D-Aspartic Acid

Comment in Anesth Analg. 2005 Mar;100(3):754-756. doi: 10.1213/01.ANE.0000144429.39988.9B. Whether preemptive analgesic interventions are more effective than conventional regimens in managing acute postoperative pain remains controversial. We systematically searched for randomized controlled trials that specifically compared preoperative analgesic interventions with similar postoperative analgesic interventions via the same route. The retrieved reports were stratified according to five types of analgesic interventions: epidural analgesia, local anesthetic wound infiltration, systemic N-methyl-d-aspartic acid (NMDA) receptor antagonists, systemic nonsteroidal antiinflammatory drugs (NSAIDs), and systemic opioids. The primary outcome measures analyzed were the pain intensity scores, supplemental analgesic consumption, and time to first analgesic consumption. Sixty-six studies with data from 3261 patients were analyzed. Data were combined by using a fixed-effect model, and the effect size index (ES) used was the standardized mean difference. When the data from all three outcome measures were combined, the ES was most pronounced for preemptive administration of epidural analgesia (ES, 0.38; 95% confidence interval [CI], 0.28-0.47), local anesthetic wound infiltration (ES, 0.29; 95% CI, 0.17-0.40), and NSAID administration (ES, 0.39; 95% CI, 0.27-0.48). Whereas preemptive epidural analgesia resulted in consistent improvements in all three outcome variables, preemptive local anesthetic wound infiltration and NSAID administration improved analgesic consumption and time to first rescue analgesic request, but not postoperative pain scores. The least proof of efficacy was found in the case of systemic NMDA antagonist (ES, 0.09; 95% CI, -0.03 to 0.22) and opioid (ES, -0.10; 95% CI, -0.26 to 0.07) administration, and the results remain equivocal.

INTRODUCTION: About 20-30% of cases of infertility are attributed to male factor and males are also contributing to infertility in a further 20%. Idiopathic male subfertility is the commonest cause in most cases. D-aspartic acid (D-Asp) is an endogenous amino acid occurring in several tissues and cells of both invertebrates and vertebrates. The current study is one of the first to evaluate the in vivo supplementation of D-aspartic acid in idiopathic male infertility. Thus, we aimed in the current study to evaluate the in vivo effect of D-aspartic acid, zinc and co-enzyme Q 10 supplementation on different semen parameters and serum testosterone level in idiopathic male infertility. METHODS: A total of 75 infertile patients were recruited from the outpatient andrology clinic from March 2023 to June 2024. The current study was registered at the UMIN clinical registry trials prior to initiating the study (UMIN000050023). Group (A) included 24 infertile patients who received 2660 mg d-aspartic acid plus 200 mg of ubiquinol plus 10 mg zinc once daily for 3 months. Group (B) included 24 infertile patients who received placebo (starch granules) daily for 3 months. RESULTS: Interestingly, patients in group (A) who received 2660 mg d-aspartic acid plus 200 mg of ubiquinol plus 10 mg zinc once daily for 3 months showed significant improvement in progressive sperm motility after 3 months (10.63 ± 8.64 vs 15.21 ± 12.11, p=0.047). Also, they showed highly significant increase in total testosterone level (5.06 ± 1.74 vs 5.89 ± 1.62, p=0.009). CONCLUSIONS: D-aspartic acid plus ubiquinol plus zinc are promising ingredients that showed good results when administrated once daily to infertile males.

