Association of Monoamine Oxidase A with Tumor Burden and Castration Resistance in Prostate Cancer.

BACKGROUND: Metastatic burden and aggressive behavior determine severity stratification and guide treatment decisions in prostate cancer (PCa). Monoamine oxidase A (MAOA) may promote tumor burden and drug/castration resistance in PCa. A positive association will pave the way for MAOA inhibitors such as moclobemide for PCa therapy. OBJECTIVE: To analyze MAOA in peripheral blood mononuclear cells qualitatively and p38, c-Jun N-terminal kinases, nuclear factor kappa B, and their phosphorylated forms, vascular endothelial growth factor (angiogenesis), transforming growth factor beta, interleukin 6, and tumor necrosis factor-α (cytokines), Bcl-2 associated X, B-cell lymphoma 2, and P53 (apoptosis), prostate-specific membrane antigen, and epithelial cell adhesion molecules (surface markers) in plasma of patients with PCa. METHODS: This was a 1-year pilot study in which patients with PCa were recruited and stratified into 2 groups and subgroups: treatment-naive with (M1) (n = 23) or without (M0) (n = 23) bone metastasis; hormone-sensitive prostate cancer (n = 26) or hormone/castration-resistant prostate cancer (n = 26). MAOA was detected using ELISA and other proteins were detected using immunoblotting technique. RESULTS: MAOA was detected in 8.6% of M0 compared with 30.4% of M1 patients, and in 7.7% of hormone-sensitive compared with 27% of hormone/castration resistant PCa patients, associating it with bone metastasis and castration resistance. Multivariable regression analysis showed a correlation of MAOA with serum prostate-specific antigen, a marker for progression in PCa (Pearson correlation coefficient r = 0.30; P < 0.01). In patients with positive MAOA, there was overexpression of p38, phosphorylated-p38, c-Jun N-terminal kinases, phosphorylated c-Jun N-terminal kinases, nuclear factor kappa B, phosphorylated nuclear factor kappa B, transforming growth factor beta, vascular endothelial growth factor, interleukin 6, tumor necrosis factor α, Bcl-2 associated X, B-cell lymphoma 2, prostate-specific membrane antigen, and epithelial cell adhesion molecule in M1 compared with M0 group patients, associating these proteins with tumor burden. Overexpression of Bcl-2 associated X, tumor protein 53, c-Jun N-terminal kinases, nuclear factor kappa B, transforming growth factor beta, vascular endothelial growth factor, and prostate-specific membrane antigen and underexpression of B-cell lymphoma 2 and phosphorylated nuclear factor kappa B were observed in hormone-sensitive prostate cancer compared with hormone/castration-resistant prostate cancer, associating these proteins with castration resistance. CONCLUSIONS: Association of key molecules of oncogenesis and metastasis with MAOA suggests that MAOA inhibitors such as moclobemide might be effective in the management of PCa.

Aluminium utensils: Is it a concern?

Aluminium utensils are ubiquitous in Indian households and other developing countries. Concerns have recently been raised on the pathological effects of aluminium on the human body, due to its leaching from utensils with long-term use, which has been associated with certain clinical conditions such as anaemia, dementia and osteo-malacia. While some studies suggest that cooking in utensils or aluminium foils is safe, others suggest that it may lead to toxic levels of aluminium in the body. However, studies have shown that leaching of aluminium from cooking utensils depends on many factors such as pH, temperature and cooking medium. In healthy controls, 0.01 %-1 % of orally ingested aluminium is absorbed from the gastrointestinal tract and is eliminated by the kidney. Although the metal has a tendency to accumulate in tissues and may result in their dysfunction, the literature suggests that the apprehension is more apt in patients with chronic renal insufficiency. This article offers solutions to mitigate the risk of aluminium toxicity.

Role of Platelet-rich Plasma in Unexplained Recurrent Implantation Failure - A Systematic Review and Meta-analysis of Randomised Control Trials.

