Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach.

(R)-Homobenzylic amines are key structural motifs present in (R)-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of (R)-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines.

Adjunctive antidepressants for the acute treatment of bipolar depression: A systematic review and meta-analysis.

BACKGROUND: The depressive phase of bipolar disorder causes significant functional impairment and disease burden. The efficacy and safety of antidepressants in the treatment of bipolar depression has long been a subject of debate. AIMS: To synthesize evidence of the effectiveness, risk of mood switching, and tolerability of adjunctive antidepressants in acute bipolar depression compared to using mood stabilizers or antipsychotics alone. METHOD: Multiple databases were searched for randomized controlled trials, including open label and double-blinded, for patients ages 18 or older with acute bipolar depression, comparing efficacy and adverse events in those who used adjunctive antidepressants versus without. Risk of bias and outcomes were assessed using the Cochrane Risk of Bias Tool. This study has PROSPERO registration CRD42016037701. RESULTS: Nineteen studies met inclusion criteria. Adjunctive antidepressants showed no significant effect on improving response rate (RR=1.10, 95%CI: 0.98-1.23). Subgroup analysis showed that adjunctive antidepressants with antipsychotics had a small but significantly better response rate compared to antipsychotics alone, which was not seen with adjunctive antidepressants with mood stabilizers. However, that finding was limited by studies predominantly using olanzapine as the antipsychotic medication. Adjunctive antidepressants had no clinically significant impact (but a small statistically significant impact) on improving depressive symptoms (SMD=-0.13, 95%CI: -0.24 to -0.02). There was no association with increased mood switch (RR=0.97, 95%CI: 0.68-1.39) and there was an association with lower dropout due to inefficacy (RR=0.66, 95%CI: 0.45∼0.98). CONCLUSIONS: There is no evidence of adjunctive antidepressants clinically improving response rate or depressive symptoms for acute bipolar depression. They are well tolerated, without increasing the risk of short-term mood switch.

A Retrospective Examination of the Impact of Pharmacotherapy on Parent-Child Interaction Therapy.

Objective: Parent-child interaction therapy (PCIT) is an evidence-based approach for children aged 2-7 years with disruptive behavior problems. This study examined the effectiveness of PCIT with and without concurrent pharmacotherapy. Methods: A convenience sample was collected from a retrospective chart review of preschool-aged children treated with PCIT at the Mayo Clinic Young Child Clinic between 2016 and 2020. Quantitative and qualitative data were abstracted from all patients. The sample was divided into two groups based on psychotropic medications status (medicated and unmedicated) at the initiation of PCIT. Effectiveness of treatment was assessed with the change in Eyberg Child Behavior Inventory (ECBI) score. The change over time in ECBI score was compared between the two PCIT groups with and without concurrent pharmacotherapy using a linear mixed model. Results: Of the 62 youth, 38.71% were females. Mean age was 4.71 ± 1.17 years. The mean baseline ECBI score was 148.74 ± 30.86, indicating clinically significant disruptive behaviors. The mean number of PCIT sessions was 6.59 ± 3.82. There was no statistically significant difference in ECBI scores between the two groups at pre-PCIT (medication group: 149.68, standard error [SE] = 11.61 vs. unmedicated group: 147.92, SE = 10.93, p = 0.8904) and at post-PCIT (medication group: 116.27 [SE = 11.89] vs. unmedicated group: 128.86 [SE = 11.57], p = 0.3464). There was a statistically significant improvement in ECBI scores for both groups after completing therapy (medication group = -33.41 [-22.32%], SE = 6.27, p < 0.0001; d = 1.144; unmedicated group = -19.06 [-12.88%], SE = 5.78, p = 0.0022; d = 1.078). Conclusions: PCIT reduced disruptive behaviors in this sample of young children regardless of concurrent pharmacotherapy. Future prospective studies should consider one particular pharmacological agent and long-term outcomes of treatment. PCIT and certain pharmacological treatments could have complex and important bidirectional priming effects for both treatments.

Restless legs syndrome following the use of ziprasidone: a case report.

Restless legs syndrome (RLS) is a common sleep-related movement disorder characterised by an uncomfortable urge to move the legs that occurs during periods of inactivity. Although there have been many case reports on antipsychotic-induced RLS, ziprasidone has never been reported as a cause of RLS. We present a case of a female patient with schizophrenia who presented with symptoms of RLS following the administration of high doses of ziprasidone added to quetiapine and valproate. The patient's symptoms of RLS occurred following the administration and titration of ziprasidone to 160 mg, and were relieved upon reducing the dose to 120 mg/day. Other potential causative medications and differential diagnoses that could have caused similar symptoms were excluded. Clinicians should be aware of the potential for ziprasidone-induced RLS. Dopamine and serotonin interaction could be the mechanism underlying ziprasidone-induced RLS.

Meta-analysis of cognitive function in Chinese first-episode schizophrenia: MATRICS Consensus Cognitive Battery (MCCB) profile of impairment.