BACKGROUND: Despite the implementation of various postoperative management strategies, the prevalence of postoperative fatigue syndrome (POFS) remains considerable among individuals undergoing laparoscopic radical gastrectomy. While the N-methyl-D-aspartic acid receptor antagonist esketamine has demonstrated efficacy in enhancing sleep quality and alleviating postoperative pain, its impact on POFS remains uncertain. Consequently, the objective of this study is to ascertain whether perioperative administration of esketamine can effectively mitigate the occurrence of POFS in patients undergoing laparoscopic radical gastrectomy. METHODS: A total of 133 patients diagnosed with gastric cancer were randomly assigned to two groups, namely the control group (Group C) (n = 66) and the esketamine group (Group E) (n = 67), using a double-blind method. The Group C received standardized anesthesia, while the Group E received esketamine in addition to the standardized anesthesia. The primary outcome measure assessed was the Christensen fatigue score at 3 days after the surgical procedure, while the secondary outcomes included the disparities in postoperative fatigue, postoperative pain, sleep quality, and adverse reactions between the two groups. RESULTS: In the group receiving esketamine, the fatigue scores of Christensen on the third day after surgery were significantly lower compared to the Group C (estimated difference, -0.70; 95% CI, -1.37 to -0.03; P = 0.040). Additionally, there was a significant decrease in the occurrence of fatigue in the Group E compared to the Group C on the first and third days following surgery (P < 0.05). Also, compared to individuals who had distal gastrectomy, those who had entire gastrectomy demonstrated a higher degree of postoperative tiredness reduction with esketamine. Furthermore, the Group E exhibited reduced postoperative pain and improved sleep in comparison to the Group C. Both groups experienced similar rates of adverse events. CONCLUSIONS: The use of esketamine during the perioperative period can improve POFS after laparoscopic radical gastrectomy, without adverse reactions. TRIAL REGISTRATION: Registered in the Chinese Clinical Tr

The aim of this study was to evaluate the effects of D-aspartic acid (DAA) supplementation during a simulated altitude protocol on the hormonal and hematological responses in athletes. We hypothesized that DAA supplementation would contribute to an increase in the luteinizing hormone (LH), free, and testosterone and a greater increase in hematological variables. Sixteen male boxers participated; they were randomly assigned to an experimental group (DAA) or a control group (C) and underwent 14 days of supplementation, 6 g/day of DAA. Both DAA and C participants were exposed to normobaric hypoxia (FiO2 = 15.5%; 2500 m) for 10-12 h a day over a period of 11 days. The results showed that DAA had no significant effect on resting, LH, or the testosterone/cortisol ratio during the training camp. Hypoxic exposure significantly (p < 0.05) increased red blood cell and reticulocyte counts as well as hemoglobin and hematocrit concentrations in both groups, but DAA had no significant effect on these changes. In conclusion, we found that DAA supplementation at a dose of 6 g/day for 14 days does not affect the testosterone, cortisol, or hematological responses of athletes during.

WHAT IS KNOWN AND OBJECTIVE: Esketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist, which has stronger sedative and analgesic effects and fewer adverse events than ketamine. The effects of low-dose esketamine on haemodynamics and postoperative quality of recovery in elderly patients have not been evaluated. To evaluate whether low-dose esketamine can be safely used for anaesthesia induction in the elderly. METHODS: Eighty elderly patients were selected for unilateral total knee replacement under general anaesthesia from February 2021 to August 2021. Patients were randomly divided into two groups (n = 40): control group (C group) and esketamine group (K group). During induction of anaesthesia, the control group was intravenously injected with normal saline of equal volume, and the esketamine group was intravenously injected with 0.2-mg/kg esketamine. Both groups were induced by etomidate, sufentanil and rocuronium and maintained by combined intravenous and inhaled anaesthesia during operation. MAIN OUTCOME MEASURES: HR, SBP, DBP, MAP and BIS values were recorded before induction of anaesthesia (T0 ), immediately before endotracheal intubation (T1 ), 1min(T2 ) and 5min(T3 ) after endotracheal intubation, surgical skin incision (T4 ), 1min(T5 ) and 5min(T6 ) after surgical skin incision. RESULTS: Compared with the C group, SBP, DBP, MAP, HR and BIS of the K group were significantly higher at T1 -T3 (p < 0.05). There were no significant differences in SBP, DBP, MAP, HR and BIS between the two groups at T4 -T6 (p > 0.05). Compared with T0 , SBP, MAP and BIS values of the two groups at T1 -T6 were decreased (p < 0.05). DBP of the K group at T2 was not significantly different from DBP at T0 (p < 0.05), but DBP of the C group decreased from T1 to T6 (p < 0.05). Compared with T0 , HR in both groups decreased at T1 , T3 , T4 , T5 and T6 (p < 0.05). Compared with the C group, the incidence of cough in the K group was significantly lower (p < 0.05); There was no significant difference in the number of myoclonus during induction between the two groups (p > 0.05). Compared with the C group, the number of hypotension episodes in the K group during induction was

