration of interests S.-H.U., S.-H.Y., S.-Y.L., H.H.L., and C.S. have a granted patent (no. US10544113 B2) covering BPRMU191., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Obstructive sleep apnea and vitamin D deficiency are associated with multiple complications with increased morbidity and mortality. However, the relationship between these two entities remains unclear, with clinical studies demonstrating contradictory results. This narrative review aims to present the current evidence and understanding of this relationship and discuss the possible mechanisms linking these two disease entities. Finally, we summarize and propose areas of opportunity for future research., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Innovative treatments of refractory epilepsy are widely desired, for which chemogenetic technology can provide region- and cell-type-specific modulation with relative noninvasiveness., Objectives: We aimed to explore the specific applications of chemogenetics for locally and remotely networks controlling hippocampal seizures., Methods: A virus coding for a modified human Gi-coupled M4 muscarinic receptor (hM4Di) on pyramidal cells was injected into either the right hippocampal CA3 or the bilateral anterior nucleus of the thalamus (ANT) in rats. After one month, seizures were induced by 4-aminopyridine (4-AP) injection into the right CA3. Simultaneously, clozapine-N-oxide (CNO) (2.5 mg/kg) or clozapine (0.1 mg/kg), the specific ligands acting on hM4Di, were injected intraperitoneally. We also set up hM4Di control and clozapine control groups to eliminate the influence of viral transfection and the ligand alone on the experimental results., Results: For both local and remote controls, the mean seizure duration was significantly reduced upon ligand application in the experimental groups. Seizure frequency, on the other hand, only showed a significant decrease in local control, with a lower frequency in the clozapine group than in the CNO group. Both the effects of CNO and clozapine were time-dependent, and clozapine was faster than CNO in local seizure control., Conclusion: This study shows the potency of chemogenetics to attenuate hippocampal seizures locally or remotely by activating the transfected hM4Di receptor with CNO or clozapine. ANT is suggested as a potentially safe chemogenetic application target in the epileptic network for focal hippocampal seizures., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Recent studies found white coats to be reservoirs for bacteria and medical students did not conform to proper hygiene measures when using these white coats. We investigated the knowledge, attitude, and practice (KAP) of medical students toward white coat use in clinical settings (LAUNDERKAP)., Methods: A validated, online-based survey was disseminated to 670 students from four Malaysian medical schools via random sampling. Scores were classified into good, moderate, or poor knowledge and practice, and positive, neutral, or negative attitude. Mann-Whitney U and Kruskal-Wallis tests were used to analyze the relationship between demographic variables and knowledge, attitude, and practice scores., Results: A total of 492/670 students responded (response rate: 73.4%). A majority showed negative attitudes (n = 246, 50%), poor knowledge (n = 294, 59.8%), and moderate practice (n = 239, 48.6%). Senior and clinical year students had more negative attitudes. Male students had higher knowledge, while students from private medical schools and preclinical years had better practice. There was a significant relationship between attitude and practice (r = 0.224, P < .01), as well as knowledge and practice (r = 0.111, P < .05)., Conclusions: The results demonstrate the need for more education to improve medical students' infection control practices. Our results can also guide decision-making among administrators on the role of white coats as part of medical student attire., (Copyright © 2023 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

PURPOSE  : Obstructive sleep apnea (OSA) is a chronic, sleep-related breathing disorder which leads to increased cardiovascular risks. Vitamin D deficiency is associated with various cardiometabolic complications, including increased cardiovascular morbidity and mortality. We aimed to analyze the difference in serum 25-hydroxyvitamin D (25-OHD) level, prevalence of vitamin D insufficiency and deficiency, and the effect of CPAP treatment on serum 25-OHD levels among adult patients with OSA., Methods: We pooled data from 18 observational studies involving 5592 individuals. Baseline parameters that might have contributed to the significant differences observed were also analyzed., Results: Patients with OSA had significantly lower serum 25-OHD levels (pooled d +  - 0.74 [95% CI: - 1.19 to - 0.28], p < 0.01) and higher prevalence of vitamin D deficiency (pooled log (odds ratio) 0.98 [95% CI: 0.30 to 1.67], p < 0.01) compared to those without OSA. Subgroup analysis demonstrated that these differences were significant only in moderate OSA and severe OSA. Neither age nor BMI nor geographical latitude contributed significantly to the differences observed in serum 25-OHD levels. The use of CPAP did not lead to significant changes in serum 25-OHD levels., Conclusion: Patients with OSA have lower serum 25-OHD levels with a higher prevalence of vitamin D deficiency, regardless of age or BMI, pointing to an independent association between vitamin D and OSA., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin-angiotensin-aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin-angiotensin-aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04-0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05-60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11-7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42-10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86-5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57-6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin-angiotensin-aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED 50 value of 127.1 ± 34.65 μg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Medical students' white coats were found to harbor harmful organisms. This could be due to non-compliance to white coat hygiene measures. Therefore, we aim to develop and validate a questionnaire to assess the of knowledge, attitude, and practice (LAUNDERKAP) of white coat use among medical students in Malaysia., Methods: This study was conducted in 4 local medical schools. LAUNDERKAP was developed via literature review and had 3 domains: attitude, knowledge, practice. An expert panel assessed the content validity and clarity of wording. LAUNDERKAP was then piloted among 32 medical students. To test construct validity and internal consistency, 362 medical students were approached. Construct validity was assessed using exploratory factor analysis. Internal consistency was evaluated using Cronbach alpha for attitude and practice, while Kuder-Richardson 20 (KR-20) was used for knowledge., Results: A total of 319 of 362 students responded. Exploratory factor analysis extracted 1 factor each for attitude and knowledge respectively, and 3 factors for practice. Cronbach alpha for attitude was 0.843 while KR-20 for knowledge was 0.457. Cronbach alpha for practice ranged from 0.375 to 0.689. The final LAUNDERKAP contained 32-items (13 attitude, 9 knowledge, 10 practice)., Conclusions: LAUNDERKAP had adequate psychometric properties and can be used to assess KAP of medical students towards white coat use., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

