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Medical Sciences

Relapse on ketamine followed by severe and prolonged withdrawal: A cautionary case and review of potential medical therapies

Author: Matthew P. Prekupec, Rachel S. Sussman, Yelizaveta Sher, Anna Lembke

Manuscript ID: JNSCI#17-0814


Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist used medically as a dissociative anesthetic. It has been used recreationally since the 1970s. In recent years, ketamine has been investigated in the treatment of depression and chronic pain. Given ketamine’s addictive potential, increasing medical use has led to the possibility of patients with substance use disorders (SUD) who relapse on ketamine after medical exposure. We present the case of a patient with opioid use disorder on buprenorphine who was exposed to ketamine in the emergency department (ED), then procured it from the darknet to “self-medicate his depression.” After using heavily for 15 days, he experienced debilitating withdrawal syndrome requiring intensive care unit admission.  Ketamine use should be in the differential of any young patient who presents to the ED with agitation and visual hallucinations or nystagmus. Moreover, the benefits of therapeutic ketamine use should be weighed carefully against the risk of relapse in those with SUD.  In cases where ketamine use is absolutely necessary for high-risk patients, we recommend that dosing be limited to the sub-dissociative range (0.2-0.5 mg/kg). We also recommend the use of a slow infusion rather than bolus. For patients with ketamine withdrawal, benzodiazepines and/or anti-glutamatergic anticonvulsants may be helpful to alleviate symptoms.



A microRNA cluster (let-7c, miRNA-99a, miRNA125b, miRNA-155 and miRNA-802) encoded at chr21q21.1-chr21q21.3 and the phenotypic diversity of Down’s syndrome (DS; trisomy 21)

Author: Zhao Y, Jaber V, Percy ME, Lukiw WJ

Manuscript ID: JNSCI#17-0812


Down’s syndrome (DS) is the most common genetic cause of intellectual disability and cognitive deficit
attributable to a naturally-occurring abnormality in gene dosage. DS is caused by a triplication of all or part of human chromosome 21 (chr21) and currently there are no effective treatments for this incapacitating human neurodevelopmental disorder. First described by the English physician John Langdon Down in 1862, propelled by the invention of karyotype analytical techniques in the early 1950s and the discovery in 1959 by the French geneticist Jerome Lejune that DS resulted from an extra copy of chr21, DS was the first neurological disorder linking a chromosome dosage imbalance to a defect in intellectual development and cognitive disruption. Especially over the last 60 years, it has been repeatedly demonstrated that DS is not an easily defined disease entity but rather possesses a remarkably wide variability in the ‘phenotypic spectrum’ associated with this trisomic disorder. This commentary describes the presence of a 5 member cluster of chr21-encoded microRNAs (miRNAs) that includes let-7c, miRNA-99a, miRNA125b, miRNA-155 and miRNA-802, located on the long arm of human chr21 and spanning the chr21q21.1-chr21q21.3 region, just upstream from the beta amyloid precursor (βAPP) gene, and reviews the potential contribution of these 5 miRNAs to the DS phenotype.

Medical Sciences

Refractory versus resistant hypertension: Novel distinctive phenotypes

Author: Tanja Dudenbostel, Mohammed Siddiqui, Nitin Gharpure, David A. Calhoun

Manuscript ID: JNSCI#17-0810


Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients.  It is defined as blood pressure (BP) >140/90 mmHg treated with ≥3 antihypertensive medications, including a diuretic, if tolerated. Refractory hypertension is a novel phenotype of severe antihypertensive treatment failure. The proposed definition for refractory hypertension, i.e. BP >140/90 mmHg with use of ≥5 different antihypertensive medications, including a diuretic and a mineralocorticoid receptor antagonist. In comparison to RHTN, refractory hypertension seems to be less prevalent than RHTN. This review focuses on current knowledge about this novel phenotype compared with RHTN including definition, prevalence, mechanisms, characteristics and comorbidities, including cardiovascular risk.  In patients with RHTN excess fluid retention is thought to be a common mechanism for the development of RHTN. Recently, evidence has emerged suggesting that refractory hypertension may be more of neurogenic etiology due to increased sympathetic activity as opposed to excess fluid retention. Treatment recommendations for RHTN are generally based on use and intensification of diuretic therapy, especially with the combination of chlorthalidone and spironolactone.  Based on findings from available studies, such an approach does not seem to be a successful strategy to control BP in patients with refractory hypertension and effective sympathetic inhibition in such patients, either with medications and/or device based approaches may be needed.



Time Course of Changes in Neuromuscular Parameters from the Quadriceps During Maximal Isokinetic Muscle Actions

Author: Cory M. Smith, Terry J. Housh, Ethan C. Hill, Joshua L. Keller, Glen O. Johnson, Richard J. Schmidt

Manuscript ID: JNSCI#17-0729


Purpose: The purposes of the present study were to identify the time course of changes in neuromuscular responses and to infer about the motor unit control strategies used to maintain force from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) during a fatiguing maximal concentric isokinetic leg extension workbout.

Methods: Thirteen men performed 25 maximal concentric isokinetic leg extension muscle actions at 120°s-1. Electromyography, (EMG), mechanomyography (MMG), and force were simultaneously collected from the VL, VM, and RF during each of the 25 repetitions. A combined regression and mean comparisons analysis was used to examine the time course of changes in maximal isokinetic peak force as well as EMG amplitude (RMS), EMG mean power frequency (MPF), MMG RMS, and MMG MPF from the VL, VM, and RF.

