Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Strongyloides stercoralis Infection in Humans: A Narrative Review of the Most Neglected Parasitic Disease.

Strongyloidiasis is a helminth infection affecting 613.9 million people annually, mainly in the tropics and subtropics. The reported seroprevalence in the United States is 4% with most of the cases reported in immigrants. Human T-lympho-tropic virus 1 (HTLV-1) infections, hypogammaglobulinemia, immunosuppressant use - particularly steroid use, alcoholism, and malnutrition have been associated with an increased risk of strongyloidiasis. Recently, cases of strongyloidiasis hyperinfection syndrome have been described in coronavirus disease 2019 (COVID-19) patients treated with steroids as well. This brief review discusses the epidemiology, clinical features, management, and prevention of strongyloidiasis including some facts about the infection in pregnancy, transplant recipients, and COVID-19 patients. We conducted an online search using the PubMed, Scopus, and Google Scholar databases. Strongyloidiasis can be asymptomatic or present with mild symptoms. Strongyloides stercoralis is known to cause autoinfection. In immunocompromised individuals, it can present with severe symptoms, hyperinfection, or disseminated disease. Reported mortality in cases of disseminated Strongyloidiasis is 87.1%. Serology and detection of larvae in stool by direct microscopy are the most commonly used methods to diagnose strongyloidiasis. The drug of choice for the treatment is ivermectin. However, the use of ivermectin in human pregnancy is not well studied, and its teratogenic risks are unknown. Proactive screening of strongyloidiasis is necessary in immunocompromised individuals to prevent severe disease.

Carbamazepine Reduces Sharp Wave-Ripple Complexes and Exerts Synapse-Specific Inhibition of Neurotransmission in Ex Vivo Hippocampal Slices.

Higher therapeutic concentrations of the antiseizure medication carbamazepine (CBZ) are associated with cognitive side effects. Hippocampal sharp wave-ripple complexes (SPW-Rs) are proposed to participate in memory consolidation during periods of quiet and slow-wave sleep. SPW-Rs are generated in the CA3 region and are regulated by multiple synaptic inputs. Here, we used a multi-electrode array to determine the effects of CBZ on SPW-Rs and synaptic transmission at multiple hippocampal synapses. Our results demonstrate that CBZ reduced SPW-Rs at therapeutically relevant concentrations (IC50 = 37 µM) and altered the core characteristics of ripples, important for information processing and consolidation. Moreover, CBZ inhibited neurotransmission in a synapse-specific manner. CBZ inhibition was most potent at the medial-perforant-path-to-CA3 and mossy-fiber-to-CA3 synapses (IC50s ~ 30 and 60 µM, respectively) and least potent at medial-perforant-path-to-dentate granule cell synapses (IC50 ~ 120 µM). These results suggest that the synapse-specific CBZ inhibition of neurotransmission reduces SPW-Rs and that the CBZ inhibition of SPW-Rs may underlie the cognitive impairments observed with therapeutic doses of CBZ.

Non-invasive evaluation of pulmonary glutathione in the exhaled breath condensate of otherwise healthy alcoholics.

BACKGROUND: Chronic alcoholism is associated with an elevated risk for pulmonary infection and a 3-fold chance for incidence and mortality of acute respiratory distress syndrome with critical injury. Limited sampling of the alveolar lining fluid has restricted clinical studies of the role of glutathione (GSH) redox balance in pulmonary function and diseased states. Non-invasive sampling in the exhaled breath condensate (EBC) to monitor alveolar GSH would facilitate research in pulmonary oxidative stress. METHODS: EBC was collected from otherwise healthy subjects with and without a history of alcohol abuse. Reduced and oxidized EBC glutathione (GSH and GSSG, respectively), pH, and hydrogen peroxide were measured. RESULTS: GSH was statistically decreased in alcohol abusers only when normalized to protein (4.7nmol/mg protein [0.75, 11.4] vs. 13.4 [7.8, 26.4], p=0.03). In contrast, GSSG was significantly elevated in the EBC from alcohol abusers when compared to controls, 5.62 [0.45, 8.94] vs. 0.50nM [0.38, 0.80], p=0.03. Thus, a greater percentage was in the oxidized GSSG form when subjects abused alcohol (35.3% [11.8, 58.1] vs. 5.2 [3.6, 6.1], p<0.001). These concentrations represented a 40mV shift in GSH redox state towards a more oxidized state. CONCLUSIONS: Proper sample preparation was essential to prevent GSH loss and artificial oxidation. The shift in redox potential or %GSSG, which were not affected by dilution, may serve as better markers of pulmonary oxidative stress. Furthermore, these data suggested that the oxidant stress observed in the lavage fluid of otherwise healthy alcoholics could be measured non-invasively in the EBC.

Chronic alcoholism alters systemic and pulmonary glutathione redox status.

RATIONALE: Previous studies have linked the development and severity of acute respiratory distress syndrome with a history of alcohol abuse. In clinical studies, this association has been centered on depletion of pulmonary glutathione and subsequent chronic oxidant stress. OBJECTIVES: The impact on redox potential of the plasma or pulmonary pools, however, has never been reported. METHODS: Plasma and bronchoalveolar lavage fluid were collected from otherwise healthy alcohol-dependent subjects and control subjects matched by age, sex, and smoking history. MEASUREMENTS AND MAIN RESULTS: Redox potential was calculated from measured reduced and oxidized glutathione in plasma and lavage. Among subjects who did and did not smoke, lavage fluid glutathione redox potential was more oxidized in alcohol abusers by approximately 40 mV, which was not altered by dilution. This oxidation of the airway lining fluid associated with chronic alcohol abuse was independent of smoking history. A shift by 20 mV in plasma glutathione redox potential, however, was noted only in subjects who both abused alcohol and smoked. CONCLUSIONS: Chronic alcoholism was associated with alveolar oxidation and, with smoking, systemic oxidation. However, systemic oxidation did not accurately reflect the dramatic alcohol-induced oxidant stress in the alveolar space. Although there was compensation for the oxidant stress caused by smoking in control groups, the capacity to maintain a reduced environment in the alveolar space was overwhelmed in those who abused alcohol. The significant alcohol-induced chronic oxidant stress in the alveolar space and the subsequent ramifications may be an important modulator of the increased incidence and severity of acute respiratory distress syndrome in this vulnerable population.