Defective Mitochondrial Quality Control during Dengue Infection Contributes to Disease Pathogenesis.

Mitochondrial fitness is governed by mitochondrial quality control pathways comprising mitochondrial dynamics and mitochondrial-selective autophagy (mitophagy). Disruption of these processes has been implicated in many human diseases, including viral infections. Here, we report a comprehensive analysis of the effect of dengue infection on host mitochondrial homeostasis and its significance in dengue disease pathogenesis. Despite severe mitochondrial stress and injury, we observed that the pathways of mitochondrial quality control and mitochondrial biogenesis are paradoxically downregulated in dengue-infected human liver cells. This leads to the disruption of mitochondrial homeostasis and the onset of cellular injury and necrotic death in the infected cells. Interestingly, dengue promotes global autophagy but selectively disrupts mitochondrial-selective autophagy (mitophagy). Dengue downregulates the expression of PINK1 and Parkin, the two major proteins involved in tagging the damaged mitochondria for elimination through mitophagy. Mitophagy flux assays also suggest that Parkin-independent pathways of mitophagy are also inactive during dengue infection. Dengue infection also disrupts mitochondrial biogenesis by downregulating the master regulators PPARγ and PGC1α. Dengue-infected cells release mitochondrial damage-associated molecular patterns (mtDAMPs) such as mitochondrial DNA into the cytosol and extracellular milieu. Furthermore, the challenge of naive immune cells with culture supernatants from dengue-infected liver cells was sufficient to trigger proinflammatory signaling. In correlation with our in vitro observations, dengue patients have high levels of cell-free mitochondrial DNA in their blood in proportion to the degree of thrombocytopenia. Overall, our study shows how defective mitochondrial homeostasis in dengue-infected liver cells can drive dengue disease pathogenesis. IMPORTANCE Many viruses target host cell mitochondria to create a microenvironment conducive to viral dissemination. Dengue virus also exploits host cell mitochondria to facilitate its viral life cycle. Dengue infection of liver cells leads to severe mitochondrial injury and inhibition of proteins that regulate mitochondrial quality control and biogenesis, thereby disrupting mitochondrial homeostasis. A defect in mitochondrial quality control leads to the accumulation of damaged mitochondria and promotes cellular injury. This leads to the release of mitochondrial damage-associated molecular patterns (mt-DAMPs) into the cell cytoplasm and extracellular milieu. These mt-DAMPs activate the naive immune cells and trigger proinflammatory signaling, leading to the release of cytokines and chemokines, which may trigger systemic inflammation and contribute to dengue disease pathogenesis. In correlation with this, we observed high levels of cell-free mitochondrial DNA in dengue patient blood. This study provides insight into how the disruption of mitochondrial quality control in dengue-infected cells can trigger inflammation and drive dengue disease pathogenesis.

Tubercular Meningitis with Acute Inflammatory Demyelinating Polyneuropathy-Trigger or Chance.

Tuberculosis being a global pandemic causes an array of neurological presentations ranging from tuberculoma, meningitis, radiculomyelitis, brain abscess, and so on.Association of Guillain-Barre syndrome with tuberculosis has been reported five to six times in the past. The authors report a case of a young female with tubercular meningitis on antitubercular therapy and steroids who went on to develop acute areflexic quadriparesis and diagnosed as a case of acute motor sensory axonal neuropathy variety of acute inflammatory demyelinating polyneuropathy (AIDP) who responded positively to plasmapheresis. The authors present the first case of an association between tubercular meningitis and subsequent development of AIDP.

Smokeless Tobacco and Stroke - A Clinico-epidemiological Follow-up Study in A Tertiary Care Hospital.

INTRODUCTION: Among the modifiable risk factors for stroke, tobacco smoking is well recognized. In some studies the use of Smokeless Tobacco (ST) has also been contributed as a risk factor for ischemic stroke. Use of ST is very common in South-East Asia. The form of ST varies according to the geographical and cultural variation. AIM: To study the various clinical symptoms and radiological findings of stroke due to different types of ST. MATERIALS AND METHODS: This was a prospective hospital based study carried out over a period of 2 years. All the cases within age group of 16 - 60 years and with a clinical and radiological diagnosis of acute stroke were included in the study. The Fagerström Test for Nicotine Dependence for ST of more than 6 was taken as the inclusion criteria. Patients having other addictions like smoked tobacco, alcohol, etc., and with important risk factors like hypertension, diabetes, dyslipidemia were excluded. The cases were extensively investigated and followed up for at least 6 months. Analysis was done using the Statistical Package for Social Sciences (SPSS- version 16.0). Descriptive statistics like percentage, mean were used wherever appropriate. RESULTS: During a period of 2 years, a total of 54 patients were studied. Forty two (77.7%) were males and 12(22.3%) were females. The mean age at presentation was 42.72(± 8.6) years and among all 96.3% patients were diagnosed as ischemic stroke. Among ST, pan was most commonly used in 21(38.9%) patients with an average of 14.6(±3.27) years of addiction. Hemiplegia was the predominant symptom on presentation (46, 85.2%). According to Oxfordshire Stroke Classification, partial anterior circulation infarct was most common in 20(38.4%). The mean Modified Rankin scale after 5 days of hospital stay was 3.83(±1.03) and after 6 months of follow-up was 2.1(±0.8). Patients were counseled for deaddiction and after 6 months follow-up 48(88.8%) patients had quit ST. CONCLUSION: ST is an important etiological factor for young ischemic stroke. This is the first study depicting clinical symptomatology of ST addicted ischemic stroke patients from India. Considering the increasing prevalence of ST use in south-east Asia, further long term studies are needed from this region.