Intracellular DAMPs in Neurodegeneration and Their Role in Clinical Therapeutics.

Neuroinflammation is the major implication of neurodegeneration. This is a complex process which initiates from the cellular injury triggering the innate immune system which gives rise to damage-associated molecular patterns (DAMPs) which are also recognized as endogenous danger indicators. These originate from various compartments of the cell under pathological stimulus. These are very popular candidates having their origin in the intracellular compartments and organelles of the cell and may have their site of action itself in the intracellular or at the extracellular spaces. Under the influence of the pathological stimuli, they interact with the pattern-recognition receptor to initiate their pro-inflammatory cascade followed by the cytokine release. This provides a good opportunity for diagnostic and therapeutic interventions creating better conditions for repair and reversal. Since the major contributors arise from the intracellular compartment, in this review, we have attempted to focus on the DAMP molecules arising from the intracellular compartments and their specific roles in the neurodegenerative events explaining their downstream mediators and signaling. Moreover, we have tried to cover the latest interventions in terms of DAMPs as clinical biomarkers which can assist in detecting the disease and also target it to reduce the innate-immune activation response which can help in reducing the sterile neuroinflammation having an integral role in the neurodegenerative processes.

Age-dependent assessment of selenium nanoparticles: biodistribution and toxicity study in young and adult rats.

Aim: To study the biodistribution and toxicology of selenium nanoparticles (SeNPs) versus their bulk counterpart in young and adult male rats in a 28-day study. Methods: SeNPs were synthesized and conjugated with indocyanine green to assess comparative biodistribution by in vivo imaging and further characterized by transmission electron microscopy, Fourier transform infrared, scanning electron microscopy/energy dispersive x-ray spectroscopy, UV and ζ-analysis. The toxicity of bulk selenium was evaluated relative to its nano form by hematology indices, redox, inflammatory markers and histopathology. Results: Indocyanine green-conjugated nanoparticles showed preferential accumulation in the liver, followed by testis and kidney. The protective effect of SeNPs was more significantly observed in young livers than in adults compared with the bulk counterpart. Conclusion: Age-dependent monitoring and diagnosis of toxicity may need different biomarkers of selenium and may also provide better understanding of SeNPs as therapeutics.

Selenium is an essential element in the body. Its bioactive properties can protect against neurological conditions, diabetes, cancer and other chronic disorders. However, selenium in various biological forms (bulk) can be toxic. Selenium nanoparticles (SeNPs) have unique properties which might prevent this toxicity, providing a potential alternative for selenium supplementation and therapy. However, more studies are needed to see where SeNPs localize in the body, as well as comparing their toxicology with conventional forms of selenium in different age groups. We synthesized and characterized SeNPs of 70­90 nm, then injected them into young and adult rats to see where they distributed in the body. This was compared with rats injected with bulk selenium. SeNPs showed preferential accumulation in the liver, followed by the testes and kidneys. Next, the toxicity profiles of SeNPs and bulk selenium were established by measuring a series of health markers in the liver. It was found that the protection against toxicity provided by SeNPs was more significant in younger rats. Our results demonstrate that the same dose may behave differently in different age groups and that bulk selenium induces different toxicities in young and adult rats compared with SeNPs, highlighting the importance of different indicators of health for the monitoring of selenium-related toxicity when designing selenium-based therapeutics.

Sudden Unexpected Death in Epilepsy.