Prolonged status epilepticus (SE) in humans causes high mortality and brain inflammation-associated neuronal injury and morbidity in survivors. Currently, the only effective treatment is to terminate the seizures swiftly to prevent brain damage. However, reliance on acute therapies alone would be imprudent due to the required short response time. Follow-on therapies that can be delivered well after the SE onset are in an urgent need. Cannabinoid receptor type 2 (CB2), a G protein-coupled receptor that can be expressed by activated brain microglia, has emerged as an appealing anti-inflammatory target for brain conditions. In the current study, we reported that the CB2 inverse agonism by our current lead compound SMM-189 largely prevented the rat primary microglia-mediated inflammation and showed moderate neuroprotection against N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity in rat primary hippocampal cultures containing both neurons and glia. Using a classical mouse model of epilepsy, in which SE was induced by systemic administration of kainate (30 mg/kg, i.p.) and proceeded for 1 h, we demonstrated that SE downregulated the CB1 but slightly upregulated CB2 receptor in the hippocampus. Transient treatment with SMM-189 (6 mg/kg, i.p., b.i.d.) after the SE was interrupted by diazepam (10 mg/kg, i.p.) prevented the seizure-induced cytokine surge in the brain, neuronal death, and behavioral impairments 24 h after SE. Our results suggest that CB2 inverse agonism might provide an adjunctive anti-inflammatory therapy that can be delivered hours after SE onset, together with NMDA receptor blockers and first-line anti-convulsants, to reduce brain injury and functional deficits following prolonged seizures.

Several basic pharmacokinetic and pharmacological studies were conducted as part of a group of studies to clarify the drug-drug interaction (DDI) between memantine (MEM), a drug used to treat Alzheimer's disease, and yokukansan (YKS), a traditional Japanese Kampo medicine used to treat behavioral and psychological symptoms of dementia. The pharmacokinetic studies showed that there were no statistically significant differences in MEM concentrations in the plasma, brain, and urine between mice treated with MEM alone and with MEM plus YKS. Regarding candidate active ingredients of YKS, there were also no statistically significant differences in concentrations of geissoschizine methyl ether in the plasma and brain, urine, glycyrrhetinic acid in the plasma, and isoliquiritigenin in the urine, in mice treated with YKS alone or with MEM plus YKS. The pharmacological studies showed that isoliquiritigenin, which has an N-methyl-d-aspartic acid (NMDA) receptor antagonistic effect, did not affect the inhibitory effect of MEM on NMDA-induced intracellular Ca2+ influx in primary cultured rat cortical neurons. Moreover, YKS did not affect either the ameliorative effects of MEM on NMDA-induced learning and memory impairment, or the MEM-induced decrease in locomotor activities in mice. These results suggest that there is probably no pharmacokinetic or pharmacological interaction between MEM and YKS in mice, but more detailed studies are needed in the future. Our findings provide important information for future studies, to clarify the DDI more regarding the efficacy and safety of combined use of these drugs in a clinical situation.

Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with TAK-063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with TAK-063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that TAK-063 enhanced N-methyl-D -aspartic acid receptor-mediated synaptic responses in both direct and indirect pathway MSNs to a similar extent. Further evaluation using pathway-specific markers revealed that coadministration of TAK-063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK-063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine- or MK-801-induced hyperactivity in rats and MK-801-induced deficits in prepulse inhibition in mice. TAK-063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK-063 may produce augmented antipsychotic-like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents. © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine-induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug-abuse-induced acute toxicity.

