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Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Introduction: Premenstrual dysphoric disorder (PMDD) is a severe and debilitating form of Premenstrual syndrome (PMS) affecting women in their reproductive age. There is paucity of Indian research in this area among adolescents. Aims: To determine the prevalence of PMDD in adolescent school students, and to study relationship between PMDD and anxiety, depression, self-esteem and quality of life (QOL). Materials and Methods: A cross-sectional survey was conducted on 100 adolescent students of an urban school. The Premenstrual symptom screening tool for adolescents (PSST-A), Hamilton anxiety (HAM-A) and Depression (HAM-D) Scale, Rosenberg self esteem scale (RSES) and The women’s quality of life questionnaire were employed. Results: All participants reported at least one PMS symptom of minimal severity and 68% had at least one PMS symptom of moderate-severe intensity. Twenty five percent of the participants had ‘moderate-to severe’ PMS. None of the participants qualified for PMDD. Disruption of daily activities was reported by 35% while 22% missed school due to PMS. A statistically significant relationship was found between PSST scores and HAM-D score (p Conclusion: Although PMS and PMDD pose a difficulty, majority of adolescents do not have significant anxiety, experience positive self-esteem and good quality of life. There is a need for multi-centric and multi-disciplinary research to further elucidate the factors associated with PMS and PMDD in this population. Keywords: Premenstrual dysphoric disorder, Premenstrual symptoms, Adolescents, Depression, Anxiety, Self-esteem, Quality of life.

Quality of life and self-esteem in patients with psoriasis, vitiligo and healthy controls: A cross sectional study, p Introduction: Psoriasis and vitiligo are among the most common chronic skin diseases, which have a negative impact on the psychosocial well-being. Patients may experience social rejection and stigmatization. So, the aim of this present study is to

IntroductionHeart failure is a major contributor to morbidity and mortality in the geriatric population, with no promising therapy currently available with considerable benefit. Testosterone therapy is an emerging viable treatment option given its beneficial effects, including improving cardiac functional capacity, alleviating symptoms and low cost, among others.MethodsWe have planned an open-label, parallel design, 1:1 randomised controlled trial, which aims to recruit 986 adult males above the age of 60 diagnosed with chronic stable heart failure fulfilling the eligibility criteria. The participants will be randomised into 2 groups of 493 each. Both groups will receive standard recommended treatment regimen of chronic stable heart failure and intervention arm participants will receive additional testosterone gel. All participants will be assessed at baseline, 4 weeks, 6 weeks and 12 weeks. The primary endpoints will assess the differences in functional capacity, frailty and quality of life at 3 months compared with baseline. The secondary endpoints will include the mean change from baseline at 3 months in cardiac remodelling using echocardiography, serum brain natriuretic peptide levels, the incidence of adverse drug reaction.Statistical analysisThe data will be analysed with the help of SPSS 23 software. Primary objectives of change in 6-minute walk test, frailty index and quality of life will be analysed using the student’s t-test. The statistical significance will be defined as p valueEthical clearanceInstitutional Ethics Committee clearance taken via letter no AIIMS/IEC/20/847, dated 21 November 2020. This study involves human participants and was approved by institutional ethical committee, DHR Reg: EC/NEW/Inst/2020/1046CDSCO, Reg No: ECR/736/Inst/UK/2015/RR-18. Participants gave informed consent to participate in the study before taking part.Trial registration number(CTRI)—REF/2020/12/030292.

The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive neurodegenerative disorders unified by the accumulation of lysosomal auto-fluorescent material called lipofuscin. The only form that occurs via autosomal-dominant inheritance exhibits adult onset and is sometimes referred to as Parry type NCL. The manifestations may include behavioral symptoms followed by seizures, ataxia, dementia, and early death. Mutations in the gene DNAJC5 that codes for the presynaptic co-chaperone cysteine string protein-α (CSPα) were recently reported in sporadic adult-onset cases and in families with dominant inheritance. The mutant CSPα protein may lead to disease progression by both loss and gain of function mechanisms. Iron chelation therapy may be considered as a possible pharmaceutical intervention based on our recent mechanism-based proposal of CSPα oligomerization via ectopic Fe-S cluster-binding, summarized in this review.