BACKGROUND: Compromised neurocognition is a core feature of schizophrenia. With increasing studies researching cognitive function of Chinese patients with first-episode schizophrenia (FES) using MATRICS Consensus Cognitive Battery (MCCB), it is not clear about the level and pattern of cognitive impairment among this population. AIM: To provide a meta-analysis systematically analysing studies of neurocognitive function using MCCB in Chinese patients with FES. METHODS: An independent literature search of both Chinese and English databases up to 13 March 2019 was conducted by two reviewers. Standardised mean difference (SMD) was calculated using the random effects model to evaluate the effect size. RESULTS: 56 studies (FES=3167, healthy controls (HC)=3017) were included and analysed. No study was rated as 'high quality' according to Strengthening the Reporting of Observational Studies in Epidemiology. Compared with HCs, Chinese patients with FES showed impairment with large effect size in overall cognition (SMD=-1.60, 95% CI -1.82 to -1.38, I 2=67%) and all seven cognitive domains, with the SMD ranging from -0.87 to -1.41. In nine MCCB subtests, patients with FES showed significant difference in Symbol Coding (SMD=-1.90), Trail Making Test (TMT) (SMD=-1.36), Continuous Performance Test-Identical Pairs (SMD=-1.33), Hopkins Verbal Learning Test (SMD=-1.24), Brief Visuospatial Memory Test (SMD=-1.18), Mazes (SMD=-1.16), Category Fluency (SMD=-1.01), Spatial Span (SMD=-0.69) and Mayer-Salovey-Caruso Emotional Intelligence Test (SMD=-0.38). CONCLUSIONS: Our meta-analysis demonstrates that Chinese patients with FES show neurocognitive deficits across all seven MCCB cognitive domains and all nine subtests, particularly in two neurocognitive domains: speed of processing and attention/vigilance, with the least impairment shown in social cognition. Symbol Coding and TMT may be the most sensitive tests to detect cognitive deficit in Chinese patients with FES.

Knockdown of the oncogene lncRNA NEAT1 restores the availability of miR-34c and improves the sensitivity to cisplatin in osteosarcoma.

Aberrant expressions of long non-coding RNAs (lncRNAs) are the culprits of carcinogenesis via regulating the tumor suppressor or oncogene. LncRNA nuclear enriched abundant transcript 1 (NEAT1) has been identified to be an oncogene to promote tumor growth and metastasis of many cancers. However, the clinical significance and function of NEAT1 in osteosarcoma (OS) remain to be discovered. We here collected OS tissues (n=40) and adjacent non-tumor tissues (n=20) to determine the expression of NEAT1 and its clinical significance. NEAT1 was overexpressed in OS tissues, which positively correlated with tumor size, Enneking stage, and distant metastasis of OS patients. The elevated level of NEAT1 was confirmed in OS cell lines including MG63 and HOS in vitro Knockdown of NEAT1 by two siRNAs induced impaired cell vitalities, promoted the apoptosis, and G0/G1 arrest in two cell lines, which was associated with inhibited anti-apoptosis signals BCL-2 pathway and cell cycle-related cyclin D1 (CCND1) signals. Moreover, the tumor suppressor miR-34c was negatively regulated and inhibited by NEAT1 in OS. Suppression of miR-34c could up-regulate the expressions of its target genes BCL-2 and CCND1 to antagonize the effects of NEAT1 knockdown. Furthermore, overexpressed NEAT1 reduced the sensitivity of cisplatin (DDP) and inhibited DDP-induced apoptosis and cell cycle arrest via miR-34c The results in vivo also confirmed that knockdown of NEAT1 sensitized the OS cells to DPP-induced tumor regression, delayed the tumor growth with reduced levels of Ki-67, BCL-2, and cyclin D1 signals, suggesting that NEAT1 is an oncogene and chemotherapy resistant factor in OS.

Evaluation of a Neurokinin-1 Antagonist in Preventing Multiple-day Cisplatin-induced Nausea and Vomiting.

OBJECTIVE: To perform a prospective non-randomized comparison of the effectiveness and safety of combined neurokinin-1 antagonist aprepitant treatment with the standard multiple-day cisplatin regimen for the prevention of cisplatin-induced nausea and vomiting (CINV). METHODS: Patients being administered 3-day cisplatin-based chemotherapy (25 mg/m2/d) who had never received aprepitant were given either the standard regimen (tropisetron and dexamethasone) or the aprepitant regimen (aprepitant plus tropisetron and dexamethasone). The primary endpoint was the complete response (CR) in the overall phase (OP, 0-120 h) between the combined aprepitant triple regimen group and the standard group. Secondary endpoints were the CR in the acute phase (AP, 0-24 h) and delay phase (DP, 25-120 h) between the two groups. The first time of vomiting was also compared by Kaplan-Meier curves. The impact of CINV on the quality of life was assessed by the Functional Living Index-Emesis (FLIE). Aprepitant-related adverse effects (AEs) were also recorded. RESULTS: A CR was achieved by 80.0% in the aprepitant group compared with 56.0% in the standard group during the OP (P =0.018)as well as during the DP. However, during the AP, the aprepitant and standard therapy groups achieved identical CR rates (98.0%, P =1.000). A longer time to first emesis was documented for the aprepitant group than for the standard group. No effect of CINV on quality of life as assessed by FLIE was reported by 44.7% of aprepitant therapy patients and 24.0% of standard therapy patients (P=0.035). The main aprepitant-related AEs were fatigue and constipation, but there was no significant difference between groups. CONCLUSION: Combined aprepitant therapy is recommended for the prevention of multiple-day CINV because of its improved CINV control rate and safety.

[A new method for heart sound analysis in time domain].

In order to discriminate normal and abnormal heart sounds accurately and effectively, a new method is proposed to analyze heart sounds, namely heart sound characteristic waveform (HSCW) method. Digital stethoscope is used to collect heart sound signals. The recorded data are transmitted to a computer by USB interface for analysis based on HSCW, which is extracted from an analytical model of single degree-of-freedom (SDOF). Furthermore, a case study on the normal and abnormal cardiac sounds is demonstrated to validate the usefulness and efficiency of the proposed HSCW method. Besides, in order to test the accuracy of discriminating normal and abnormal heart sounds, 40 normal and 20 abnormal heart sounds are collected and analyzed, the accuracy performances are achieved by 92.5% and 95.0%, respectively.