Cyclosporine A (CsA) is an immunosuppressive drug commonly used in organ transplant patients to prevent allograft rejections. Ketamine is a pediatric anesthetic that noncompetitively inhibits the calcium-permeable N-methyl-d-aspartic acid receptors. Adverse drug-drug interaction effects between ketamine and CsA have been reported in mammals and humans. However, the mechanism of such drug-drug interaction is unclear. We have previously reported adverse effects of combination drugs, such as verapamil/ketamine and shown the mechanism through intervention by other drugs in zebrafish embryos. Here, we show that ketamine and CsA in combination produce developmental toxicity even leading to lethality in zebrafish larvae when exposure began at 24 h post-fertilization (hpf), whereas CsA did not cause any toxicity on its own. We also demonstrate that acetyl l-carnitine (ALCAR) completely reversed the adverse effects. Both ketamine and CsA are CYP3A4 substrates. Although ketamine and CsA independently altered the expression of the hepatic marker CYP3A65, a zebrafish ortholog of human CYP3A4, both drugs together induced further increase in CYP3A65 expression. In the presence of ALCAR, however, CYP3A65 expression was normalized. ALCAR has been shown to prevent ketamine toxicity in mammal and zebrafish. In conclusion, CsA exacerbated ketamine toxicity and ALCAR reversed the effects. These results, providing evidence for the first time on the reversal of the adverse effects of CsA/ketamine interaction by ALCAR, would prove useful in addressing potential occurrences of such toxicities in humans. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1-0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. Published by Elsevier Inc.

BACKGROUND: The purpose of this study was to determine how the activation of different regulatory domains of the NMDA complex affects the antianxiety effect of antagonists acting at its distinct binding sites. METHODS: The anxiolytic-like activity was assessed by the elevated plus-maze test in mice. RESULTS: The anxiolytic activity of CGP 37849 (a competitive NMDA receptor antagonist) and L-701,324 (an antagonist at glycine site) was confirmed, but effects of both were significantly reduced by N-methyl-D-aspartic acid (NMDA) or by D-serine agonists at glutamate and glycine site of the NMDA receptor complex, respectively. CONCLUSION: The obtained data suggest that stimulation of the glutamate or glycine recognition site of the NMDA receptor complex significantly decreases the antianxiety properties of antagonists of either site.

Type 2 diabetes mellitus (T2DM) is known to be associated with increased risk of cognitive impairment including Alzheimer disease. Recent studies have suggested an interaction between angiotensin II and N-methyl-d-aspartic acid (NMDA) glutamate receptors. We previously reported that stimulation of the angiotensin II type 2 (AT2) receptor exerts brain protective effects. A newly developed AT2 receptor agonist, compound 21 (C21), has enabled examination of the direct effect of AT2 receptor stimulation in vivo. Accordingly, we examined the possible synergistic effect of C21 and memantine on cognitive impairment in T2DM mice, KKAy. KKAy were divided into four groups; (1) control, (2) treatment with C21 (10 μg/kg/day), (3) treatment with memantine (20mg/kg/day), and (4) treatment with both for 4 weeks, and subjected to Morris water maze tasks. Treatment with C21 or memantine alone at these doses tended to shorten escape latency compared to that in the control group. C21 treatment increased cerebral blood flow (CBF), but memantine did not influence CBF. Treatment with C21 or C21 plus memantine increased hippocampal field-excitatory postsynaptic potential (f-EPSP). Moreover, treatment with memantine or C21 increased acetylcholine level, which was lower in KKAy than in wild-type mice, and C21 plus memantine treatment enhanced memantine or C21-induced acetylcholine secretion. This study provides an insight into new approaches to understand the interaction of angiotensin II and neurotransmitters. We can anticipate a new therapeutic approach against cognitive decline using C21 and memantine.