We identified, via high-throughput screening using a FLIPR® calcium assay, compound 1, which incorporated a dihydroquinolinyl-2-oxoethylsulfanyl-(1H,5H)-pyrimidinedione core and activated the μ-opioid receptor (MOR) in the presence of naloxone or naltrexone. A structure-activity relationship study of the analogs of 1 led to the design of compound 21, which activated MOR in the presence of naloxone with an EC 50 of 3.3 ± 0.2 μM. MOR activation by the compound 21-antagonist pair was antagonist-dependent. Compound 21 did not affect the potency of the orthosteric agonist, morphine, toward MOR, indicating that it affected the function of MOR antagonists rather than that of the agonists. Computer modeling of the compound 21-MOR-naloxone complex revealed major interactions between compound 21 and MOR, including hydrogen bonding with Ser196, π-π stacking with Tyr149, and sulfur-aromatic interaction with Trp192. This study may pave the way for developing agents capable of safe and effective MOR modulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Altered expression patterns of Na + -K + -2Cl - (NKCC1) and K + -Cl - (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD)., Materials and Methods: We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting., Results: Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group., Conclusion: Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Xing, Zhang, Wang, Lai, Cheng, Li, Yu, Yan, Xu, Piao, Zeng, Loh, Zhang and Yang.)

Both primary aldosteronism and obstructive sleep apnea are well-known causes of hypertension and contribute to increased cardiovascular morbidity and mortality independently. However, the relationship between these two entities remains unclear, with studies demonstrating contradictory results. This review aims to collate and put into perspective current available research regarding the association between primary aldosteronism and obstructive sleep apnea. The relationship between these two entities, clinical characteristics, clinical implications, outcomes of treatment, potential causal links and mechanisms are hereby presented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Loh and Sukor.)

We aim to explore the microscopic neurophysiology of focal cortical dysplasia (FCD) induced epileptogenesis in specific macroscopic brain regions, therefore mapping a micro-macro neuronal network that potentially indicates the epileptogenic mechanism. Epileptic and relatively non-epileptic temporal neocortex specimens were resected from FCD and mesial temporal lobe epilepsy (mTLE) patients, respectively. Whole-cell patch-clamping was performed on cells from the seizure onset zone (SOZ) and non-SOZ inside the epileptogenic zone (EZ) of FCD patients, as well as the non-epileptic neocortex of mTLE patients. Microscopic data were recorded, including membrane characteristics, spontaneous synaptic activities, and evoked action potentials. Immunohistochemistry was also performed on parvalbumin-positive (PV+) interneurons. We found that SOZ interneurons exhibited abnormal neuronal expression and distribution as well as reduced overall function compared with non-SOZ and mTLE interneurons. The SOZ pyramidal cells experienced higher excitation but lower inhibition than the mTLE controls, whereas the non-SOZ pyramidal cells exhibited intermediate excitability. Action potential properties of both types of neurons also suggested more synchronized neuronal activity inside the EZ, particularly inside the SOZ. Together, our research provides evidence for a potential neurocircuit underlying SOZ epileptogenesis and non-SOZ seizure susceptibility. Further investigation of this microscopic network may promote understanding of the mechanism of FCD-induced epileptogenesis., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objective: Obesity is prevalent and has a negative impact on women's health, including sexual dysfunction. Recent review articles suggest improvement in Female Sexual Function Index (FSFI) and proportion of female sexual dysfunction (FSD) among women with obesity after bariatric surgery., Methods: We pooled data from 16 observational studies involving 953 women. The study outcomes were mean FSFI scores and proportion of FSD before and after bariatric surgery. We also sub-analyzed whether age and duration of follow-up affected these outcomes., Results: The mean age of the subjects was 39.4 ± 4.2 years. Body mass index (BMI) showed significant reduction postoperatively ( p < 0.0001). Bariatric surgery led to significant improvement in total FSFI score ( p = 0.0005), and all sexual domains except pain. Bariatric surgery reduced the odds of having FSD by 76% compared with those who did not undergo operation (OR 0.24, 95% CI = 0.17, 0.33, p < 0.0001). Our sub-analysis demonstrated a significant reduction in the proportion of FSD for patients <40 years of age. The improvement of total FSFI scores and reduction in proportion of FSD remained significant within the first 12 months after surgery. Univariate meta-regression showed that BMI was not a significant covariate for improvement of FSFI scores ( β = 0.395, p = 0.1, 95% CI = 0.884, 0.095)., Conclusions: Bariatric surgery is shown to improve sexual function scores and prevalence of FSD. This is especially significant among women <40 years of age. This benefit remained significant within the first year after surgery. This appears to be an additional benefit for these patients.