Point mutations in cysteine string protein-α (CSPα) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL), a rapidly progressing and lethal neurodegenerative disease with no treatment. ANCL mutations are proposed to trigger CSPα aggregation/oligomerization, but the mechanism of oligomer formation remains unclear. Here we use purified proteins, mouse primary neurons and patient-derived induced neurons to show that the normally palmitoylated cysteine string region of CSPα loses palmitoylation in ANCL mutants. This allows oligomerization of mutant CSPα via ectopic binding of iron–sulfur (Fe–S) clusters. The resulting oligomerization of mutant CSPα causes its mislocalization and consequent loss of its synaptic SNARE-chaperoning function. We then find that pharmacological iron chelation mitigates the oligomerization of mutant CSPα, accompanied by partial rescue of the downstream SNARE defects and the pathological hallmark of lipofuscin accumulation. Thus, the iron chelators deferiprone (L1) and deferoxamine (Dfx), which are already used to treat iron overload in humans, offer a new approach for treating ANCL. Mutations in cysteine string protein-α (CSPα) cause its aggregation and adult-onset neuronal ceroid lipofuscinosis. Abnormal binding of Fe–S clusters to CSPα mutants is now implicated in driving aggregation, which can be reversed in neurons by clinically approved iron chelators.

Background: To better understand the psychiatric disorders and cognition in Parkinson's disease (PD) and its impact on quality of life (QoL), patients need to be studied soon after diagnosis, before initiation of dopamine replacement therapy. Aim: This study aims to compare the nature and frequency of psychiatric morbidity, cognitive dysfunction, and quality of life in drug-naive patients with PD and healthy controls. Materials and Methods: The cross-sectional, comparative study was conducted in tertiary care center. Fifty drug-naive PD patients and fifty healthy controls were included and assessed on Modified Hoehn and Yahr scale, PD Questionnaire 8, Kolkata cognitive screening battery, General Health Questionnaire-12, and Hamilton Anxiety and Depression Rating Scale (HAM-A and HAM-D). Results: The mean scores of HAM-A and HAM-D of patients with PD were significantly higher than that of the comparison group. The patients with PD had statistically significant impairment in verbal fluency, Mini-Mental State Examination, calculation, memory immediate recall, visuoconstructional ability, and memory (delayed recall and recognition) in comparison to patients without PD. No statistically significant difference was observed with respect to object naming between the two groups. Conclusion: QoL of a PD patient is adversely affected by both the motor and nonmotor symptoms of the disease such as depression, anxiety, apathy, sleep disturbances, and cognitive impairment. The link between nonmotor symptoms and reduced QoL has important implications for the management of PD because the nonmotor symptoms often appear before patients are given anti-parkinsonian therapy. Screening of nonmotor symptoms in early stage of disease will decrease the morbidity and mortality and improve the QoL.

Vitiligo is an acquired hypomelanotic disorder of the skin resulting from loss of functional melanoctyes and it affects approximately 0.5-1% of individuals. 25% of vitiligo in children are diagnosed before 10 years of age. The age of onset of vitiligo in children ranges between 4 to 8 years. Depigmentation in oral cavity can be easily noted and awareness about the condition can be created if they are not aware about vitiligo elsewhere in their body and can be guided for the treatment. RESUMEN: El vitíligo es un trastorno hipomelanótico en la piel que resulta de la pérdida de melanocitos funcionales y afecta aproximadamente al 0,5-1% de los individuos. El 25% de los casos de vitiligo en niños se diagnostican antes de los 10 años. La edad de aparición del vitiligo en los niños oscila entre los 4 y los 8 años. La despigmentación en la cavidad oral se puede notar fácilmente y se puede crear conciencia sobre la afección, si no son conscientes del vitiligo en otras partes de su cuerpo, y pueden ser guiados para el tratamiento.