Epilepsy is a complex neurological condition with numerous etiologies and treatment options. In a subset of these patients, sudden unexpected death can occur, and to date, there are numerous explanations as to the pathophysiological mechanisms and how to mitigate these catastrophic outcomes. Approximately 2.3 million Americans have epilepsy, and nearly 150,000 people develop the condition each year. Sudden unexpected death in epilepsy (SUDEP) accounts for 2-18% of all epilepsy-related deaths and this is equivalent to one death in 1000 person-years of diagnosed epilepsy. It is more common in young adults aged 20-45. Seizures in the past year; the absence of terminal remission in the last five years; increased seizure frequency, particularly GTCS; and nocturnal seizures are the most potent modifiable risk factors for SUDEP. Patients not receiving any antiepileptic drug therapy are at higher risk of SUDEP. Patient education on medication compliance; care plans for seizure clusters (rescue medicines); epilepsy self-management programs; and lifestyle changes to avoid seizure-triggering factors, including avoiding excessive alcohol use and sleep deprivation, should be provided by health care providers. Continued research into SUDEP will hopefully lead to effective interventions to minimize occurrences. At present, aggressive control of epilepsy and enhanced education for individuals and the public are the most effective weapons for combating SUDEP. This narrative review focuses on updated information related to SUDEP epidemiology; pathophysiology; risk factor treatment options; and finally, a discussion of important clinical studies. We seek to encourage clinicians who care for patients with epilepsy to be aggressive in controlling seizure activity and diligent in their review of risk factors and education of patients and their families about SUDEP.

The association of reduced left ventricular strains with increased extracellular volume and their collective impact on clinical outcomes.

BACKGROUND: Myocardial fibrosis and left ventricular (LV) longitudinal strain are independently associated with adverse clinical outcomes. However, the relationship between tissue properties and strain indices as well as their collective impact on outcomes are yet to be fully elucidated. We aim to investigate the relationship between LV global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) with extracellular volume (ECV) and their collective impact. METHODS: Consecutive patients referred for clinical cardiovascular magnetic resonance (CMR) due to cardiomyopathy were prospectively enrolled. All patients underwent CMR with T1 mapping. ECV was calculated incorporating native and post-contrast T1 as well as hematocrit. LV GLS, GCS, and GRS were assessed by feature tracking. Hazard ratios and Kaplan-Meier curves were produced to assess the association between strains and T1 mapping indices with a composite outcome of all-cause mortality and hospitalized heart failure. RESULTS: The study consisted of 259 patients with mixed referring diagnoses of non-ischemic/ischemic cardiomyopathy and 21 normal controls. Decreased GLS, GCS and GRS were associated with increased ECV, increased native T1, and reduced post-contrast T1 in a dose dependent manner when T1 or ECV was in the abnormal range. After a mean follow-up of 31 ± 23 months, 41 events occurred including 37 heart failure admissions and 4 deaths. Kaplan-Meier plots demonstrated that reduced strains were associated with reduced event-free survival predominantly in patients with increased ECV (≥ 28.3%). The worst outcome was among those with both reduced strains and increased ECV. In the multivariable models, increased ECV, reduced post-contrast T1 and reduced strains in all 3 directions remained predictors of outcome risk, respectively. CONCLUSION: Our findings highlight the intrinsic link between altered CMR tissue properties and impaired myocardial mechanical performance and additionally demonstrate improved risk stratification by characterizing tissue property among patients with reduced strain.

The Association between Left Ventricular Diastolic Dysfunction and Myocardial Scar and Their Collective Impact on All-Cause Mortality.

BACKGROUND: Left ventricular diastolic dysfunction (DD) and myocardial scar are important contributors to cardiovascular morbidity and mortality. The aim of this study was to test the hypothesis that myocardial scar is a substrate of DD and that collectively they contribute to increased risk for all-cause mortality. METHODS: The study included 607 consecutive patients who underwent echocardiography and cardiac magnetic resonance imaging within 1 week. DD was assessed by echocardiography according to the contemporary guidelines and myocardial scar by late gadolinium enhancement (LGE). All-cause mortality was the main outcome. RESULTS: Scar prevalence was significantly higher comparing no DD with mild and advanced DD (25%, 61%, and 80%, respectively; P < .001), and scar burden was greater by semiquantitative LGE scores (1.4 ± 3.4, 4.8 ± 6.3, and 6.8 ± 8.8, respectively; P < .001). After 10 years of follow-up, 50 patients (8.2%) had died. The mortality incidence was significantly higher comparing no DD with mild and advanced DD (2.5, 17.3, and 55.7 deaths per 1,000 person-years, respectively; P < .001). It was also higher in patients with higher LGE scores (4.3, 22.7, and 35.2 deaths per 1,000 person-years in groups with LGE scores of 0, 1-6, and ≥7, respectively; P < .001). The risk for death was higher among patients with both DD and scar. The additive interaction of DD and scar for mortality was significant (P < .001). In the multivariate Cox proportional-hazards analysis, DD and scar were associated with mortality (P < .001). CONCLUSIONS: There is a strong link between the echocardiographic findings of DD and the morphologic changes of myocardial tissue. DD assessed according to contemporary guidelines effectively differentiates mortality risk. The additive interaction of DD and scar on mortality risk highlights the pivotal role of myocardial tissue characterization in patients with DD.