During the past 20 years experimental evidence has accumulated demonstrating that the appearance of theta rhythm requires a certain level of excitation of local neuronal networks. In this study we extended our earlier in vitro observations concerning the involvement of cholinergic and GABAergic neurotransmission in hippocampal theta production. Specifically, we investigated whether the hippocampal neuronal network is capable of generating theta oscillations in the presence of N-methyl-d-aspartic acid (NMDA) in a brain slice preparation. To answer this question, the effect of different concentrations of NMDA (Experiment I) and the effect of interaction between NMDA and GABAA/B agonists and antagonists on field potentials recorded in the CA3c region of hippocampal formation (HPC) slice preparations (Experiment II) was examined. We demonstrated for the first time that apart from the epileptiform activity recorded in almost all series of Experiments I and II, only the perfusion of HPC slices with NMDA in doses of 30 and 50 μM, as well as the perfusion of HPC slices with NMDA and GABAB agonist baclofen (50 μM NMDA+50 μM BACL), resulted in the appearance of individual theta epochs. The best synchronized theta oscillations obtained after administration of 50 μM NMDA+50 μM BACL resembled theta activity induced by a bath perfusion of 50 μM carbachol. In light of the obtained results we conclude that besides the cholinergic and GABAergic input, NMDA glutamatergic drive is also important for the appearance of theta oscillations in HPC in vitro.

RATIONALE: Memantine is a N-methyl-D-aspartic acid receptor (NMDAR) channel blocker that binds to dizocilpine sites and appears well tolerated during chronic use. Published studies suggest NMDAR antagonists prevent development of tolerance to effects of morphine by blocking NMDAR hyperactivation. OBJECTIVES: We sought to compare effects of memantine to those of the more frequently studied dizocilpine and to evaluate memantine as a potential adjunct to modify tolerance to mu-opioid receptor agonists. METHODS: Sprague-Dawley rats were trained to discriminate morphine (3.2 mg/kg) and saline under fixed ratio 15 schedules of food delivery. Potency and maximal stimulus or rate-altering effects of cumulative doses of morphine were examined 30 min after pretreatment with dizocilpine (0.032-0.1 mg/kg) or memantine (5-10 mg/kg) and after chronic treatment with combinations of dizocilpine or memantine and morphine, 10 mg/kg twice daily, for 6 to 14 days. Effects of dizocilpine or memantine on morphine antinociception were examined in a 55 °C water tail-withdrawal assay with drug treatments parallel to those in discrimination studies. RESULTS: Acutely, memantine attenuated while dizocilpine potentiated the stimulus and antinociceptive effects of morphine. Neither chronic dizocilpine nor memantine blocked tolerance to the stimulus effects of morphine. In contrast, combined treatment with dizocilpine (0.1 mg/kg) blocked tolerance to antinociceptive effects of lower (0.1~3.2 mg/kg) but not higher doses of morphine, whereas memantine did not block tolerance. CONCLUSIONS: Memantine and dizocilpine interacted differently with morphine, possibly due to different NMDAR binding profiles. The lack of memantine-induced changes in morphine tolerance suggests that memantine may not be a useful adjunct in chronic pain management.

Testosterone boosters are heavily marketed on social media and marketplaces to men with claims to significantly increase testosterone. Lax industry regulation has allowed sales of supplements to thrive in the absence of verification of their purported benefits. Our primary objective was to systematically review all data published in the last two decades on testosterone boosters and determine their efficacy. Our outcome of interest was total testosterone increase versus placebo in four different populations: male athletes, men with late-onset hypogonadism infertile men and healthy men. Following search and screening, 52 studies were included in our review, relating to 27 proposed testosterone boosters: 10 studies of cholecalciferol; 5 zinc/magnesium; 4 Tribulus terrestris and creatine; 3 Eurycoma longifolia and Withania somnifera; 2 betaine, D-aspartic acid, Lepidium meyenii and isoflavones; while the remainder were single reports. Our findings indicate that most fail to increase total testosterone. The exceptions were β-hydroxy β-methylbutyrate and betaine, which can be considered effective for male athletes. Eurycoma longifolia, a blend of Punica granatum fruit rind and Theobroma cacao seed extracts (Tesnor™) and purified Shilajit extract (PrimaVie™) can be considered possibly effective for men with late-onset hypogonadism; Eurycoma longifolia and Withania somnifera possibly effective for healthy men; and a non-hormonal aromatase inhibitor (Novadex XT™) possibly effective for male athletes. © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