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a paraneoplastic disorder that may be seen in patients with a known malignancy but more commonly is seen in those without any history of cancer. It leads to multiple uveal tumors with exudative retinal detachment along with thickening of the choroid and generally carries a poor prognosis. Its etio-pathogenesis is poorly understood but is said to involve factors secreted by the systemic malignancy that lead to proliferation of melanocytes in the uvea.We report the presentation and management of a female with history of treated frontal lobe meningioma who presented with neovascular glaucoma along with B-DUMP and was found to have recurrence of the meningioma on neuro-imaging.Central nervous system meningiomas can cause B-DUMP and management of the malignancy may lead to partial resolution of posterior segment manifestations of B-DUMP.

Phacolytic glaucoma is one of the varieties of various lens induced glaucoma, also known as lens protein glaucoma is a sequelae of hypermature cataract. In our case 60 years old male presented with lid edema, pain, redness, loss of vision of right eye with exudates or fluffy deposits in the anterior chamber mimicking endophthalmitis. Endophthalmitis is infection of eye involv ing aqueous and vitreous humors with exudates in vitreous cavity. Here we report a cytology proven case of lens induced glaucoma managed with phacoemulsification and intraocular lens implantation followed by good visual outcome. This case highlights the importance of right and early diagnosis. Keywords: Phacolytic glaucoma, Cataract, Endophthalmitis.

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for -synuclein (SNCA). -Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the -synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, p(nom)=1 p(adj)=1) and rs356219 (OR 1.28; p(nom)=0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, p(nom)=0.020), which survived Bonferroni correction (p(adj)=0.039); again, no association for NACP-Rep1 (OR 0.8, p=0.317, p(adj)=0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect -synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.

Natural products and their scaffolds encompasses an array of molecular entities as starting points for drug designing and discovery. In the past two decades, phytochemically driven Lantadenes and their modified analogues have attracted lots of attention due to their tumor necrosis factor-α induced nuclear factor-kappa B inhibition and consequently their promising anticancer potential. Earlier reports described the synthesis of esters at C-3 and C-22 of pentacyclic triterpenoid Lantadene, and their evaluation to inhibit tumor necrosis factor-α induced nuclear factor-kappa B along with cytotoxicity against A549 lung cancer cells. In the modern drug discovery process, molecular docking have become an integral part of drug design. Combination of computational platforms and experimental strategies have allowed many successful stories in the discovery of new structure-based or mechanism drugs. Thus as a continuation of our research concerning Lantadenes and their significance, present study has been undertaken to predict binding mode, pharmacokinetic and drug likeness using Vlife MDS Biopredicta and ADMETlab tools. In silico inspired grip docking approach was utilized to estimate binding interactions of all the optimized Lantadenes and their modified ester against nuclear factor-kappa B receptor (PDB ID: 1LE9). In addition, all the compounds were screened for pharmacokinetic profile and drug likeness as an important consideration for the selection of compounds with desirable prosperities using ADMETlab tools. Ligand-receptor analysis revealed Lantadene parent nuclei and their modified analogues as potent inhibitors of nuclear factor-kappa B receptor based on binding energy (-21.16 to -42.56 kcal/mol), number of interactions and bond length. Furthermore, most of the analogues were found to have good ADMET profiles. Cumulative computational analyses provided the lead Lantadene analogue 10 and can be considered as a potential candidate for detailed mechanistic studies against lung cancer.