Aims: We aimed to examine if bariatric surgery was associated with a reduction in the prevalence of depressive and anxiety symptoms among people with obesity., Materials and Methods: We pooled data from 49 studies involving 11,255 people with obesity who underwent bariatric surgery. The study outcomes were the prevalence of depressive and anxiety symptoms among these patients pre- and post-surgery., Results: There was a significant reduction in body mass index (BMI) post-operatively (pooled d+: -13.3 kg/m 2 [95% confidence interval [CI] 15.19, -11.47], p < 0.001). The pooled proportion of patients with anxiety symptoms reduced from 24.5% pre-operatively to 16.9% post-operatively, with an odds ratio (OR) of 0.58 (95% CI 0.51, 0.67, p < 0.001). The reduction remained significant in women aged ≥40 years and irrespective of post-operative BMI. There were significant reductions in Hospital Anxiety and Depression Score (HADS) (anxiety component) by 0.64 (pooled d+: -0.64 [95% CI -1.06, -0.22], p = 0.003) and Generalized Anxiety Disorder Assessment-7 score by 0.54 (pooled d+: -0.54 [95% CI -0.64, -0.44], p < 0.001). The pooled proportion of depressive symptoms reduced from 34.7% pre-operatively to 20.4% post-operatively, with an OR of 0.49 (95% CI 0.37, 0.65, p < 0.001). The reduction remained significant irrespective of patient's age and post-operative BMI. There were also significant reductions in HADS score (depressive component) (pooled d+: -1.34 [95% CI -1.93, -0.76], p < 0.001), Beck's Depression Inventory score (pooled d+: -1.04 [95% CI -1.46, -0.63], p < 0.001) and Patient Health Questionnaire-9 score (pooled d+: -1.11 [95% CI -1.21, -1.01], p < 0.001)., Conclusion: Bariatric surgery was associated with significant reduction in the prevalence and severity of depressive and anxiety symptoms among people with obesity., (© 2021 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Objective: We aimed to explore the feasibility of using scalp-recorded high-frequency oscillations (HFOs) to evaluate the efficacy and prognosis of adrenocorticotropic hormone (ACTH) treatment in patients with infantile spasms., Methods: Thirty-nine children with infantile spasms were enrolled and divided into seizure-free and non-seizure-free groups after ACTH treatment. Patients who were seizure-free were further divided into relapse and non-relapse subgroups based on the observations made during a 6-month follow-up period. Scalp ripples were detected and compared during the interictal periods before and after 2 weeks of treatment., Results: After ACTH treatment, the number and channels of ripples were significantly lower, whereas the percentage decrease in the number, spectral power, and channels of ripples was significantly higher in the seizure-free group than in the non-seizure-free group. In addition, the relapse subgroup showed higher number and spectral power and wider distribution of ripples than did the non-relapse subgroup. Changes in HFOs in terms of number, spectral power, and channel of ripples were closely related to the severity of epilepsy and can indicate disease susceptibility., Significance: Scalp HFOs can be used as an effective biomarker to monitor the effect and evaluate the prognosis of ACTH therapy in patients with infantile spasms., (© 2021 International League Against Epilepsy.)

Accurate epileptogenic zone (EZ) or seizure onset zone (SOZ) localization is crucial for epilepsy surgery optimization. Previous animal and human studies on epilepsy have reported that changes in blood oxygen level-dependent (BOLD) signals induced by epileptic events could be used as diagnostic markers for EZ or SOZ localization. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) recording is gaining interest as a non-invasive tool for preoperative epilepsy evaluation. However, EEG-fMRI studies have reported inconsistent and ambiguous findings. Therefore, it remains unclear whether BOLD responses can be used for accurate EZ or SOZ localization. In this study, we used simultaneous EEG-fMRI recording in a rat model of 4-aminopyridine-induced acute focal seizures to assess the spatial concordance between individual BOLD responses and the SOZ. This was to determine the optimal use of simultaneous EEG-fMRI recording in the SOZ localization. We observed a high spatial consistency between BOLD responses and the SOZ. Further, dynamic BOLD responses were consistent with the regions where the seizures were propagated. These results suggested that simultaneous EEG-fMRI recording could be used as a noninvasive clinical diagnostic technique for localizing the EZ or SOZ and could be an effective tool for mapping epileptic networks., (Copyright © 2021. Published by Elsevier Inc.)

Opioids, like morphine and naloxone, regulate the proliferation and neuronal differentiation of neural stem cells (NSCs) in a receptor-independent and ten-eleven translocation methylcytosine dioxygenase (TET1)-dependent manner in vitro. Whether naloxone regulates hippocampal NSCs and contextual learning in vivo in a similar manner was determined. Naloxone infusion increased the Ki67 and Doublecortin positive cells in subgranular zone of wild type mice, which suggested the increased proliferation and differentiation of hippocampal NSCs in vivo and was consistent with the in vitro functions of naloxone. In addition, naloxone infusion also facilitated the contextual learning and memory of wild type mice. To determine the contribution of μ-opioid receptor (OPRM1) and TET1 to these functions of naloxone, several types of knockout mice were used. Since Tet1 -/- mice have high deficiency in contextual learning and memory, Tet1 +/- mice were used instead. The abilities of naloxone to regulate NSCs and to facilitate contextual learning were significantly impaired in Tet1 +/- mice. In addition, these abilities of naloxone were not affected in Oprm1 -/- mice. Therefore, naloxone facilitates contextual learning and memory in a receptor-independent and Tet1-dependent manner, which provides new understanding on the receptor-independent functions of opioids.

Accurate localization of the epileptogenic zone (EZ) is a key factor to obtain good surgical outcome for refractory epilepsy patients. However, no technique, so far, can precisely locate the EZ, and there are barely any reports on the combined application of multiple technologies to improve the localization accuracy of the EZ. In this study, we aimed to explore the use of a multimodal method combining PET-MRI, fluid and white matter suppression (FLAWS)-a novel MRI sequence, and high-frequency oscillation (HFO) automated analysis to delineate EZ. We retrospectively collected 15 patients with refractory epilepsy who underwent surgery and used the above three methods to detect abnormal brain areas of all patients. We compared the PET-MRI, FLAWS, and HFO results with traditional methods to evaluate their diagnostic value. The sensitivities, specificities of locating the EZ, and marking extent removed versus not removed [RatioChann(ev)] of each method were compared with surgical outcome. We also tested the possibility of using different combinations to locate the EZ. The marked areas in every patient established using each method were also compared to determine the correlations among the three methods. The results showed that PET-MRI, FLAWS, and HFOs can provide more information about potential epileptic areas than traditional methods. When detecting the EZs, the sensitivities of PET-MRI, FLAWS, and HFOs were 68.75, 53.85, and 87.50%, and the specificities were 80.00, 33.33, and 100.00%. The RatioChann(ev) of HFO-marked contacts was significantly higher in patients with good outcome than those with poor outcome ( p < 0.05). When intracranial electrodes covered all the abnormal areas indicated by neuroimaging with the overlapping EZs being completely removed referred to HFO analysis, patients could reach seizure-free ( p < 0.01). The periphery of the lesion marked by neuroimaging may be epileptic, but not every lesion contributes to seizures. Therefore, approaches in multimodality can detect EZ more accurately, and HFO analysis may help in defining real epileptic areas that may be missed in the neuroimaging results. The implantation of intracranial electrodes guided by non-invasive PET-MRI and FLAWS findings as well as HFO analysis would be an optimized multimodal approach for locating EZ., Competing Interests: XZ was employed by the company Siemens Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Yu, Ren, Wang, Yan, Chen, Yan, Wang, Xing, Zhang, Zhang, Loh, Zhang and Yang.)

