The Role of Allogeneic Stem Cell Transplantation in Multiple Myeloma: A Systematic Review of the Literature.

Multiple myeloma (MM) is an indolent B-cell malignancy, where treatment is aimed at preventing organ dysfunction from light chain accumulation (slowing disease progression) and inducing remission. Allogeneic stem cell transplant (allo-SCT), through graft versus myeloma (GVM) effects, has the potential to induce remission to a potentially curative-like state. In this systematic review, we aimed to understand this relationship to the risks and severity of disease in categorized patients and gain an updated comprehension of the future of allo-SCT in MM treatment. We conducted this review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched the PubMed database to obtain the specified literature with both the use of keywords and Medical Subject Headings (MeSH). A total of 16 relevant articles were included for discussion after the quality appraisal was completed, as appropriate, by either the Cochrane tool or Newcastle-Ottawa checklist. Our review concludes that while allo-SCT may benefit high-risk patients, successful procedures may incorporate a tandem autologous hematopoietic stem cell transplant approach in combination with novel pharmacologic contributions for which there is an observed synergy in the modulation of the immunologic microenvironment. Furthermore, tailored patient selection by evaluating pre-transplant factors including high-risk cytogenetics, age, and pre-salvage International Staging System (ISS) can predict post-transplantation success including non-relapse mortality. Successive research should continue to revise and update treatment options as the evolving therapeutic drug regimens may change over the course of indolent disease.

Type 2 Diabetes and Causes of Sudden Cardiac Death: A Systematic Review.

Type 2 diabetes mellitus has been on the rise in recent years. A major cause of death in the United States is myocardial infarction with underlying coronary artery disease. Impairment of tissue insulin sensitivity in type 2 diabetes is a significant factor for sudden cardiac death. The complex pathophysiology stems from coexisting cardiovascular disease and complications of impaired tissue sensitivity to insulin. Long-term diabetics with underlying kidney disease and those requiring dialysis have systemic inflammation that adds to an increased risk of death. During times of pathological stress, myocardial tissue will express substrates and growth factors that cause conduction disequilibrium and predispose to sudden cardiac death. Diabetes is a modifiable risk factor in the prevention of sudden cardiac arrest. Specific prevention measures aimed towards lifestyle modification and medications are important to prevent diabetes and decrease mortality of future cardiac death. In recent times, drugs that compete with glucose in the proximal convoluted tubule of the nephron have clinical significance in lowering the risk of sudden cardiac arrest.

New Evidence in the Pathogenesis of Celiac Disease and Type 1 Diabetes Mellitus: A Systematic Review.

Celiac disease (CD) and type 1 diabetes mellitus (T1DM) are autoimmune diseases that coexist frequently. These illnesses share a common genetic background. This study aims to review the different pathophysiologic mechanisms that have been studied about the coexistence of CD and T1DM, to contrast them, and to summarize their specific role in these autoimmune diseases. We conducted a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist and used the Medical Subject Headings (MeSH) search strategy to obtain relevant articles. We found 585 papers which were reduced to 355 after removing duplicates. Later, the filters and inclusion/exclusion criteria were applied which ended the search with 78 articles. Finally, we reviewed the articles that contained information about the pathogenesis of CD and T1DM, their coexistence, and how the pathogenesis impacts clinical outcomes. The reviewed studies strongly conclude that the presence of human leukocyte antigen (HLA) genes DQ2 and DQ8 are high-risk for developing the coexistence of CD and T1DM. We found that killer immunoglobulin-like receptor (KIR) genes, enterovirus infection in gut cells, and gut microbiota dysbiosis with the predominance of Bacteroides spp. also play a role in the pathogenesis and development of symptoms of CD in patients with the previous diagnosis of T1DM. CD4+ and CD8+ cell levels vary among patients and studies, consequently, more study on this topic is needed.

Unraveling the Association Between Schizophrenia and Substance Use Disorder-Predictors, Mechanisms and Treatment Modifications: A Systematic Review.

Individuals with schizophrenia are particularly vulnerable to substance abuse problems. Comorbidity with substance use disorders (SUDs) frequently results in early death and increased dysfunction observed in schizophrenia. This dual diagnosis can be explained through multiple general mechanisms. Tobacco, alcohol, cannabis, and cocaine are substances widely used by individuals with schizophrenia. This study highlights the predictors, mechanisms responsible for the relationship between substance use disorder and schizophrenia and how it can help with the treatment of both disorders. The publications were rigorously reviewed after being found in multiple databases. The study's inclusion criteria were research published within the last five years, publications written in English, full-text availability, and human studies. A total of ten papers were selected for examination from a total of 9,106 articles found using the search method across several databases. This study follows the rules listed within the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 2009. The information gathered from these published studies was used to investigate the elements that contribute to the link between schizophrenia and substance abuse. Here, we evaluate a close relationship between schizophrenia and substance use disorders. The articles studied exhibit a bidirectional association between the two disorders in most individuals. From our analysis, the comorbidity between the two disorders is partially due to shared polygenic liability. Individuals with schizophrenia have dysfunctional Mesocorticolimbic brain reward circuits indicating a history of substance use. An underlying genetic vulnerability to schizophrenia may be triggered by extensive cannabis usage at a young age. A combination of psychological and pharmacological interventions for both disorders can significantly improve the outcome.

