Critical Prognostic Factors in Cerebral Venous Sinus Thrombosis: An Observational Study.

Background: Cerebral venous sinus thrombosis (CVST) presents with a wide variety of neurological symptoms in various combinations and has a high mortality rate of up to 50%. Recent advances in neuroimaging and therapeutic interventions have brought it down to 10%-20%. The study aims to identify critical prognostic factors associated with poor outcomes in patients with CVST. Materials and Methods: All cases of CVST aged >18 years from July 2015 to July 2020 who were not terminally ill and bedridden before the illness were evaluated at the entry point for various risk factors and after 30 days for outcome assessment with the modified Rankin scale (mRS). The outcome was dichotomized, applying mRS <3 as a good outcome, and analyzed with the Chi-square test or the Fischer's exact test in a bivariate analysis to identify associated variables. Results: A total of 149 subjects were studied. Glasgow Comma Scale (GCS) <9 (P<0.001), focal neurological deficits (P = 0.05), the presence of a mass effect (P<0.001), and the need for decompressive hemicraniectomy (P<0.001) were associated with poor outcomes. Age, gender, diagnostic delay, seizures at onset, papilledema, parenchymal lesions, deep sinus involvement, and multiple sinus thrombosis were not associated with a poor outcome. Conclusion: In our study, early diagnosis and treatment of CVST is associated with an overall favorable outcome even in the presence of traditional poor prognostic factors such as age, seizures at onset, deep sinus involvement, and multiple sinus involvement in the face of conventional risk factors. A large country-wide prospective study might help in elucidating the poor prognostic factors.

Relevance of Geographical and Biochemical Factors in Causation of Cerebral Venous Sinus Thrombosis: An Observational Analytical Study.

Objectives: There is a higher prevalence of cerebral venous sinus thrombosis (CVST) in more recent times, owing to increased awareness, clinical diagnostic skills, and advancements in neuroimaging modalities. This study aimed to identify and characterize the geographical, clinical, and etiological profiles of patients with CVST that may be relevant to planning appropriate diagnostic and therapeutic strategies to improve functional recovery. Methods and Results: A retrospective observational study was carried out at a tertiary care hospital between March 2014 and October 2018. The demographics and clinical profile of the hospitalized patients were extracted from the Medical Record Division. Choropleth maps were created to present the geographic distribution of the patients with CVST admitted to our hospital. A total of 145 patients with CVST were included in the study. Etiological factors revealed striking abnormalities in red blood cells counts and serum homocysteine. Analyzing the geographical distribution of the patients with CVST showed most of the patients hailed from Central Karnataka Plateau 106 (73%). Polycythemia was most commonly seen in patients residing in the Central Karnataka Plateau 21 (62%). Conclusion: It is inferred that large scale community-based studies to identify a genetic abnormality like a mutant erythropoietin gene should be undertaken to plan effective diagnostic, therapeutic, and preventive measures.

Is the antiseizure effect of ketogenic diet in children with drug-resistant epilepsy mediated through proinflammatory cytokines?

In order to understand whether the antiseizure mechanism of ketogenic diet (KD) is mediated through its anti-inflammatory effect, we measured the serum concentrations of cytokines IL- 1ß and IL-6 in 21 children with drug-resistant epilepsy. We found a significant reduction in the levels of serum IL- 1ß and IL-6 levels at one-year of KD therapy compared to baseline. However, we did not find any correlation between decrease in the serum concentrations of these interleukins with the reduction in seizure frequency at one-year of KD therapy, which may be due to the small sample size and heterogeneous patient population we studied. Future studies should try to overcome these limitations.

Can change in gut microbiota composition be used as a surrogate marker of treatment efficacy of ketogenic diet in patients with drug-resistant epilepsy?

To answer the question posed in the title of the manuscript, we critically examined the connection between ketogenic diet (KD), gut microbiota (GM), and epilepsy. We conclude that although the evidence for a KD-GM-epilepsy link is fairly robust in rodent epilepsy models, it is very hard to draw meaningful conclusions in humans. The limitations of human studies that have investigated the KD-microbiota-epilepsy relationship include small sample size, a heterogeneous patient population with regard to age and epilepsy type, failure to account for the effect of dietary habits, antiseizure drugs (ASDs) and comedications on GM composition, variability in the KD administered and in the duration of the intervention, and different approaches used in sequencing the microbiome. Although alteration in the GM composition may be a potential indicator of responsiveness/resistance to a KD, we need well-designed randomized case-control and cohort studies involving a large number of a fairly homogenous population of patients with epilepsy adjusted to their habitual dietary habits and region of residence before labeling it as a surrogate marker. Research in this direction may also help us to unravel the mysteries of GM-brain axis not only concerning epilepsy but also in other neurological diseases.