OBJECTIVE: This study aimed to systematically investigate whether anti-androgens could significantly reduce Obsessive-Compulsive Disorder (OCD) symptoms compared to placebo or usual care in OCD patients. METHODS: PubMed, EMBASE, CENTRAL and International Clinical Trials Registry Platform (ICTRP) databases were searched up to October 2018 using relevant keywords. All randomized and if not available non-randomized studies conducted on a population including OCD patients who were administered with anti-androgen, which reported changes in their symptoms, were included. The studies on compulsive hypersexuality were excluded. Required data were extracted from full-text of the included articles by two independent authors. One randomized and four non-randomized trials were found. RESULTS: The only randomized trial showed that flutamide, an anti-androgen agent, was effective in reducing compulsion scores in male OCD patients with comorbid Tourette syndrome, compared to placebo. Three out of four non-randomized trials showed that different anti-androgens including finasteride, cyproterone acetate and triptorelin were effective in reducing OCD symptoms. The only study, which failed to show the efficacy of an anti-androgen agent, administered OCD patients with flutamide. Despite the positive results, available studies provide the evidence with low quality based on the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) approach. CONCLUSION: Available studies are not sufficient for a precise answer to our study question. There is still a need for further large randomized blinded clinical trials to evaluate the effectiveness of antiandrogens in OCD patients. It is recommended that gender, comorbidities and subscales of Yale- Brown Obsessive-Compulsive Score (Y-BOCS) should be considered in designing the studies and interpreting their results.

OBJECTIVES: Association between the D-repeat of asporin (ASPN) gene and osteoarthritis (OA) was still inconsistent. We performed this meta-analysis to systematically assess the D-repeat polymorphisms in OA susceptibility. METHODS: Relevant studies were enrolled by searching databases. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used for evaluating the association between ASPN gene and OA. Heterogeneity was calculated using the Q statistic, and three different subgroup analyses were performed on ethnicity, gender, and OA positions respectively. False discovery rate (FDR) was applied to regulate the multiple comparisons. RESULTS: Twelve qualified articles involving 5190 OA patients and 5167 healthy controls were included. With D13 polymorphism, Caucasian male patients have low OA susceptibility (P = .008, PFDR = .024, OR [95% CI] = 0.83 [0.73-0.95]). As to D14 polymorphism, all male patients (P = .0004, PFDR = .001, OR [95% CI] = 1.38 [1.15-1.64]), Asian male patients (P = .01, PFDR = .01, OR [95% CI] = 1.72 [1.11-2.66]), and Caucasian male patients (P = .005, PFDR = .001, OR [95% CI] = 1.32 [1.09-1.60]) have high OA susceptibility. In the pooled-population of KOA with D14 polymorphism, overall male patients (P = .03, PFDR = .045, OR [95% CI] = 1.35 [1.02-1.78]) and Asian male patients (P = .01, PFDR = .03, OR [95% CI] = 1.72 [1.11-2.66]) have high OA risk. With D16 polymorphism, Latin America patients may have high OA risk (P = .04, PFDR = .15, OR [95% CI] = 1.43 [1.02-2.01]). CONCLUSION: Our results suggest that D-repeat of ASPN gene is mainly associated with male patients. The D13 polymorphism plays a protective role for OA in Caucasians male individuals while D14 plays a risk factor for KOA in male patients.

OBJECTIVE: Describe basic science, animal models and clinical data related to timing of treatment in status epilepticus (SE). METHODS: We summarized the results of 15 studies that reported time to treatment in SE, and reviewed basic and clinical literature. RESULTS: SE is a life-threatening and time-sensitive emergency that requires immediate treatment. Current guidelines recommend escalation of anti-seizure medications (ASM) within specified time frames. Prolonged seizures may lead to changes in the composition and location of gamma-aminobutyric acid A receptors (GABAAR) and N-Methyl-d-aspartic acid receptors (NMDAR), leading to loss of inhibition and increased excitation. These biochemical changes are apparent in specific animal models having progressive resistance to benzodiazepines (BZD) with longer seizures. Later treatments lead to decreased response to BZD, longer seizures, greater need of continuous infusions, potential brain injury and increased in-hospital mortality. Despite mounting evidence that early treatment of SE is more effective and safer, treatment and ASM escalation is often delayed compared to protocols. Literature review of 2212 patients with SE showed an average time to treatment of 42.4 min and time to hospital arrival of 56 min. Also, only 51.8% of patients received treatment by emergency medical services and 12.8% by their families, including patients with a previous diagnosis of epilepsy or with prior SE. CONCLUSIONS: Morbidity and mortality may be avoided with rapid, effective treatment of SE. Treatment application and escalation remains delayed especially in outpatient settings, potentially leading to suboptimal outcomes. Implementation techniques and quality improvement methodologies may provide avenues for improving outcomes in SE.