ObjectiveTo examine whether sleep and pain-related traits have a causal effect on the risk of neurodegeneration.DesignTwo-sample Mendelian randomization using an inverse-variance weighted (IVW) estimate of the summary effect estimates.SettingGenetic data on sleep and pain-related traits and neurodegenerative disorders (NDD) from various cohorts comprising individuals predominantly of European ancestry.ParticipantsParticipants from the International Sleep Genetic Epidemiology Consortium (ISGEC), UK Biobank sleep and chronotype research group, International Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC)ExposuresSelf-reported chronotype (CHR), morning preference (MP), insomnia symptoms (INS), sleep duration (SP), short sleep (SS), long sleep (LS), and multisite chronic pain (MCP)Main outcome measuresAge-related macular degeneration (AMD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Parkinson’s disease (PD)ResultsWe considered a threshold of P=0.00142 as significant accounting for multiple testing, and PIVW = 1.19, 95% CI 1.08, 1.32, P = 0.00073). We observed suggestive evidence of influence of different sleep traits on neurodegeneration: CHR on AMD (ORIVW = 1.27, 95% CI 1.08, 1.49, P = 0.0034), SS on AD (ORIVW 1.26, 95% CI 1.08, 1.46, P = 0.0044), and INS on ALS (ORIVW 1.55, 95% CI 1.12, 2.14, P = 0.0123). The association of SS with AD was, however, lost after the exclusion of overlapping UKB samples. Using pain as exposure, our study failed to observe any role of pain in neurodegeneration. Results were largely robust to reverse causal analyses and sensitivity analyses accounting for horizontal pleiotropy.ConclusionsOur study highlighted the role of morning preference as a risk factor for AMD and provided suggestive evidence of different sleep traits on a wide spectrum of neurodegenerative diseases.

Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb–/– mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches.

We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90, p −9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

There have been recent reports of children presenting with severe multi-system hyperinflammatory syndrome resembling Kawasaki disease (KD) during current COVID-19 pandemic. Exact pathophysiology is unknown, however, most of the children have multi-organ dysfunction and respiratory system involvement is less common compared to adults. These patients have certain characteristic laboratory parameters different from those seen in children with KD. However, only limited literature is available at present for identification and management of such patients. We report a young girl who presented with fever, rash and other manifestations mimicking classic KD and fulfilling the case definitions for pediatric multi-system inflammatory syndrome. She had lymphopenia, thrombocytopenia and hyponatremia in the absence of macrophage activation syndrome, similar to that seen in patients reported from UK and Italy. Clinical manifestations resolved and laboratory parameters improved with intravenous immunoglobulin and corticosteroids. Early recognition is important to administer immunomodulatory therapy which may be life saving for these patients.Several cases of a severe multi-system inflammatory syndrome have been reported in children during the current COVID-19 pandemic. Clinical manifestations may resemble Kawasaki disease (KD) which is the most common childhood vasculitis. A 7-year-old-girl presented with fever, rash and abdominal pain. Examination showed maculopapular rash over lower limbs, back, right ear, trunk and abdomen; erythema and swelling over bilateral upper eyelids; conjunctival injection; reddened lips and erythema over palms and soles. She had lymphopenia, thrombocytopenia, with elevated erythrocyte sedimentation rate, C-reactive protein (CRP), pro-brain natriuretic peptide and interleukin-6 (IL-6). Real-time polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was negative. Serology, however, could not be performed due to unavailability. Macrophage activation syndrome was ruled out with normal ferritin and triglyceride with raised fibrinogen level. Echocardiography showed normal coronary diameters. Child received meropenem, intravenous immunoglobulin, aspirin and methylprednisolone. She improved with resolution of fever, decrease in CRP, increase in platelet and lymphocyte count. Index child had features similar to those reported from UK and Italy: features of KD, abdominal pain, lymphopenia, thrombocytopenia, elevated IL-6 and myocardial dysfunction with no significant respiratory involvement. Pediatricians should be aware of such uncommon presentation in children to initiate early treatment with immunomodulatory therapy.