Although the roles of opioid receptors in neurogenesis have been implicated in previous studies, the mechanism by which κ-opioid receptor (OPRK1) regulates adult neurogenesis remains elusive. We now demonstrate that two agonists of OPRK1, U50,488H and dynorphin A, inhibit adult neurogenesis by hindering neuronal differentiation of mouse hippocampal neural stem cells (NSCs), both in vitro and in vivo. This effect was blocked by nor-binaltorphimine (nor-BNI), a specific antagonist of OPRK1. By examining neurogenesis-related genes, we found that OPRK1 agonists were able to downregulate the expression of Pax6, Neurog2, and NeuroD1 in mouse hippocampal NSCs, in a way that Pax6 regulates the transcription of Neurog2 and Neurod1 by directly interacting with their promoters. Moreover, this effect of OPRK1 was accomplished by inducing expression of miR-7a, a miRNA that specifically targeted Pax6 by direct interaction with its 3'-UTR sequence, and thereby decreased the levels of Pax6, Neurog2, and NeuroD1, thus resulted in hindrance of neuronal differentiation of NSCs. Thus, by modulating Pax6/Neurog2/NeuroD1 activities via upregulation of miR-7a expression, OPRK1 agonists hinder the neuronal differentiation of NSCs and hence inhibit adult neurogenesis in mouse hippocampus., (©AlphaMed Press 2021.)

Background: Most studies showing association between mothers with obesity in pregnancy or excessive gestational weight gain (GWG) and adverse neonatal outcome were cross-sectional or retrospective. Many included patients are with gestational diabetes mellitus (GDM), which is a strong risk factor for this adverse outcome. There are no prospective studies on this topic in Malaysia. This study aimed to examine prospectively the effects of obesity in pregnancy and GWG, independent of GDM, on neonatal outcome., Methods: Pregnant mothers in the first trimester, who presented to health clinics in Kuching, were screened. Mothers with existing diabetes mellitus or GDM were excluded using 75-g oral glucose tolerance test during the first and second trimesters. Participants with the first trimester BMI ≥ 23 kg/m 2 were recruited as overweight/obese group, whereas those with BMI 18.5-22.9 kg/m 2 were taken as the comparison group. At every trimester visit, mothers' weights were recorded. Babies' birth weight and occurrence of adverse neonatal outcome were documented., Results: There were 123 mothers recruited as overweight/obese group (mean BMI 29.0 kg/m 2  ± 4.45) and 102 mothers as comparison group (mean BMI 20.4 kg/m 2  ± 1.48). The number of low birth weight was similar between groups: 9.8% in overweight/obese group, 6.9% in the comparison group ( p  = 0.416). More than half of these babies were born to mothers with inadequate GWG (58.3% in obese group vs. 57.1% in control group, p  = 0.077). There was no significant difference in the mean birth weight (3000 g ± 454.5 vs. 3038 g ± 340.8, p  = 0.471), preterm delivery (8.13% vs. 3.92%, p  = 0.193), and admission rate to neonatal intensive care unit (8.13% vs. 7.85%, p  = 0.937) between groups. There was a positive correlation between the total GWG in overweight/obese group on baby's weight ( r  = 0.222, p  = 0.013). Inadequate GWG was not correlated with lower birth weight ( p  = 0.052)., Conclusions: Obesity in pregnancy was not associated with poor neonatal outcome in this small sample of women in Malaysia. Total GWG showed a weak correlation with baby's birth weight in overweight/obese group., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies. Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development, plasticity, and disorders of the mammalian central nervous system. Neural stem cells (NSCs), originating from the neuroepithelium, generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain., Main Body: Here, we summarized recent research in proteins responsible for the establishment, maintenance, interpretation, and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs. In addition, we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases., Conclusion: Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.

Objective: To evaluate the effect of adding DPP4 inhibitor (DPP4-i) on glycemic variability (GV) in patients with type 2 diabetes mellitus (T2DM) treated with premixed human insulin (MHI)., Methodology: We conducted a prospective study in patients with T2DM on twice-daily MHI with or without metformin therapy. Blinded continuous glucose monitoring was performed at baseline and following 6 weeks of Vildagliptin therapy., Results: Twelve patients with mean (SD) age of 55.8 (13.1) years and duration of disease of 14.0 (6.6) years were recruited. The addition of Vildagliptin significantly reduced GV indices (mmol/L): SD from 2.73 (IQR 2.12-3.66) to 2.11 (1.76-2.55), p =0.015; mean amplitude of glycemic excursions (MAGE) 6.94(2.61) to 5.72 (1.87), p =0.018 and CV 34.05 (8.76) to 28.19 (5.36), p =0.010. In addition, % time in range (3.9-10 mmol/l) improved from 61.17 (20.50) to 79.67 (15.33)%, p =0.001; % time above range reduced from 32.92 (23.99) to 18.50 (15.62)%, p =0.016; with reduction in AUC for hyperglycemia from 1.24 (1.31) to 0.47 (0.71) mmol/day, p =0.015. Hypoglycemic events were infrequent and the reduction in time below range and AUC for hypoglycemia did not reach statistical significance., Conclusion: The addition of DPP4-I to commonly prescribed twice-daily MHI in patients with T2DM improves GV and warrants further exploration., Competing Interests: The authors declared no conflicts of interest., (© 2021 Journal of the ASEAN Federation of Endocrine Societies.)

