No treatments exist to slow or halt Parkinson’s disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain. Administration of LRRK2 ASOs to the brain reduces LRRK2 protein levels and fibril-induced α-syn inclusions. Mice exposed to α-syn fibrils treated with LRRK2 ASOs show more tyrosine hydroxylase (TH)-positive neurons compared to control mice. Furthermore, intracerebral injection of LRRK2 ASOs avoids unwanted phenotypes associated with loss of LRRK2 expression in the periphery. This study further demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of α-syn inclusions. Importantly, this study points toward LRRK2 ASOs as a potential therapeutic strategy for preventing PD-associated pathology and phenotypes without causing potential adverse side effects in peripheral tissues associated with LRRK2 inhibition.

Purpose:To document the status of pediatric eye care in India.Materials and Methods:A list of institutions providing eye care was compiled from various sources, including government officials, professional bodies of ophthalmologists, and national and international non-governmental organizations (NGO) working in the field of eye care in India. A questionnaire on eye care services was sent to all known eye care institutions in the country. Workshops and regional meetings were organized to maximize response. Validity of data was ensured by observational visits to 10% of the institutions who responded.Results:Out of 1204 institutions contacted, 668 (55.5%) responded to the questionnaire. Of these, 192 (28.7%) reported that they provided pediatric eye care services. A higher proportion (48.3%) of NGO hospitals reported separate pediatric ophthalmology units compared to other providers (P< 0.001). Eighty per cent of advanced care eye hospitals had dedicated outpatient, and 40% had dedicated inpatient facilities for children (P< 0.001). The advanced eye care hospitals attended to a larger number of pediatric clients (P < 0.001), and performed more pediatric eye surgeries compared to secondary and tertiary care hospitals (P < 0.001). Eighty- three per cent of advanced care centers and 72.4% of NGO hospitals had an anesthesiologist for pediatric eye service. Refractive error was the commonest reason for seeking service. The commonest surgical procedure was pediatric cataract surgery followed by squint surgery.Conclusion:Pediatric eye care services are not adequate in India.

Background Hyperuricemia is implicated in cardiovascular and cerebrovascular diseases. This study evaluated associations between uric acid (UA), cardiovascular health and neurocognitive function in adolescent and adult survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. Methods 126 adolescent (mean[SD] age 14.6[5.0]; 7.8[1.7] years post-diagnosis) and 226 adult survivors (age 25.4[4.2] years; 18.1[4.4] years post-diagnosis) completed comprehensive neurocognitive testing. Concurrent UA measurements were conducted for both groups. For adult survivors, cardiovascular risk factors were assessed; and UA measurements during adolescence (12.3[4.0] years before neurocognitive testing) were also collected. UA levels were categorized into quartiles for age- and gender-based ranking, and associations with neurocognitive outcomes were examined. Results Survivors demonstrated worse attention, processing speed and executive functions than population norms (p's<0.05). Adolescent survivors with elevated UA had poorer attention (p=0.04), visual-processing speed (p=0.03) and cognitive flexibility (p=0.02). UA was not associated with neurocognitive outcomes in adult survivors. Adult survivors developed dyslipidemia (46%), hypertension (32%) and abdominal obesity (26%), and high UA during adolescence was associated with these cardiovascular risk factors as adults (all p's<0.01). Fine-motor processing speed was slower in adult survivors with dyslipidemia (p=0.04) and abdominal obesity (p=0.04). Poorer attention was marginally associated with hypertension (p=0.06). Conclusions Elevated UA is associated with neurocognitive performance in adolescent survivors. In adult survivors, relative elevation of UA during adolescence was predictive of cardiovascular health, which was associated with poorer neurocognitive outcomes. Impact Future studies should evaluate the mediating role of chronic cardiovascular health conditions between elevated UA and subsequent neurocognitive impairment in survivors.

BackgroundEvidence from high income countries shows mothers who are supplemented with folic acid in their periconceptional period and early pregnancy have significantly reduced adverse outcomes like birth defects. However, in India there is a paucity of data on association of birth defects and folic acid supplementation. We identified a few important questions to be answered using separate scientific methods and then planned to triangulate the information.ObjectiveIn this paper, we describe the protocol of our study that aims to determine the association of folic acid and pregnancy outcomes like neural tube defects (NTDs) and orofacial clefts (OFCs). We decided to fill the gaps in knowledge from India to determine public health consequences of folic acid deficiency and factors influencing dietary and periconceptional consumption of folic acid.MethodsThe proposed study will be carried out in five stages and will examine the questions related to folic acid deficiency across selected locations in South and North India. The study will be carried out over a period of 4 years through the hierarchical evidence-based approach. At first a systematic review was conducted to pool the current birth prevalence of NTDs and orofacial clefts OFCs in India. To investigate the population prevalence, we plan to use the key informant method to determine prevalence of NTDs and OFCs. To determine the normal serum estimates of folic acid, iron, and vitamin B12 among Indian women (15-35 years), we will conduct a population-based, cross-sectional study. We will further strengthen the evidence of association between OFCs and folic acid by conducting a hospital-based, case-control study across three locations of India. Lastly, using qualitative methods we will understand community and health workers perspective on factors that decide the intake of folic acid supplements.ResultsThis study will provide evidence on the community prevalence of birth defects and prevalence folic acid and vitamin B12 deficiency in the community. The case-control study will help understand the association of folic acid deficiency with OFCs.ConclusionsThe results from this study are intended to strengthen the evidence base in childhood disability for planning and policy initiatives.

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