Importance Impaired glucose and obesity are known characteristics of patients with PD, although it is unclear whether the dysfunction precedes or results from the neurodegeneration. Objective To assess whether glycemic traits and anthropometric traits can influence the risk of PD in 33,674 cases and 449,056 healthy controls using Mendelian randomization (MR) framework. Design, setting, and participants We investigated causality with a two-sample bidirectional MR approach in the European population. We used the inverse variance-weighted (IVW), weighted median (WME), and weighted mode (MBE) methods to compute effect estimates with summary statistics from available meta-analyses of genome-wide association studies (GWAS) on glycemic and anthropometric traits that used discovery cohorts. We conducted sensitivity analyses with prioritized genetic instruments that used different study designs including employment of different study cohorts and body mass index (BMI) adjusted exposures, and exclusion of overlapping samples between risk factors and outcome datasets, and potential pleiotropic genetic instruments. Main outcome and measures PD, glycemic and anthropometric traits Results We observed a risky effect of PD on fasting glucose (FG) (IVW: β = 0.0188 per log-odds of PD; 95% CI 0.0062–0.0313, p-value = 0.0055). We further observed a protective effect of PD on type 2 diabetes (T2D) (WME: OR = 0.946 per log-odds of PD; 95% CI 0.929–0.983, p-value = 0.0051). A direct causal role of waist-hip ratio (WHR) was also observed in PD (IVW OR = 0.735; 95% CI = 0.622-0.868 per 1-SD of WHR, p = 0.0003). However, the association was lost after WHR was adjusted for body mass index (BMI) (IVW OR = 0.889; 95% CI = 0.779-1.037 per 1-SD of WHR adjusted for BMI, p = 0.1429) indicating that the observed association is mediated via BMI The associations were further retained after the exclusion of overlapping UK Biobank (UKB) samples in the PD dataset. Conclusions and relevance Our results showed that PD patients are glucose tolerant with protection against T2D. Furthermore, central obesity may be protective against PD development, independent of glucose levels. The implication of different indices of glycemic control and body fat distribution on the PD symptomatology deserves further investigation. Key points Question Are glucose and obesity associated with Parkinson’s disease? Findings Using bi-directional Mendelian randomization (MR) approach, and using Parkinson disease (PD) as an exposure, our study found that a 1-log odds increase in genetic predisposition to PD was associated with 0.0188 mmol/l increase in fasting glucose concentration. The genetic predisposition to PD was also associated with a 5.4% lower risk of type-2 diabetes (T2D). We found that a 1-SD increase in waist-hip ratio (WHR) was associated with a 26.5% lower risk of PD in the European population, likely to be mediated via body mass index. Meaning A strong genetic predisposition towards glucose tolerance was observed in PD patients. and PD patients are protective against T2D. Further, an increase in WHR lowers the risk of PD. Our study thereby suggests potential roles of body fat distribution and glycemic traits on PD symptomatology.

Purpose: To evaluate postoperative outcomes of cataract surgery in children with persistent hyperplastic primary vitreous (PHPV) and factors affecting outcomes. Methods: We analyzed 29 eyes of 28 children with PHPV presenting at a tertiary care center in northern India. All eyes underwent phacoaspiration followed by primary posterior capsulotomy with or without cauterization of persistent fetal vasculature under general anesthesia. Hydrophobic intraocular lens was implanted in selective cases. Postoperative outcomes such as clarity of visual axis, need for secondary surgical procedures, and complications were noted. Results: Out of a total of 28 children (16 male and 12 female), 27 were unilateral while 1 patient had bilateral involvement. Mean age at surgery was 25.14 months, ranging from 2 months to 144 months. Mean axial length of the globe at surgery was 19.66 ± 2.28 mm. Cataract surgery with intraocular lens implantation was done in 22 eyes whereas 7 were left aphakic. The most common intraoperative complication noted was intraoperative bleed in 11 eyes (37.9%) resulting in postoperative hyphema in 9 eyes (31%) and vitreous hemorrhage in 8 eyes (27.5%). Visual axis opacification was seen in 12 eyes and all required membranectomy. Three eyes developed glaucoma while retinal detachment was noted in 2 eyes and 1 of them became phthisical. Conclusions: Favorable outcome was more often achieved in anterior PHPV. Surgical outcomes in eyes with PHPV undergoing cataract surgery are limited by intraoperative and postoperative complications such as hyphema, vitreous hemorrhage, recurrent visual axis opacification, glaucoma, and retinal detachment.

