Does lumbar spinal decompression or fusion surgery influence outcome parameters in patients with intrathecal morphine treatment for persistent spinal pain syndrome type 2 (PSPS-T2).

OBJECTIVES: Intrathecal morphine pump (ITMP) infusion therapy is efficient in managing chronic pain refractory to standard treatment. This study evaluates pain relief and improvement of quality of life in chronic pain patients after intrathecal morphine pump implantation for treatment of persistent pain after lumbar spinal fusion surgery and lumbar spinal decompression alone. METHODS: Forty three chronic pain patients that received an ITMP at our department between 2009 and 2019 were retrospectively analyzed divided into 2 cohorts (lumbar spinal fusion surgery and lumbar spinal decompression alone). Pain intensity was evaluated using the numeric rating scale (NRS), quality of life was assessed by EQ-5D-3L, mental health was assessed by Beck Depression Inventory (BDI-V), and Pain Catastrophizing Scale (PCS). Morphine dosage was assessed over time. Data was collected preoperatively, 6 and 24 months postoperatively. Statistical analysis was performed using Friedman's analysis of variance to evaluate the development of NRS, PCS, BDI and EQ-5D-3L over time and Mann-Whitney-U-test for the differences between these parameters in the different cohorts. A two-sided p-value <0.05 was considered statistically significant. RESULTS: Median age was 64 years (IQR25-75 56-71 years). NRS, EQ-5D-3L, BDI-V, and PCS showed a significant overall improvement after 6 and 24 months compared to baseline data (p<0.001). No statistically significant differences between patients with lumbar spinal fusion surgery and lumbar spinal decompression alone were seen. Furthermore, no statistically significant differences for age and gender were seen. The initially administered median morphine dosage was significantly higher in the fusion group (3.0 mg/day; IQR25-75 1.5-4.2 mg/day) compared to the decompression-alone group (1.5 mg/day; IQR25-75 1.0-2.6 mg/day); (p=0.027). CONCLUSIONS: This retrospective study showed that ITMP have a major long-term impact on pain relief, improve the quality of life, psychological distress, as well as pain catastrophizing in patients with chronic pain following lumbar spinal surgery independent of the previous surgical procedure. After ITMP implantation initial median morphine dosage seems to be significantly higher after spinal fusion compared to decompressive surgery alone.

mTOR/HDAC1 Crosstalk Mediated Suppression of ADH1A and ALDH2 Links Alcohol Metabolism to Hepatocellular Carcinoma Onset and Progression in silico.

Hepatocellular carcinoma (HCC) is ranked the third deadliest cancer worldwide whose molecular pathogenesis is not fully understood. Although deregulated metabolic pathways have been implicated in HCC onset and progression, the mechanisms triggering this metabolic imbalance are yet to be explored. Here, we identified a gene signature coding catabolic enzymes (Cat-GS) involved in key metabolic pathways like amino acid, lipid, carbohydrate, drug, and retinol metabolism as suppressed in HCC. A higher expression of deregulated Cat-GS is associated with good survival and less aggressive disease state in HCC patients. On the other hand, we identified mTOR signaling as a key determinant in HCC onset and progression, whose hyperactivation is found associated with poor survival and aggressive disease state in HCC patients. Next, out of Cat-GS, we established two key regulators of alcohol metabolism, alcohol dehydrogenase 1A (ADH1A) and aldehyde dehydrogenase 2 (ALDH2), as being transcriptionally suppressed by histone deacetylase 1 (HDAC1) at the downstream of mTORC1 signaling. Suppressed ADH1A and ALDH2 expression aligns well with HCC-specific molecular profile and can efficiently predict disease onset and progression, whereas higher ADH1A and ALDH2 expression is associated with good survival and less aggressive disease state in HCC patients. Overall, our in silico findings suggest that transcriptional suppression of alcohol metabolism regulators, ADH1A and ALDH2, at the downstream of mTOR signaling is, in part, responsible for triggering oncogenic transformation of hepatocytes resulting in disease onset and progression in HCC.