Objective: Neuromodulatory anterior thalamic deep brain stimulation (DBS) is an effective therapy for intractable epilepsy, but few patients achieve complete seizure control with thalamic DBS. Other stimulation sites may be considered for anti-seizure DBS. We investigated bilateral low-frequency stimulation of the endopiriform nuclei (LFS-EPN) to control seizures induced by intracortically implanted cobalt wire in rats., Methods: Chronic epilepsy was induced by cobalt wire implantation in the motor cortex unilaterally. Bipolar-stimulating electrodes were implanted into the EPN bilaterally. Continuous electroencephalography (EEG) was recorded using electrodes placed into bilateral motor cortex and hippocampus CA1 areas. Spontaneous seizures were monitored by long-term video-EEG, and behavioral seizures were classified based on the Racine scale. Continuous 1-Hz LFS-EPN began on the third day after electrode implantation and was controlled by a multi-channel stimulator. Stimulation continued until the rats had no seizures for three consecutive days., Results: Compared with the control and sham stimulation groups, the LFS-EPN group experienced significantly fewer seizures per day and the mean Racine score of seizures was lower due to fewer generalized seizures. Ictal discharges at the epileptogenic site had significantly reduced theta band power in the LFS-EPN group compared to the other groups., Interpretation: Bilateral LFS-EPN attenuates cobalt wire-induced seizures in rats by modulating epileptic networks. Reduced ictal theta power of the EEG broadband spectrum at the lesion site may be associated with the anti-epileptogenic mechanism of LFS-EPN. Bilateral EPN DBS may have therapeutic applications in human partial epilepsies., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Polycystic ovarian syndrome (PCOS) is a common disorder characterized by clinical or biochemical hyperandrogenism and ovulary dysfunction. Female sexual dysfunction (FSD) adversely affects quality of life and interpersonal relationships. We aimed to compare the prevalence of FSD in women with and without PCOS., Methods: We pooled data from 28 observational studies involving 6256 women. Apart from the total prevalence of FSD, subgroup analyses based on different PCOS diagnostic criteria and obesity status (body mass index [BMI] ≥ 25 kg/m 2 ) were performed. The differences in total and subscale scores of the Female Sexual Function Index (FSFI) among women with and without PCOS were also compared., Results: Women with PCOS were younger (mean ± SD 28.56 ± 3.0 vs 31.5 ± 3.2 years, p < 0.001) with higher BMI (28.5 ± 4.2 vs 27.0 ± 6.1 kg/m 2 , p < 0.001), Ferriman-Gallwey score (10.0 ± 3.2 vs 4.0 ± 2.1, p < 0.001), and serum total testosterone level (2.34 ± 0.58 nmol/L vs 1.57 ± 0.60 nmol/L, p < 0.001) compared with women without PCOS. The prevalence of FSD among women with and without PCOS was 35% and 29.6%, respectively. There was no significant difference in total FSFI score (24.59 ± 3.97 vs 26.04 ± 3.05, p = 0.237) between the two groups. Women with PCOS, however, had significantly lower scores in the pain (p < 0.001) and satisfaction subscales (p = 0.010) compared with women without PCOS. Women with PCOS had 1.32 higher odds (95% CI 1.07, 1.61) of having FSD than women without PCOS., Conclusion: Women with PCOS have a higher risk of FSD than those without PCOS. Although total FSFI scores were not significantly different, women with PCOS tended to report dyspareunia and lack of sexual satisfaction.

During Ramadan, Muslims fast from sunrise (Sahur) to sunset (Iftar) and are required to abstain from food and fluids, including oral and injectable medications. Patients with diabetes who fast during Ramadan are at risk of developing hyperglycemia with increased risk of ketoacidosis, hypoglycemia, dehydration and thrombosis. Pre-Ramadan education and preparation of a fasting patient are essential to reduce severe complications. This review paper summarizes studies to date on oral and injectable medications available for patients with type 2 diabetes during Ramadan fasting, as well as recommendations on management of these patients during Ramadan. Although there is limited data on the use of Metformin, Acarbose and Thiazolidinedione in Ramadan, they appear to be safe. Sulphonylurea, especially Glibenclamide, is associated with higher risk of hypoglycemia during Ramadan fasting, hence may need adjustment in dosing and timing. The incretin group and SGLT2 inhibitor use during Ramadan fasting is associated with low risk of hypoglycemia with no increased adverse events. Insulin regimes need to be individualized for patients who fast during Ramadan.

Morphine is a strong painkiller acting through mu-opioid receptor (MOR). Full-length 7-transmembrane (TM) variants of MOR share similar amino acid sequences of TM domains in rodents and humans; however, interspecies differences in N- and C-terminal amino acid sequences of MOR splice variants dramatically affect the downstream signaling. Thus, it is essential to develop a mouse model that expresses human MOR splice variants for opioid pharmacological studies. We generated 2 lines of fully humanized MOR mice (hMOR; mMOR mice), line #1 and #2. The novel murine model having human OPRM1 genes and human-specific variants was examined by reverse-transcription polymerase chain reaction and the MinION nanopore sequencing. The differences in the regional distribution of MOR between wild-type and humanized MOR mice brains were detected by RNAscope and radioligand binding assay. hMOR; mMOR mice were characterized in vivo using a tail-flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, and rectal temperature measurement. The data indicated that wild-type and humanized MOR mice exhibited different pharmacology of morphine, including antinociception, tolerance, sedation, and withdrawal syndromes, suggesting the presence of species difference between mouse and human MORs. Therefore, hMOR; mMOR mice could serve as a novel mouse model for pharmacogenetic studies of opioids.

The abilities of opioids to activate downstream signaling pathways normally depend on the binding between opioids and their receptors. However, opioids may also function in a receptor-independent manner, especially in neural stem cells (NSCs) in which the expression of opioid receptors and endogenous opioid agonists is low. When two opioids, morphine and naloxone, were used during the early stage of NSC differentiation, increased neurogenesis was observed. However, naloxone methiodide, a membrane impenetrable analog of naloxone, did not affect the NSC differentiation. The abilities of morphine and naloxone to facilitate neurogenesis were also observed in opioid receptor-knockout NSCs. Therefore, morphine and naloxone promote neurogenesis in a receptor-independent manner at least during the early stage. In addition, the receptor-independent functions of opioids were not observed in methylcytosine dioxygenase ten-eleven translocation 1 (Tet1) knockout NSCs. When the expression of opioid receptors increased and the expression of Tet1 decreased during the late stage of NSC differentiation, morphine, but not naloxone, inhibited neurogenesis via traditional receptor-dependent and miR181a-Prox1-Notch-related pathway. In summary, the current results demonstrated the time-dependent effects of opioids during the differentiation of NSCs and provided additional insight on the complex functions of opioids., (© 2020 Federation of American Societies for Experimental Biology.)

