The aim of the present study is to evaluate the interdependency between heart rate variability (HRV) and inflammatory markers in patients with severe traumatic brain injury (TBI). A prospective exploratory study was done with a sample size of 89 patients. HRV of these patients was recorded using a telemetric device. The recordings were made on day 1 of the patients' admission into the intensive care unit followed by serial recordings on day 3 and day 10. Serum samples of the patients were also collected on these days for analysis of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor alpha levels using enzyme-linked immunosorbent assay kits. The outcome assessment was done using the Disability Rating Scale at discharge and Glasgow Outcome Scale-Extended at 6 months post-trauma. The data were analyzed by grouping the patients on based on mortality and outcome. In the present study, there was significant subclinical autonomic dysfunction in patients with severe TBI. Among the serum cytokines, levels of IL-10 had a significant impact on outcome. An increase in IL-10 levels correlated with the unfavorable outcome. This study highlights the association between the HRV parameters and immune response. The timely management of both autonomic and immune dysfunction in patients with severe TBI may have an impact in preventing the secondary injury process.

The steroid hormone, oestradiol, has pleiotropic functions. The protective effects of oestradiol are attributed to its anti-inflammatory, antioxidant, anti-atherogenic, anti-apoptotic, vasodilatory activities and regulation of micro RNA. Oestradiol upregulates endothelial nitric oxide synthase gene expression and increases the production of nitric oxide, an important vasodilator. It suppresses the renin-angiotensin system and monitors haemodynamic stress. The hormone maintains the integrity of blood vessels by reducing oxidative stress while upregulating the expression of antioxidant enzymes and prevents vascular inflammation by regulating pro-and anti-inflammatory cytokines. Aneurysmal subarachnoid haemorrhage (aSAH) occurring as a consequence of the rupture of an intracranial aneurysm is a devastating cerebrovascular event, representing 5-7% of all strokes. Postmenopausal women are more susceptible to aSAH compared to men in the same age group. This gender disparity has been attributed to reduced levels of the vascular protective hormone oestradiol following menopause. This review is focused on the protective role of oestradiol on vasculature and how the drop in oestradiol levels after menopause dramatically increases the incidence of aSAH in women. During menopause, oestradiol deficiency may affect vascular integrity causing dysregulation of vascular homeostasis by affecting the renin-angiotensin-aldosterone system (RAAS) and inflammatory and apoptotic cascades, resulting in the weakening of the cerebral arterial wall and potentially to development of an aneurysm and its rupture. In view of the role of oestradiol in maintaining vascular integrity, treatments involving hormone replacement could be a promising approach in postmenopausal women who are at risk of developing or rupturing an intracranial aneurysm.

I would like to dedicate this thesis to my familymy parents, Ramesh Rengaswamy and Vijay Ramesh who have always been the constant source of unconditional love, support and encouragement, my brother Dr. Sridharan Ramesh, for always being there whenever I needed moral support, motivation and guidance and to my partner Sudarsanan Krishnan, for the cheers, support and sacrifices throughout this journey. iii

Context Endothelial nitric oxide synthase (eNOS) gene polymorphisms are found to predict predisposition to aneurysmal rupture and development of vasospasm in a patient of subarachnoid hemorrhage (SAH). eNOS gene polymorphisms are also found to predict invasiveness of malignant cells. Studies are not available in literature to describe the effect of eNOS gene polymorphisms and correlation between aneurysm and carcinoma. This study aims to investigate whether positive cancer history influences clinical outcome following SAH and eNOS gene polymorphisms. Materials and Methods The eNOS gene polymorphisms were analyzed in seven consecutive patients (mean age, 52.28 ± 20 years) with a diagnosis of invasive systemic tumors from 2011 to 2017. The eNOS 4a/4b eNOS -786T> eNOS894G > T polymorphisms of the eNOS gene were determined by polymerase chain reaction and restriction fragment length polymorphism. Results Seven patients of aneurysmal SAH in association with malignancies were studied for eNOS polymorphisms expression and outcome. Three patients had carcinoma cervix: one patient of carcinoma breast and one each of transitional cell carcinoma of urinary bladder, spindle cell carcinoma of left kidney, and untreated patient of atypical pituitary (adenoma). A genotype study of eNOS gene polymorphisms in these patients shows common polymorphisms are involved in the determination of disease progression in malignancies and aneurysmal SAH. Conclusion Patients who expressed 4ab, eNOS -786T > TT/CC/TC, eNOS894G > T GG/GT polymorphisms did better than patients who expressed only 4bb, though both were associated with poor prognosis.

Context:Cerebral vasospasm remains a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Reduced bioavailability of nitric oxide has been associated with the development of cerebral vasospasm after aSAH. Such data is not available in Indian population.Aims:The objective of the study was to measure the plasma total nitric oxide (nitrite and nitrate-NOx) level in aSAH patients and healthy controls treated at a tertiary hospital in India and to investigate a possible association between plasma total nitric oxide level and cerebral vasospasm and clinical outcome following treatment in patients with aSAH.Settings and Design:A case-control study of aSAH patients was conducted. Plasma total NOx levels were estimated in aSAH patients with and without vasospasm and compared the results with NOx levels in healthy individuals.Materials and Methods:aSAH in patients was diagnosed on the basis of clinical and neuro-imaging findings. Plasma total NOx levels in different subject groups were determined by Griess assay.Results:Plasma total NOx level was found to be significantly decreased in patients with aSAH when compared to controls. Plasma total NOx level in the poor-grade SAH group was lower than that in the good-grade SAH group. Plasma total NOx level further reduced in patients with angiographic (P < 0.05) and clinical vasospasm.Conclusions:Reduced plasma NOx level is seen in aSAH patients as compared to normal individuals. In aSAH patients reduced levels are associated with increased incidence of cerebral vasospasm and poor outcome. Plasma total NOx level could be used as a candidate biomarker for predicting vasospasm and outcome for this pathology.