Background and Aims: Emergency front of neck access (FONA) is the final step in a Can't Intubate–Can't Oxygenate (CICO) scenario. In view of maintaining simplicity and promoting standardized training, the 2015 Difficult Airway Society guidelines recommend surgical cricothyroidotomy using scalpel, bougie, and tube (SBT) as the preferred technique. \ud \ud Material and Methods: We undertook a survey over a 2-week period to evaluate the knowledge and training, preferred rescue technique, and confidence in performing the SBT technique. Data were collected from both anesthetists and surgeons. \ud \ud Results: One hundred and eighty-nine responses were collected across four hospitals in the United Kingdom. The majority of participants were anesthetists (55%). One hundred and eleven (59%) respondents were aware of the national guidelines (96.2% among anesthetists and 12.9% among surgeons). Only 71 (37.6%) respondents indicated that they had formal FONA training within the last one year. Seventy-five anesthetists (72.8%) knew that SBT equipment was readily available in their department, while most surgeons (81.2%) did not know what equipment available. One hundred and five (55.5%) respondents were confident in performing surgical cricothyroidotomy in a situation where the membrane was palpable and only in 33 (17.5%) where the cricothyroid membrane was not palpable. \ud \ud Conclusion: This survey has demonstrated that despite evidence of good training for anesthetists in FONA, there are still shortfalls in the training and knowledge of our surgical colleagues. In an emergency, surgeons may be required to assist or secure an airway in a CICO situation. Regular multidisciplinary training of all clinicians working with anesthetized patients should be encouraged and supported.

Purpose: To report epidemiology of uveitis in a tertiary-care referral institute in North India.Methods: Hospital records of patients with uveitis between June 2011 and September 2014 were retrospectively analyzed.Results: Of the 1912 patients, 56.64% were males. Anterior uveitis (43.04%) was the most common manifestation followed by posterior uveitis (24.58%), panuveitis (16.21%), and intermediate uveitis (10.66%). Specific etiologies could be ascertained in 60.56%. Tuberculosis (22.9%) was the most common infectious and HLA-B27-associated uveitis (9.46%) among non-infectious causes.Conclusions: There is a trend towards a decrease in idiopathic etiologies of uveitis. Tuberculosis remains the most common infectious etiology in North India.

We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

Alzheimer's disease (AD) is characterized by two major pathological lesions in the brain, amyloid plaques and neurofibrillary tangles (NFTs) composed mainly of amyloid-β (Aβ) peptides and hyperphosphorylated tau, respectively. Although accumulation of toxic Aβ species in the brain has been proposed as one of the important early events in AD, continued lack of success of clinical trials based on Aβ-targeting drugs has triggered the field to seek out alternative disease mechanisms and related therapeutic strategies. One of the new approaches is to uncover novel roles of pathological tau during disease progression. This review will primarily focus on recent advances in understanding the contributions of tau to AD.

Background\ud \ud Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that both involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in SCZ patients before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders.\ud Methods\ud \ud We analyzed recent large genome-wide associations studies (GWAS) on SCZ (n=77,096) and PD (n=417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci.\ud Results\ud \ud We observed genetic enrichment in PD conditional on associations with SCZ, and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified nine novel PD risk loci and one novel SCZ locus at conditional FDR