Systems biology based meth-miRNA-mRNA regulatory network identifies metabolic imbalance and hyperactive cell cycle signaling involved in hepatocellular carcinoma onset and progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading cause of cancer associated deaths worldwide. Independent studies have proposed altered DNA methylation pattern and aberrant microRNA (miRNA) levels leading to abnormal expression of different genes as important regulators of disease onset and progression in HCC. Here, using systems biology approaches, we aimed to integrate methylation, miRNA profiling and gene expression data into a regulatory methylation-miRNA-mRNA (meth-miRNA-mRNA) network to better understand the onset and progression of the disease. METHODS: Patients' gene methylation, miRNA expression and gene expression data were retrieved from the NCBI GEO and TCGA databases. Differentially methylated genes, and differentially expressed miRNAs and genes were identified by comparing respective patients' data using two tailed Student's t-test. Functional annotation and pathway enrichment, miRNA-mRNA inverse pairing and gene set enrichment analyses (GSEA) were performed using DAVID, miRDIP v4.1 and GSEA tools respectively. meth-miRNA-mRNA network was constructed using Cytoscape v3.5.1. Kaplan-Meier survival analyses were performed using R script and significance was calculated by Log-rank (Mantel-Cox) test. RESULTS: We identified differentially expressed mRNAs, miRNAs, and differentially methylated genes in HCC as compared to normal adjacent tissues by analyzing gene expression, miRNA expression, and methylation profiling data of HCC patients and integrated top miRNAs along with their mRNA targets and their methylation profile into a regulatory meth-miRNA-mRNA network using systems biology approach. Pathway enrichment analyses of identified genes revealed suppressed metabolic pathways and hyperactive cell cycle signaling as key features of HCC onset and progression which we validated in 10 different HCC patients' datasets. Next, we confirmed the inverse correlation between gene methylation and its expression, and between miRNA and its targets' expression in various datasets. Furthermore, we validated the clinical significance of identified methylation, miRNA and mRNA signatures by checking their association with clinical features and survival of HCC patients. CONCLUSIONS: Overall, we suggest that simultaneous (1) reversal of hyper-methylation and/or oncogenic miRNA driven suppression of genes involved in metabolic pathways, and (2) induction of hyper-methylation and/or tumor suppressor miRNA driven suppression of genes involved in cell cycle signaling have potential of inhibiting disease aggressiveness, and predicting good survival in HCC.

Pattern of positive, negative and general psychopathological symptoms among schizophrenia patients at primary care setting: A comparative study.

OBJECTIVE: To investigate the patterns of positive, negative and general psychopathology symptoms on the Positive and Negative Syndrome Scale among a variety of schizophrenia patients. METHODS: The cross-sectional study was conducted at the Institute of Behavioural Sciences, Dow University of Health Sciences, Karachi, in 2016-17, and comprised schizophrenia patients aged 18-52 years registered with the institute regardless of gender, socioeconomic class, marital status and severity of the diseases. The Positive and Negative Syndrome Scale was administered after one month of psychotropic medication. SPSS 21 was used for data analysis. RESULTS: :Of the 104 patients, 62(59.6%) were males; 42(40.4%) were single; 45(43.3%) were married; 17(16.3%) were divorced/separated; 31(29.8%), belonged to low social class; 35(33.7%) to middle; and 38(36.5%) to upper class. Patients' scores were significantly different between in door and out-door patients (p<0.05); between patients who had come with single or multiple episodes (p<0.05), and between patients with acute and chronic phases of illness (p<0.05) in terms of positive, negative and general psychopathology symptoms. CONCLUSIONS: Out-door patients, those with multiples episodes and chronic illness were found more vulnerable compared to in-door patients, those with single episode and acute illness.

Pilot randomised controlled trial of culturally adapted cognitive behavior therapy for psychosis (CaCBTp) in Pakistan.

BACKGROUND: Evidence for efficacy of cognitive-behavioural therapy (CBT) in treatment of schizophrenia is growing. CBT is effective and cost efficient in treating positive and negative symptoms. To effectively meet the needs of diverse cultural groups, CBT needs to be adapted to the linguistic, cultural and socioeconomic context. We aimed to assess the feasibility, efficacy and acceptability of a culturally adapted CBT for treatment of psychosis (CaCBTp) in a low-income country. METHODS: Rater-blind, randomised, controlled trial of the use of standard duration CBT in patients with psychosis from a low-income country. Participants with a ICD-10 diagnosis of psychosis were assessed using Positive and Negative Syndrome Scale for Schizophrenia (PANSS), Psychotic Symptom Rating Scales (PSYRATS), and the Schedule for Assessment of Insight (SAI) (baseline, 3 months and 6 months). They were randomized into the intervention group (n = 18) and Treatment As Usual (TAU) group (n = 18). The intervention group received 12 weekly sessions of CaCBTp. RESULTS: The CaCBTp group had significantly lower scores on PANSS Positive (p = 0.02), PANSS Negative (p = 0.045), PANSS General Psychopathology (p = 0.008) and Total PANSS (p = 0.05) when compared to TAU at three months. They also had low scores on Delusion Severity Total (p = 0.02) and Hallucination Severity Total (p = 0.04) of PSYRATS, as well as higher scores on SAI (p = 0.01) at the same time point. At six months only the improvement in PANSS positive scores (p = 0.045) met statistical significance.. CONCLUSIONS: It is feasible to offer CaCBTp as an adjunct to TAU in patients with psychosis, presenting to services in a lower middle-income country. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02202694 (Retrospectively registered).