There is unmet need to design an analgesic with fewer side effects for severe pain management. Although traditional opioids are the most effective painkillers, they are accompanied by severe adverse responses, such as respiratory depression, constipation symptoms, tolerance, withdrawal, and addiction. We indicated BPR1M97 as a dual mu opioid receptor (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor full agonist and investigated the pharmacology of BPR1M97 in multiple animal models. In vitro studies on BPR1M97 were assessed using cyclic-adenosine monophosphate production, β-arrestin, internalization, and membrane potential assays. In vivo studies were characterized using the tail-flick, tail-clip, lung functional, heart functional, acetone drop, von Frey hair, charcoal meal, glass bead, locomotor activity, conditioned place preference (CPP) and naloxone precipitation tests. BPR1M97 elicited full agonist properties for all cell-based assays tested in MOP-expressing cells. However, it acted as a G protein-biased agonist for NOP. BPR1M97 initiated faster antinociceptive effects at 10 min after subcutaneous injection and elicited better analgesia in cancer-induced pain than morphine. Unlike morphine, BPR1M97 caused less respiratory, cardiovascular, and gastrointestinal dysfunction. In addition, BPR1M97 decreased global activity and induced less withdrawal jumping precipitated by naloxone. Thus, BPR1M97 could serve as a novel small molecule dual receptor agonist for antinociception with fewer side effects than morphine. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'., (Copyright © 2019. Published by Elsevier Ltd.)

Normally, opioids function in a receptor-dependent manner. They bind to opioid receptors, activate or inhibit receptor activation, and subsequently modulate downstream signal transduction. However, the complex functions of opioids and the low expression of opioid receptors and their endogenous peptide agonists in neural stem cells (NSCs) suggest that some opioids may also modulate NSCs via a receptor-independent pathway. In the current study, two opioids, morphine and naloxone, are demonstrated to facilitate NSC proliferation via a receptor-independent and ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-dependent pathway. Morphine and naloxone penetrate cell membrane, bind to TET1 protein via three key residues (1,880-1,882), and subsequently result in facilitated proliferation of NSCs. In addition, the two opioids also inhibit the DNA demethylation ability of TET1. In summary, the current results connect opioids and DNA demethylation directly at least in NSCs and extend our understanding on both opioids and NSCs., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Primary aldosteronism (PA), the most common cause of secondary hypertension, is a well-recognized condition that can lead to cardiovascular and renal complications. PA is frequently left undiagnosed and untreated, leading to aldosterone-specific morbidity and mortality. In this review we highlight the evidence linking PA with other conditions such as (i) diabetes mellitus, (ii) obstructive sleep apnea, and (iii) bone health, along with clinical implications and proposed underlying mechanisms.

Introduction: Recent studies showed a possible association between hyperaldosteronism and secondary hyperparathyroidism leading to reduced bone health, however results are conflicting., Evidence Acquisition: We conducted a meta-analysis to evaluate the relationship between primary aldosteronism (PA) with bone biochemical markers and to assess bone mineral density in patients with primary aldosteronism., Evidence Synthesis: A total of 939 subjects were examined (37.5% with PA). Patients with PA had significantly higher serum parathyroid hormone, lower serum calcium, higher urine calcium excretion and higher serum alkaline phosphatase compared to patients without PA, with no significant difference in serum vitamin D between both groups. Bone mineral density of lumbar spine, femoral neck and total neck of femur were similar between two groups. With PA treatment, there was a significant increment in serum calcium and reduction in serum parathyroid hormone., Conclusions: PA is associated with hypercalciuria with subsequent secondary hyperparathyroidism. This potentially affects bone health. We recommend this to be part of complication screening among patients with PA.