Background: Recurrent implantation failure (RIF) is a challenging clinical situation and various strategies have been tried to improve the pregnancy rate in RIF. Platelet-rich plasma (PRP), which is obtained from the autologous blood samples of a person and is multiple times richer in platelets and other growth factors helps improve endometrial receptivity. Objective: This study has been conducted to summarise the evidence and quality of evidence available so far regarding the role of PRP in cases of unexplained RIF. Materials and Methods: An electronic database search for randomised clinical trials comparing PRP against routine care in women with unexplained RIF was performed on PubMed, EMBASE, SCOPUS and Cochrane Central. Two independent reviewers conducted a literature search and retrieved data using the predefined eligibility criteria. Bias assessment was done using the Cochrane Collaboration Network Risk of Bias Tool version 2. The quality of evidence was determined and a summary of the findings table was prepared for individual outcomes using GRADEpro software. Results: We identified 1146 records, and after removing duplicates, 531 records were screened. Out of these, 22 studies reached full-text screening and nine studies were included in the final review. We are uncertain about the effect of PRP due to the very low quality of evidence and we have little confidence that the administration of PRP had any significant effect on improving the live birth rate in women with RIF (odds ratio [OR]: 7.32, 95% confidence interval [CI]: 4.54-11.81, I2 = 40%). Similarly, the quality of evidence was low for the clinical pregnancy rate, so we are uncertain if the administration of PRP had any significant effect on the clinical pregnancy rate (OR: 3.20, 95% CI: 2.38-4.28, I2 = 0%). Interpretation: The current review suggests that there may be some beneficial effects of PRP in women with RIF, but the quality of evidence is very low and we are uncertain of the benefit and have little confidence in these findings. Limitations: Limitations are the small sample size of most studies, a short follow-up period, non-uniformity in the definition of outcomes and very low quality of evidence. Registration: The protocol was registered on PROSPERO (CRD42021292209).

Evaluation of sodium valproate loaded nanoparticles in acute and chronic pentylenetetrazole induced seizure models.

BACKGROUND AND PURPOSE: Efficacy of sodium valproate in epilepsy is limited by its poor blood brain barrier penetration and side effects. Nanoparticles may offer a better drug delivery system to overcome these limitations. This study evaluated the efficacy of sodium valproate encapsulated in nanoparticles in pentylenetetrazole (PTZ) induced acute and kindling models of seizures in male Wistar rats. METHODS: Poly lactic-co-glycolic acid (PLGA) based, polysorbate 80 stabilized sodium valproate loaded nanoparticles (nano sodium valproate) and rhodamine loaded nanoparticles (RLN) were formulated by double emulsion- solvent evaporation method and characterized for their size, shape, zeta potential and drug loading percentage. RLN was used to demonstrate blood brain barrier (BBB) permeability of nanoparticles. Serum drug levels were estimated using high performance liquid chromatography. The efficacy of standard sodium valproate (300 mg/kg) and nano sodium valproate (∼300, ∼150 and ∼75 mg/kg of sodium valproate) were evaluated in experimental animal models of seizures along with their effects on behavioral and oxidative stress parameters. Drugs were administered 60 min before PTZ in acute model. In the kindling model, drugs were administered every day while PTZ was administered on alternate days 60 min after drug administration. All the study drugs/compounds were administered intraperitoneally. RESULTS: RLN were observed to be clustered in cortex which implied that the nanoparticles crossed BBB. Both standard sodium valproate and nano sodium valproate reached therapeutic serum level at 15 min and 1 h, but were undetectable in serum at 24 h. In acute PTZ (60 mg/kg) model, nano sodium valproate (∼300 mg/kg of sodium valproate) and standard sodium valproate showed protection against seizures till 6 h and 4 h, respectively. There were significant behavioral impairment and oxidative stress with standard sodium valproate in acute model as compared to nano sodium valproate at 6 h. In kindling model, induced with PTZ (30 mg/kg, every alternate day for 42 days), complete protection from seizures was observed with nano sodium valproate (∼150 mg/kg and ∼75 mg/kg of sodium valproate) and standard sodium valproate (300 mg/kg). Similarly, significant protection from behavioral impairment and oxidative stress was observed with standard sodium valproate and nano sodium valproate as compared to PTZ. CONCLUSION: When compared to conventional therapy, nano sodium valproate showed protection from seizures at reduced doses and for a longer duration in animal models of epilepsy. This study suggests the potential of nano sodium valproate in the treatment of epilepsy.

The Tamiflu fiasco and lessons learnt.

Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved for seasonal flu by US Food and Drug Administration in 1999. A number of randomized controlled trials, systematic reviews, and meta-analysis emphasized a favorable efficacy and safety profile. Majority of them were funded by Roche, which also first marketed and promoted this drug. In 2005 and 2009, the looming fear of pandemic flu led to recommendation by prominent regulatory bodies such as World Health Organization (WHO), Centers for Disease Control and Prevention, European Medicines Agency and others for its use in treatment and prophylaxis of influenza, and it's stockpiling as a measure to tide over the crisis. Serious Adverse Events, especially neuropsychiatric events associated with Tamiflu started getting reported leading to a cascade of questions on clinical utility of this drug. A recent Cochrane review and related articles have questioned the risk-benefit ratio of the drug, besides raising doubts about the regulatory decision of approving it. The recommendations for stockpiling the said drug as given by various international organizations viz WHO have also been put to scrutiny. Although many reviewers have labeled the Tamiflu saga as a "costly mistake," the episode leaves us with some important lessons. This article takes a comprehensive relook on the subject, and we proceed to suggest some ways and means to avoid a similar situation in the future.