The Role of Vitamins in Non-Alcoholic Fatty Liver Disease: A Systematic Review.

Non-Alcoholic Fatty Liver Disease (NAFLD) emerged as the most prevalent liver disorder contributing significantly to disease burden worldwide. It manifests as a broad spectrum of hepatic damage with varying severity ranging from less serious steatosis to a more severe Non-Alcoholic Steatohepatitis (NASH), with or without fibrosis, cirrhosis, and hepatocellular carcinoma. Vitamins, on the other hand, are micronutrients that are vital for healthy well-being. Some studies have linked liver diseases with hypovitaminosis; however, there are still some gaps about the basis of their correlation. Hence, this systematic review aims to discuss the role of vitamins in the pathogenesis of NAFLD and explore their hepatoprotective potential that may benefit clinicians in managing this condition. This systematic review searched for studies indexed in the PubMed, PubMed Central, Medline, Google Scholar, and ScienceDirect databases. Inclusion and exclusion criteria were applied, duplicates were removed, and meticulous screening of articles was done systematically. Out of 729 unique studies generated using the search strategy, 17 were finally included after thorough review and quality appraisal.  NAFLD is not simply an outcome of insulin resistance and metabolic derangements; instead, it is a disease with complex underlying pathogenesis. Moreover, vitamin deficiency has been associated with NAFLD development and increased susceptibility to more severe liver damage. Derangement in vitamins correlates to the lipotoxic hepatic environment, altered immune system, unwarranted inflammation, oxidative stress, gene mutations, epigenetic modification, and gut dysbiosis seen in NAFLD. As they influence several pathophysiologic processes in the liver, vitamins A, B3, B6, B9, B12, C, D, and E are promising potential options that can impact NAFLD management. However, more well-designed studies conducted in the human population are still necessary to establish their efficacy and safety as therapeutic agents.

The Correlation Between Parkinson's Disease and Rapid Eye Movement Sleep Behavior Disorder: A Systematic Review.

Parkinson's disease (PD) is a neurodegenerative disease caused due to the destruction of dopaminergic neurons and the deposition of α-synuclein proteins, known as Lewy bodies. Generally, the diagnosis of PD is centered around motor symptoms. However, the early recognition of non-motor symptoms such as autonomic dysfunction, sleep disturbances, and cognitive and psychiatric disturbances are gaining increased attention for the early diagnosis of PD. Rapid eye movement (REM) sleep behavior disorder or REM sleep behavior disorder (RBD) is described as parasomnia, which is a condition of loss of normal muscle atonia causing the person to act out vivid dreams and it has been seen to be associated with the misprocessing of intercellular α-synuclein leading to neurodegenerative diseases such as PD. This review's objective is to highlight the significance of RBD as a prodromal premotor marker for the early detection of PD. We used PubMed as our primary database to search for articles on May 2, 2021, and a total of 1849 articles were found in our initial search using keywords and medical subject heading (MeSH) keywords. Thereafter, we removed the duplicates, applied the inclusion/exclusion criteria, and did a quality appraisal to include 10 articles in this study. We concluded that the recognition and diagnosis of RBD are of paramount importance to detect early PD, and further longitudinal studies and clinical trials are of utmost importance to understand their correlation; also, treatment trials are needed to prevent the phenoconversion of RBD into PD.

Joint molecule resolution requires the redundant activities of MUS-81 and XPF-1 during Caenorhabditis elegans meiosis.