Aims/introduction: Although patients with type 1 diabetes are medically exempt, many insist on fasting during Ramadan. Multiple daily insulin injections (MDI), premixed insulin and continuous subcutaneous insulin infusion (CSII) are commonly used. To date, little is known about the safety of Ramadan fasting in these patients., Materials and Methods: We pooled data from 17 observational studies involving 1,699 patients treated with either CSII or non-CSII (including premixed and MDI) regimen. The study outcomes were the frequencies of hypoglycemia, hyperglycemia and/or ketosis. Given the lack of patient-level data, separate analyses for premixed and MDI regimen were not carried out., Results: The CSII-treated group (n = 203) was older (22.9 ± 6.9 vs 17.8 ± 4.0 years), and had longer diabetes duration (116.7 ± 66.5 vs 74.8 ± 59.2 months) and lower glycated hemoglobin (7.8 ± 1.1% vs 9.1 ± 2.0%) at baseline than the non-CSII-treated group (n = 1,496). The non-CSII-treated group had less non-severe hypoglycemia than the CSII-treated group (22%, 95% CI 13-34 vs 35%, 95% CI 17-55). Of the non-CSII-treated group, 7.1% (95% CI 5.8-8.5) developed severe hypoglycemia, but none from the CSII-treated group did. The non-CSII-treated group was more likely to develop hyperglycemia (12%, 95% CI 3-25 vs 8.8%, 95% CI 0-31) and ketosis (2.5%, 95% CI 1.0-4.6 vs 1.6%, 95% CI 0.1-4.7), and discontinue fasting (55%, 95% CI 34-76 vs 31%, 95% CI 9-60) than the CSII-treated group., Conclusions: The CSII regimen had lower rates of severe hypoglycemia and hyperglycemia/ketosis, but a higher rate of non-severe hyperglycemia than premixed/MDI regimens. These suggest that appropriate patient selection with regular, supervised fine-tuning of the basal insulin rate with intensive glucose monitoring might mitigate the residual hypoglycemia risk during Ramadan., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Methadone is an effective therapy for opiate dependence. However, one of the commonest side effects is sexual dysfunction among male patients. Buprenorphine is an alternative to methadone. This study aimed to compare sexual desire among opiate-dependent male patients on buprenorphine (BMT) and methadone maintenance therapy (MMT)., Methods: This cross-sectional study involved 126 male opiate-dependent patient who were tested for total testosterone (TT) and prolactin levels, and were interviewed and completed the Sexual Desire Inventory-2 (SDI-2), Malay language of International Index of Erectile Function (Mal-IIEF-15) and the Malay version of the self-rated Montgomery-Asberg Depression Rating Scale (MADRS-BM) questionnaires., Results: There were 95 (75.4%) patients on MMT and 31 (24.6%) on BMT. Patients on MMT scored significantly lower in the sexual desire domain (Mal-IIEF-15 scores) ( p  < 0.01), dyadic sexual desire ( p  = 0.04) and TT plasma level ( p  < 0.01) when compared to BMT group after controlling all the confounders., Conclusions: Patients on MMT are associated with lower sexual desire when compared with patients on BMT. Smoking may further lower testosterone and, hence, sexual desire in those already on methadone., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Oxycodone, a widely prescribed and very potent oral opioid analgesic agent, is highly addictive and has many side effects, including troublesome constipation. Our studies in mice indicated that pretreatment of naltrindole did not significantly affect the analgesic efficacy of oxycodone but attenuated the tolerance and withdrawal induced by chronic oxycodone administration. Naltrindole also attenuated the oxycodone-induced rewarding and re-instatement behaviors, as shown by the conditioned place preference test. Further, oxycodone-induced decrease in intestinal transit (i.e., constipation) was reduced by naltrindole. However, naltrindole did not block the respiratory depression produced by oxycodone. Taken together, these data suggest that naltrindole can attenuate some major side effects while retaining the analgesic efficacy of oxycodone in mice. Naltrindole and oxycodone may have the potential to be a potent analgesic combination with much lower levels of oxycodone's side effects of addictive liability and constipation., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: We conducted a meta-analysis to assess the effects of vitamin D replacement on biochemical and skeletal parameters in subjects with mild primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency., Evidence Acquisition: A systematic search of all English-language medical literature published from 1980 till May 2016 using PubMed, Embase and Ovid was performed. Nine observational studies were evaluated after fulfilling the inclusion and exclusion criteria., Evidence Synthesis: A total of 547 patients were examined. All studies used vitamin D2/D3 or calcifediol (25-hydroxyvitamin D3), There was significant improvement of serum 25(OH)D with unchanged serum iPTH level after vitamin D replacement, with pooled d+: 3.10 (95% CI 2.25 to 3.95), P<0.01 and pooled d+: 0.82 (95% CI -0.35 to 1.98), P=0.16 respectively. There was neither worsening of the pre-existing hypercalcemia (pooled d+: -0.27 [95% CI -1.09 to 0.64, P=0.56]) nor hypercalciuria (pooled d+: 3.64 [95% CI -0.55 to 7.83, P=0.09]). Two studies assessed in this meta-analysis reported unchanged bone density with vitamin D replacement., Conclusions: Vitamin D replacement in subjects with mild PHPT and coexistent vitamin D deficiency improved serum 25(OH)D level without worsening of pre-existing hypercalcemia or hypercalciuria. Well-designed multicenter randomized controlled trials examining pre- and postoperative outcomes of vitamin D therapy in patients with different severities of PHPT and vitamin D inadequacy are warranted to elucidate the most appropriate vitamin D treatment protocol and determine the long-term safety concerns.

Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR - either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR ® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED 50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objectives: As is true for other chronic illnesses, perception of disease control is pivotal to patient empowerment in diabetes care. This study aimed to describe the perception of diabetes control by patients with poor glycated hemoglobin (A1C) levels so as to explore the relationship between perception and various sociodemographic and disease characteristics and to measure the patients' knowledge, attitudes and practices in diabetes care., Methods: A cross-sectional study was made involving 276 patients with type 2 diabetes mellitus. After obtaining informed consent, their sociodemographics, medical histories and most recent available blood investigations were documented. Patients were asked about their perceptions of diabetes control-whether it was excellent, moderate or poor. A Malay-language knowledge, attitudes and practice questionnaire was administered to respondents. Analyses were descriptive and exploratory., Results: The median age of the subjects and the durations of diabetes were 56 (interquartile range, 48-62) years and 8 (interquartile range, 4-13) years, respectively. The median A1C level was 9.5% (interquartile range, 8.3%-11.4%). Despite having poor A1C levels, 28.4% of patients perceived that their diabetes control was excellent; 58.9% perceived it as moderate, and only 12.7% accurately perceived it as poor. A significant number of those with higher education had wrong perceptions, indicating that other factors, such as effective communication, need to be considered. The absence of an association between perception and duration of diabetes suggests that information given over the years did not contribute to patients' understanding of disease control. Younger patients had better knowledge scores. Those with higher education levels had higher quartiles of knowledge and attitude but not practice scores., Conclusions: This study demonstrated discordance between perceived diabetes control and actual A1C levels, which may hinder effective diabetes care., (Copyright © 2018 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Morphine is a unique opioid analgesic that activates the mu-opioid receptor (MOR) without efficiently promoting its endocytosis that may underlie side effects. Our objective was to discover a novel enhancer of ligand-induced MOR endocytosis and determine its effects on analgesia, tolerance and dependence. We used high-throughput screening to identify convallatoxin as an enhancer of ligand-induced MOR endocytosis with high potency and efficacy. Treatment of cells with convallatoxin enhanced morphine-induced MOR endocytosis through an adaptor protein 2 (AP2)/clathrin-dependent mechanism, attenuated morphine-induced phosphorylation of MOR, and diminished desensitization of membrane hyperpolarization. Furthermore, co-treatment with chronic convallatoxin reduced morphine tolerance in animal models of acute thermal pain and chronic inflammatory pain. Acute convallatoxin administration reversed morphine tolerance and dependence in morphine-tolerant mice. These findings suggest convallatoxin are potentially therapeutic for morphine side effects and open a new avenue to study MOR trafficking.