Case of Acute Onset Postpartum Paraplegia: Spontaneous Spinal Epidural Hematoma-A Rare Entity.

Study Design Present study is a case report. Objective This study was to present a rare case of acute postpartum paraplegia due to spontaneous spinal epidural hematoma (SSEH). Background SSEH with incidence rate of 0.1 per 100,000 per year is an extremely rare cause of sudden onset neurological deficit in postpartum patients with no predisposing factors or intrapartum factor causing SSEH resulting in paraplegia. Material and Methods We hereby present our case of acute onset postpartum paraplegia which on magnetic resonance imaging (MRI) shows epidural hematoma around thoracic 12 to lumbar 2 (T12-L2) vertebral regions with adjacent cord changes. MRI is the investigation of choice in such cases which helps in proper timely management of patient. We planned the patient for surgical decompression of hematoma. Results Patient showed rapid reversal of neurological symptoms in postoperative period. Conclusions Acute onset postpartum paraplegia in a healthy female with no significant past history, predisposing factors or intrapartum factors may be caused by SSEH and it should be managed on emergency basis as early and proper treatment has an excellent prognosis as seen in our case.

B-Type Natriuretic Peptide: A Predictor for Mortality, Intensive Care Unit Length of Stay, and Hospital Length of Stay in Patients With Resolving Sepsis.

BACKGROUND: B-type natriuretic peptide (BNP) is a hormone secreted by cardiomyocytes in response to myocardial ischemia, increased ventricular wall tension, and overload. BNP is utilized as a diagnostic and prognostic marker in congested heart failure (CHF). Its prognostic value in sepsis is unknown. The aim of this study is to determine if BNP correlates with increased in-hospital mortality for septic patients. METHODS: This was a retrospective study of 505 patients admitted for sepsis or severe sepsis or septic shock during the period of January 2013 and August 2014. Patients that received > 3 L of intravenous fluids on presentation were included. Intensive care unit length of stay (ICULOS), hospital length of stay (HLOS) and in-hospital mortality were measured. Mean BNP level was calculated and compared to ICULOS and HLOS and in-hospital mortality. Controlled variables included ejection fraction (measured by echocardiogram within 6 months of presentation), glomerular filtration rate (calculated by Cockroft-Gault equation), patient demographics, and lactic acid trends. Exclusion criteria were no echocardiogram within 6 months of admission, no BNP levels on admission, and no repeat lactate or rising lactate levels within 24 h to indicate worsening sepsis. RESULTS: Patients' mean BNP with in-hospital mortality was 908 pg/mL as compared to mean BNP of 678 pg/mL in survivors. T-test comparisons were statistically significant (P = 0.0375). The Kaplan-Meier curve for BNP as a predictor for in-hospital mortality showed that for the first 25 days, patients with BNP higher than 500 pg/mL had a higher mortality than patients with BNP lower than 500 pg/mL. When comparing HLOS, there is a statistically significant correlation (P = 0.0046). A similar scatter plot was prepared for ICULOS which showed there was a weak positive correlation (r = 0.199). CONCLUSION: Septic patients with in-hospital mortality had an average BNP of 908 pg/mL and statistically significant higher HLOS.