The generation and resolution of joint molecule recombination intermediates is required to ensure bipolar chromosome segregation during meiosis. During wild type meiosis in Caenorhabditis elegans, SPO-11-generated double stranded breaks are resolved to generate a single crossover per bivalent and the remaining recombination intermediates are resolved as noncrossovers. We discovered that early recombination intermediates are limited by the C. elegans BLM ortholog, HIM-6, and in the absence of HIM-6 by the structure specific endonuclease MUS-81. In the absence of both MUS-81 and HIM-6, recombination intermediates persist, leading to chromosome breakage at diakinesis and inviable embryos. MUS-81 has an additional role in resolving late recombination intermediates in C. elegans. mus-81 mutants exhibited reduced crossover recombination frequencies suggesting that MUS-81 is required to generate a subset of meiotic crossovers. Similarly, the Mus81-related endonuclease XPF-1 is also required for a subset of meiotic crossovers. Although C. elegans gen-1 mutants have no detectable meiotic defect either alone or in combination with him-6, mus-81 or xpf-1 mutations, mus-81;xpf-1 double mutants are synthetic lethal. While mus-81;xpf-1 double mutants are proficient for the processing of early recombination intermediates, they exhibit defects in the post-pachytene chromosome reorganization and the asymmetric disassembly of the synaptonemal complex, presumably triggered by crossovers or crossover precursors. Consistent with a defect in resolving late recombination intermediates, mus-81; xpf-1 diakinetic bivalents are aberrant with fine DNA bridges visible between two distinct DAPI staining bodies. We were able to suppress the aberrant bivalent phenotype by microinjection of activated human GEN1 protein, which can cleave Holliday junctions, suggesting that the DNA bridges in mus-81; xpf-1 diakinetic oocytes are unresolved Holliday junctions. We propose that the MUS-81 and XPF-1 endonucleases act redundantly to process late recombination intermediates to form crossovers during C. elegans meiosis.

Carotid sinus hypersensitivity: disease state or clinical sign of ageing? Insights from a controlled study of autonomic function in symptomatic and asymptomatic subjects.

AIMS: This study sought to improve the currently limited understanding of the pathophysiology of carotid sinus hypersensitivity (CSH) by comparing autonomic function measured by heart rate variability (HRV) and baroreflex sensitivity inpatients with symptomatic CSH and asymptomatic individuals with and without CSH. METHODS AND RESULTS: Twenty-two patients with symptomatic CSH, 18 individuals with asymptomatic CSH, and 14 asymptomatic older individuals without CSH were recruited to our study. Non-invasive measurements of heart rate and blood pressure were obtained during 10 min of supine rest. Low frequency (LF), high frequency (HF), and total power spectral density (PSD) for HRV were determined using the autoregressive method. The baroreflex slope (BRS) and baroreflex effectiveness index (BEI) were determined using the sequence method for baroreflex sensitivity. There were significant increases in the LF-HRV (P = 0.014), total PSD (P = 0.031), LF:HF (P = 0.047), normalized (nu) LF-HRV (0.049), down ramp BEI (P = 0.017), and total BEI (P = 0.038) in the symptomatic CSH group compared with non-CSH controls. The asymptomatic CSH group had significantly higher LF-HRV (P = 0.001), total PSD (P = 0.002), nuLF-HRV (P = 0.026), and LF:HF (P = 0.030), as well as up, down, and total BRS (P = 0.012, P = 0.015, and P = 0.011, respectively) and BEI (P = 0.049, P = 0.001, and P = 0.006, respectively) than non-CSH control participants. CONCLUSION: This study has demonstrated an association between CSH with increased resting sympathetic activity and baroreflex sensitivity regardless of the presence of symptoms, indicating the presence of autonomic dysregulation in individuals with CSH. Our findings therefore suggest that CSH is part of a generalized autonomic disorder but do not differentiate between asymptomatic and symptomatic individuals.

Neurocardiovascular instability in cognitive impairment and dementia.

Neurocardiovascular instability (NCVI, neurally mediated disorders causing hypotension with or without bradycardia) represents abnormal neural control of the cardiovascular system and presents as dizziness, syncope, or falls. The mechanisms underpinning NCVI are incompletely understood. The three most common disorders are carotid sinus syndrome (CSS), orthostatic hypotension (OH), and vasovagal syndrome (VVS): CSS, cardioinhibition > 3 s and/or vasodepressor response > or = 50 mmHg drop in systolic pressure during carotid sinus stimulation; OH: fall in systolic blood pressure > 20 mmHg during standing; VVS: cardioinhibition > 3 s and/or vasodepressor response > 50 mmHg during prolonged head-up tilting. In fallers with cognitive impairment or dementia, the prevalence of NCVI is 70%. Multifactorial interventions, including treatment of NCVI, significantly reduce falls and syncope. The predominant components of NCVI in fallers with cognitive impairment and dementia are CSS and OH. In Lewy body and Alzheimer's dementia, the prevalence of NCVI is up to 60%, again predominantly CSS and OH. The prevalence of cardioinhibitory carotid sinus hypersensitivity is particularly high in Lewy body dementia-41% compared with 12% in Alzheimer's disease and 3% in case controls. In addition, patients with Lewy body dementia have greater heart rate slowing (>2 s) and falls in systolic blood pressure (>20 mmHg) than those with Alzheimer's disease or controls during carotid sinus stimulation. The extent of deep white matter hyperintensities on MRI correlates with systolic fall during carotid sinus stimulation (R = 0.58; p < 0.005), suggesting a possible causal association between bradyarrhythmia-induced hypotension and microvascular pathology. NCVI is common in patients with dementia and may be a reversible cause of falls and syncope. Repeated hypotensive episodes may exaggerate cognitive decline in these patients.