Background: Although depression is associated with changes in the hypothalamic-pituitary-thyroid axis, its relationship with subclinical hypothyroidism (SCH) is controversial. To date, there is a lack of data on the improvement of depressive symptoms with levothyroxine therapy among individuals with coexistent SCH., Methods: We conducted a meta-analysis to evaluate the association between SCH and depression including 1) the prevalence of depression in SCH (with a sub-analysis of the geriatric cohort), 2) thyroid stimulating hormone (TSH) level among patients with depression and 3) the effect of levothyroxine therapy among patients with SCH and coexistent depression., Results: In a pooled analysis of 12,315 individuals, those with SCH had higher risk of depression than euthyroid controls (relative risk 2.35, 95% confidence intervals [CI], 1.84 to 3.02; p < 0.001). Geriatric cohort with SCH had a 1.7-fold higher risk of depression compared with healthy controls (odds ratio 1.72, CI, 1.10 to 2.70; p = 0.020). There was no difference in the mean TSH level between individuals with depression and healthy controls (2.30 ± 1.18 vs. 2.13 ± 0.72 mIU/L, p = 0.513). In individuals with SCH and coexistent depression, levothyroxine therapy was neither associated with improvement in the Beck Depression Inventory scoring (pooled d + = - 1.05, CI -2.72 to 0.61; p = 0.215) nor Hamilton Depression Rating Scale (pooled d + = - 2.38, CI -4.86 to 0.10; p = 0.060)., Conclusion: SCH has a negative impact on depression. Early and routine screening of depression is essential to prevent morbidity and mortality. However, the use of levothyroxine among patients with SCH and coexistent depression needs to be individualized.

We have previously reported that the miR-181a/Prox1/Notch1 pathway mediates the effect of morphine on modulating lineage-specific differentiation of adult neural stem/progenitor cells (NSPCs) via a PKCε-dependent pathway, whereas fentanyl shows no such effect. However, the role of the PKCε/Prox1 pathway in mediating drug-associated contextual memory remains unknown. The current study investigated the effect of PKCε/Prox1 on morphine-induced inhibition of adult neurogenesis and drug-associated contextual memory in mice, while the effect of fentanyl was tested simultaneously. By using BrdU labeling, we were able to examine the lineages of differentiated NSPCs in adult DG. PKCε knockout blocked morphine's effects on inducing in vivo astrocyte-preferential differentiation of NSPCs, but did not alter NSPC lineages upon fentanyl treatment. Inhibited adult neurogenesis further resulted in prolonged extinction and enhanced reinstatement of morphine-induced CPP, as well as prolonged extinction of space reference memory indicated by the Morris water maze paradigm. However, after fentanyl administration, no significant changes were found between wild-type and PKCε knockout mice, during either CPP or water maze tasks. When the lentivirus encoding Nestin-promoter-controlled Prox1 cDNA was injected into hippocampi of wildtype and PKCε knockout adult mice to modulate PKCε/Prox1 activity, similar effects were discovered in adult mice injected with lentivirus encoding Prox1, and more dramatic effects were found in PKCε knockout mice with concurrent Prox1 overexpression. In conclusion, morphine mediates lineage-specific NSPC differentiation, inhibits adult neurogenesis and regulates contextual memory retention via the PKCε/Prox1 pathway, which are implicated in the eventual context-associated relapse., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Recent studies showed association between hyperaldosteronism and low bone density among patients with primary aldosteronism (PA) due to secondary hyperparathyroidism. Our objective is to assess bone turnover markers (BTM) and bone mineral density (BMD) of PA patients compared to essential hypertension., Methods: This was an open-label, prospective, case-controlled study, conducted over 12 months. Fifty-two consecutive patients referred for secondary hypertension were screened. Eighteen patients with confirmed PA (diagnosis based on the Endocrine Society clinical guideline) and seventeen matched controls with essential hypertension were recruited. BTM (CTX and P1NP), BMD, intact parathyroid hormone (iPTH), and bone profile were assessed at baseline and three months following treatment among the PA patients. Calcium intake was assessed using a validated questionnaire. Primary outcomes were the changes of bone markers and BMD following treatment of PA, and their relation to other parameters., Results: PA patients had significantly lower serum calcium and higher iPTH despite comparable vitamin D levels with control group. Both BTM were significantly higher among the PA group. BMD of lumbar spine, neck of femur and distal radius did not differ between groups. Three months following treatment, there were significant: 1) reduction in BTM; 2) improvement in the lumbar spine BMD; 3) reduction in iPTH level; and 4) increment of serum 25-OH vitamin D level., Conclusions: Our findings support that bone loss and potential fracture risk among PA patients are likely a result of aldosterone-mediated secondary hyperparathyroidism. Patients with early PA may already exhibit increased bone turnover despite no significant changes in BMD.

Background: This study evaluates the psychometric properties of the Malay version of the Brief Psychiatric Rating Scale (BPRS-M) among patients with schizophrenia in a psychiatric outpatient clinic., Methods: Ninety-nine schizophrenia outpatients were administered the Malay version of the Brief Psychiatric Rating Scale (BPRS-M), Malay version of Positive and Negative Syndrome Scale (PANSS), Malay version of Calgary Depression Scale for Schizophrenia (CDSS) and Malay version of World Health Organization Quality of Life - Brief Version (WHOQOL-BREF)., Results: An exploratory factor analysis (EFA) of BPRS-M produced a seven-factor solution which accounted for 71.4% of the total variance. It exhibited fair internal consistency (Cronbach's alpha coefficient of 0.75). "Positive symptoms" and "Resistance" factors had association with unemployment and number of antipsychotics, positively correlated with PANSS but negatively correlated with WHOQOL-BREF. "Mood disturbance" factor correlated with lifetime history of suicide attempts, Malay version of CDSS and WHOQOL-BREF (psychological). Both "Negative symptoms" and "Activation" factors were associated with male, lower education, unemployment and positively correlated with Malay version of PANSS but negatively correlated with WHOQOL-BREF., Conclusions: The BPRS-M demonstrated promising psychometric properties in terms of dimensionality, reliability, and validity that generally justifies its use in routine clinical practice in Malaysia.