Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans

Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension - the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) - synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action.     

Isolated noncompaction of right ventricle--a case report

Isolated noncompaction of ventricular myocardium (INVM) is a genetic cardiomyopathy due to abnormal arrest in endomyocardial embryogenesis between fetal 5th and 8th week. Noncompaction of right ventricle alone is rare. Here we present one such case where a young man presented with progressive right heart failure and atrial fibrillation. Subsequent evaluation by echo and cardiac magnetic resonance imaging confirmed our diagnosis. The cardinal manifestations of INVM are heart failure, arrhythmia, and embolic events and our case presented with former two manifestations. Echocardiographic criteria for diagnosing INVM are discussed.     

Syndromic versus nonsyndromic atlantoaxial dislocation: do clinico-radiological differences have a bearing on management?

Background

This prospective study attempts to study the clinico-radiological differences between patients with syndromic AAD (SAAD), non-syndromic AAD (NSAAD), and AAD with Klippel–Feil anomaly (AADKFA) that may impact management.

Methods

In 46 patients with AAD [SAAD (including Morquio, Down, Larson and Marshall syndrome and achondroplasia; n?=?6); NSAAD(n?=?20); and, AADKFS (n?=?20)], myelopathy was graded as mild (n?=?17, 37 %), moderate (15, 32.5 %) or severe (14, 30.5 %) based on Japanese Orthopaedic Association Score modified for Indian patients (mJOAS). Basilar invagination (BI), basal angle, odontoid hypoplasia, facet-joint angle, effective canal diameter, Ishihara curvature index, and angle of retroversion of odontoid and vertebral artery (VA) variations were also studied.

Statistics

Clinico-radiological differences were assessed by Fisher’s exact test, and mean craniometric values by Kruskal–Wallis test (p value ≤?0.05 significant)

Results

Incidence of irreducible AAD in SAAD (n?=?0), NSA AD (11.55 %) and AADKFS (n?=?18.90 %) showed significant difference (p?=?0.01). High incidence of kyphoscoliosis (83 %) and odontoid hypoplasia (83 %) in SAAD, and assimilated atlas and BI in NSAAD and AADKFA groups were found. In AADKFA, effective canal diameter was significantly reduced(p?=?0.017) with increased Ishihara index and increased angle of odontoid retroversion; 61 % patients had VA variations. Thirty-five patients underwent single-stage transoral decompression with posterior fusion (for irreducible AAD) or direct posterior stabilization (for reducible AAD). Postoperative mJOAS evaluation often revealed persistent residual myelopathy despite clinical improvement.

Conclusions

Myelopathy is induced by recurrent cord trauma due to reducible AAD in SAAD, and compromised cervicomedullary canal diameter in NSAAD and AADKFA. SAAD in children may be missed due to incomplete odontoid ossification or coexisting angular deformities. In AADKFA, decisions regarding vertebral levels to be included in posterior stabilization should take into consideration intact intervening motion segments and compensatory cervical hyperlordosis. Following VA injury, endovascular primary vessel occlusion/stenting across pseudoaneurysm preempts delayed rehemorrhage.     

Pathophysiology guided treatment of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease is a spectrum that ranges from benign steatosis to steatohepatitis. It has become the most common cause of chronic liver disease, and yet there continues to be a lack of effective therapeutic options. This article reviews current concepts underlying the pathophysiological basis of nonalcoholic steatohepatitis from development of insulin resistance to the establishment of fibrosis. Then using a physiology-based approach, specific targeted therapeutics are reviewed along with their drawbacks. The evidence behind current therapies is based predominantly on small trials and, thus, no recommendations can be made until larger randomized trials are conducted.