OBJECTIVE: Studies have assessed the association between aspartic acid (D)-repeat polymorphism in the gene encoding Asporin (ASPN) and knee osteoarthritis (KOA) risk, but the results were inconclusive and contradictory. Therefore, we performed a meta-analysis to investigate the association between ASPN gene D-repeat polymorphism and KOA risk. METHODS: Eligible studies were identified by searching several electronic databases for relevant reports published before September 2016. The pooled odds ratios (ORs) for the association between ASPN polymorphism and KOA and their corresponding 95% confidence intervals (CIs) were estimated using the random- or fixed-effect model. RESULTS: A total of eleven case-control studies in ten publications with 4610 KOA cases and 3621 controls were included for the ASPN D-repeat polymorphism. Overall, no significant association was detected for D14 allele carrier (D14 vs. D13: OR = 1.10, 95% CI = 0.90-1.36, p = 0.32). Meta-analysis of D14 vs. other alleles and D13 vs. other alleles showed the same pattern of KOA association as the D14 vs. D13 (OR = 1.30, 95% CI = 1.00-1.70, p = 0.06; OR = 0.93, 95% CI = 0.82-1.06, p = 0.33, respectively). Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of KOA was found in the European and Asians populations (OR = 1.05, 95% CI = 0.91-1.21, p = 0.49; OR = 0.98, 95% CI = 0.78-1.23, p = 0.88, respectively). CONCLUSIONS: The present meta-analysis suggests that the ASPN D-repeat polymorphism is not associated with an increased KOA risk. However, future large studies with gene-gene and gene-environment interactions are needed to validate these findings. LEVEL OF EVIDENCE: Level III diagnostic study.

BACKGROUND: Several recent reports have demonstrated that tyrosine (Y)-methionine (M)-aspartic acid (D)-aspartic acid (D) (YMDD) motif mutations can naturally occur in chronic HBV patients without antiviral treatment such as lamivudine therapy. This paper aims to assess the overall spontaneous incidence and related risk factors of YMDD-motif mutations among lamivudine-naïve chronic HBV carriers, so as to provide some clue for clinical treatment of hepatitis B. METHODOLOGY/PRINCIPAL FINDINGS: Chinese and English literatures were searched for studies reporting natural YMDD mutations among untreated chronic HBV patients from 2001 to 2010. The incidence estimates were summarized and analyzed by meta-analyses. Forty-seven eligible articles from eight countries were selected in this review (13 in English and 34 in Chinese). The pooled incidence of YMDD-motif mutation among untreated chronic HBV patients from eight countries was 12.21% (95% CI: 9.69%-14.95%). China had an incidence of 13.38% (95% CI: 10.90%-16.07%) and seven other countries had an incidence of 9.90% (95% CI: 3.28%-19.55%), respectively. Lamivudine therapy would increase the risk of mutations 5.23 times higher than the untreated patients. A higher HBV DNA copy number was associated with increased incidence of natural YMDD mutation. No significant difference was found in YMDD mutation incidence between groups of different gender, age, HBeAg status, patients' ALT (alanine aminotransferase) level, and between the groups of HBV genotype B and C. CONCLUSIONS: The YMDD-motif mutations can occur spontaneously with a relatively high incidence in CHB patients untreated with lamivudine. These mutations might be the consequence of accumulated base mismatch due to the nature of viral polymerase. More fundamental and clinical studies are needed to clarify the influence of YMDD mutations in hepatitis B progression and antiviral treatment.