A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation.

Inflammation is a protective immune response against invading pathogens, however, dysregulated inflammation is detrimental. As the complex inflammatory response involves multiple mediators, including the involvement of reactive oxygen species, concomitantly targeting proinflammatory and antioxidant check-points may be a more rational strategy. We report the synthesis and anti-inflammatory/antioxidant activity of a novel indanedione derivative DMFO. DMFO scavenged reactive oxygen species (ROS) in in-vitro radical scavenging assays and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In acute models of inflammation (carrageenan-induced inflammation in rat paw and air pouch), DMFO effectively reduced paw oedema and leucocyte infiltration with an activity comparable to diclofenac. DMFO stabilised mast cells (MCs) in in-vitro A23187 and compound 48/80-induced assays. Additionally, DMFO stabilised MCs in an antigen (ovalbumin)-induced MC degranulation model in-vivo, without affecting serum IgE levels. In a model of chronic immune-mediated inflammation, Freund's adjuvant-induced arthritis, DMFO reduced arthritic score and contralateral paw oedema, and increased the pain threshold with an efficacy comparable to diclofenac but without being ulcerogenic. Additionally, DMFO significantly reduced serum TNFα levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1ß, TNFα, IL6) and protein levels (COX2, MCP1), with a concurrent increase in antioxidant genes (NQO1, haem oxygenase 1 (HO-1), Glo1, Nrf2) and protein (HO-1) in LPS-stimulated macrophages. Importantly, the anti-inflammatory/antioxidant effect on gene expression was absent in primary macrophages isolated from Nrf2 KO mice suggesting an Nrf2-targeted activity, which was subsequently confirmed using siRNA transfection studies in RAW macrophages. Therefore, DMFO is a novel, orally-active, safe (even at 2 g/kg p.o.), a small molecule which targets Nrf2 in ameliorating inflammation.

A multimodal Darwinian strategy for alleviating the atherosclerosis pandemic.

The conflict between our 'primitive' genes and 'modern' lifestyle probably lies at the root of several disorders that afflict modern man. Atherosclerosis, which is relatively unknown among contemporary hunter-gatherer populations, has reached pandemic proportions in recent times. Being an evolutionary problem with several inter-related pathologies, current therapeutic strategy for treating atherosclerosis has inherent limitations. Reviewing evolution-linked risk factors suggests that there are four aspects to the etiology of atherosclerosis namely, decreased intestinal parasitism, oversensitivity of evolutionarily redundant mast cells, chronic underactivation of AMPK (cellular energy sensor) and a deficiency of vitamin D. A combination of these four causes appear to have precipitated the atherosclerosis pandemic in modern times. Man and worms co-existed symbiotically in the past. Massive de-worming campaigns could have disrupted this symbiosis, increasing nutritional availability to man (pro-obesity) at the cost of decreased immunotolerance (pro-atherogenicity). A reduction in helminth-induced chronic TH2 activation could also have enhanced TH1 polarization, eventually disrupting the reciprocal regulation of TH1/TH2 balance and resulting in atherosclerosis. The riddance of helminth infestations may have rendered mast cells immunologically redundant, making them oversensitive to inflammatory stimuli, thereby playing a pro-atherogenic role. AMPK activation exerts pleiotropic anti-atherogenic effects, such as suppression of fatty acid, cholesterol, protein synthesis, reduction of vascular smooth muscle proliferation, etc. As energy deficit is the chief stimulus for AMPK activation, the over-nourished modern man appears to be suffering from chronic underactivation of AMPK, legitimising the unrivalled supremacy of metformin, the oldest prescribed antidiabetic drug. The fact that humans evolved in the sunny tropics suggests that humans are selected for high vitamin D levels. Vitamin D deficiency is now linked to several conditions including increased risk of CV disorders, diabetes, etc. The manifold decrease in vitamin D levels in modern man justifies a need for supplementation. We therefore hypothesize that a judicious combination of mast cell stabilization, AMPK activation, vitamin D supplementation, and moderation in hygiene practices could be an evolution-based multimodal strategy for both preventing and mitigating the pandemic of atherosclerosis.