Results: Maximal isokinetic peak force decreased 21% and was accompanied by changes in neuromuscular responses from all muscles. The VL exhibited increases in EMG RMS and MMG RMS, decreases in EMG MPF, but no changes in MMG MPF. The VM only exhibited increases in EMG RMS. The RF, however, exhibited increases in EMG RMS, but decreases in EMG MPF.

Discussion: The time course of changes in neuromuscular responses allowed for the identification of the potential motor unit control strategies used to maintain and optimize force production. The motor unit control strategy utilized to maintain and optimize force production could not be explained by the After-Hyperpolarization or Muscle Wisdom theory, but could be explained by the Onion Skin Scheme.


Biological Chemistry

Controlling Epithelial to Mesenchymal Transition through Acetylation of Histone H2BK5

Author: Robert J. Mobley, Amy N. Abell

Manuscript ID: JNSCI#17-0728


Large-scale epigenetic changes take place when epithelial cells with cell-cell adhesion and apical-basal polarity transition into invasive, individual, mesenchymal cells through a process known as epithelial to mesenchymal transition (EMT). Importantly, cancers with stem cell properties disseminate and form distant metastases by reactivating the developmental EMT program. Recent studies have demonstrated that the epigenetic histone modification, H2BK5 acetylation (H2BK5Ac), is important in the regulation of EMT. For example, in trophoblast stem (TS) cells, H2BK5Ac promotes the expression of genes important to the maintenance of an epithelial phenotype. This finding lead to the discovery that TS cells and stem-like claudin-low breast cancer cells share similar H2BK5Ac-regulated gene expression linking developmental and cancer cell EMT. An improved understanding of the role of H2BK5Ac in developmental EMT and stemness will further our understanding of epigenetics in EMT-related pathologies. Here we examine the binders and regulators of H2BK5Ac and discuss the roles of H2BK5Ac in stemness and EMT.


Medical Sciences

The role of corneal stroma: A potential nutritional source for the cornea

Author: Lingling Zhang, Matthew C. Anderson, Chia-Yang Liu

Manuscript ID: JNSCI#17-0727


Corneal stroma plays a pivotal role in normal visual function.  Anatomically, it is located between the outer epithelium and the inner endothelium and is the thickest layer of the cornea. Keratocytes in the stroma produce a variety of cellular products, including growth factors/cytokines, extracellular matrix (ECM) components, and kinases. These products support normal corneal development and homeostasis. 



Cancer Prevention and Treatment by Wholistic Nutrition

Author: T. Colin Campbell

Manuscript ID: JNSCI#17-0630


Cancer is traditionally considered a genetic disease. It starts with a gene mutation, often caused by environmental carcinogens that, upon enzymatic activation, covalently bind to DNA. If these carcinogen-DNA adducts escape repair, they result in a mutation, which is inherited by daughter cells and their subsequent progeny, while accumulating more mutations thought to advance cellular independence, metastasis, and drug resistance, among other characteristics, typically observed for advanced cancer. Initiating, promoting and progressing cancer by mutations infers irreversibility because back mutations are exceedingly rare. Thus, treatment protocols typically are designed to remove or kill cancer cells by surgery, chemotherapy, immunotherapy and/or radiotherapy. However, empirical evidence exists to support a fundamentally different treatment option. For example, the development of experimental cancer in laboratory animals initiated by a powerful mutagen/carcinogen can be repetitively turned on and off by non-mutagenic mechanisms, even completely, by modifying the consumption of protein at relevant levels of intake. Similar but less substantiated evidence also exists for other nutrients and other cancer types. This suggests that cancer is primarily a nutrition-responsive disease rather than a genetic disease, with the understanding that nutrition is defined as a comprehensive, wholistic biological function reflecting the natural composition of nutrients and related substances in whole, intact food.  This function sharply contrasts with the contemporary inference that nutrition is the summation of individual nutrients acting independently. The spelling of ‘holism’ with the ‘w’ is meant to emphasize the empirical basis for this function.  The proposition that nutrition, acting wholistically, controls and even reverses disease development suggests that cancer may be treated by nutritional intervention.



Angiogenesis and Anti-tumor Immunity in the Tumor Microenvironment: Opportunities for Synergism in Intervention

Author: Christopher Lemmon, Ibrahim Sadek, Zhonglin Hao

Manuscript ID: JNSCI#17-0623


Success of angiogenesis inhibition has met with resurgence of immunomodulation in treatment of metastatic carcinomas. While each of these is effective in some cases, the response rates are low, and resistance soon emerges to single agent treatment. Will combination of the two improve response rate and duration of response through synergy? In addition to blocking neovascular formation, angiogenesis inhibitors (AI) help deliver more effective cytotoxic T lymphocytes to the tumor by improving vascular perfusion. Recent studies also showed that AI not only increased the efficacy of effector immune element but also decreased the number and function of suppressor immune cells such as T-regulatory cells, myeloid-derived suppressor cells or tumor-associated macrophages. In this review, we focus on AI and their effects on antitumor immunity in the tumor microenvironment and their potentials in boosting the efficacy of immunotherapy. In the clinical arena, trials are at the early stage to gauge the feasibility and preliminary signs of synergy.

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