Aggressive breast cancer subtypes utilize system xc-, a membrane antiporter, to import cystine for glutathione synthesis and maintenance of redox homeostasis, in turn releasing glutamate as a metabolic pro-nociceptive by-product. Metastatic breast cancers establish themselves at distal sites including bone, where changes in extracellular glutamate levels contribute to cancer-induced bone pain. We previously established that stearically blocking system xc- activity with sulfasalazine delays the onset of nociceptive behaviours and that xCT, the functional antiporter subunit, is positively regulated by signal transducer and activator of transcription 3 (STAT3). In the current investigation, a murine xenograft cancer-induced bone pain model was applied to examine whether pharmacological inhibition of phosphorylated STAT3 (pSTAT3) induces changes in nociception. A high glutamate-releasing, xCT/pSTAT3 over-expressing human breast cancer cell line was selected for injection into the distal epiphysis of the right femur of female nude mice. A 14-day regimen of intraperitoneal injections with either vehicle or the novel STAT3 inhibitor DR-1-55 commenced three weeks after initial intrafemoral bone injection. Nociceptive behaviours were temporally monitored by automated von Frey, dynamic weight bearing and open-field testing for the duration of the study, beginning at the baseline. Prior to sacrifice and at ethical end point, tumour-induced osteolytic lesions were radiographically assessed. Treatment with DR-1-55 significantly delayed the onset and severity of spontaneous and induced nociceptive behaviours, also decreasing human SLC7A11 ( xCT) mRNA levels in tumour-bearing limbs without altering osteolysis. In addition, two pro-inflammatory cytokines released by this cell line, interleukin 6 and interleukin 1β, were also down-regulated at the mRNA level in response to DR-1-55 treatment in vivo, with lower human interleukin 6 levels detected in the host circulation. This study demonstrates that targeting pSTAT3 may be a viable therapeutic means to manage cancer-induced bone pain, alone or in combination with stearic system xc- blockers.

Cancers in the bone produce a number of severe symptoms including pain that compromises patient functional status, quality of life, and survival. The source of this pain is multifaceted and includes factors secreted from tumor cells. Malignant cells release the neurotransmitter and cell-signaling molecule glutamate via the oxidative stress-related cystine/glutamate antiporter, system xC-, which reciprocally imports cystine for synthesis of glutathione and the cystine/cysteine redox cycle. Pharmacological inhibition of system xC- has shown success in reducing and delaying the onset of cancer pain-related behavior in mouse models. This investigation describes the development of a stable siRNA-induced knockdown of the functional trans-membrane system xC- subunit xCT ( SLC7A11) in the human breast cancer cell line MDA-MB-231. Clones were verified for xCT knockdown at the transcript, protein, and functional levels. RNAseq was performed on a representative clone to comprehensively examine the transcriptional cellular signature in response to xCT knockdown, identifying multiple differentially regulated factors relevant to cancer pain including nerve growth factor, interleukin-1, and colony-stimulating factor-1. Mice were inoculated intrafemorally and recordings of pain-related behaviors including weight bearing, mechanical withdrawal, and limb use were performed. Animals implanted with xCT knockdown cancer cells displayed a delay until the onset of nociceptive behaviors relative to control cells. These results add to the body of evidence suggesting that a reduction in glutamate release from cancers in bone by inhibition of the system xC- transporter may decrease the severe and intractable pain associated with bone metastases.

Bromelain, a cysteine protease exhibits promising potential in amelioration of wide variety of inflammatory disorders. Its denaturation or aggregation in gastric milieu depletes its therapeutic potential along with unpredictable prophylactic hypersensitivity reactions. Hence, efficient carrier system to improve bromelain's stability and avoid related side effects is of utmost importance. Therefore, present investigation was undertaken to prepare bromelain loaded nanostructured lipid carriers (Br-NCs) with high drug loading, stability and efficacy in rheumatoid arthritis management. Br-NCs fabricated via double emulsion solvent evaporation method were characterized for physical properties, morphology and stability. Optimized batch exhibited spherical shape, nanometric size (298.23 nm) and entrapment efficiency ~77% with sustained release behavior and improved gastric stability. Br-NCs exhibited 4.63-folds improvement in shelf-life compared to bromelain at room temperature. The protective potential of orally administered Br-NCs in rheumatoid arthritis was evaluated via assessing arthritis severity in wistar rats along with biochemical, hematological and immunological parameters. Br-NCs remarkably (p 0.05) diminished paw edema, joint stiffness, mechanical allodynia and tissue damage along with alleviation of oxidative stress and immunological markers. Radiological joint alterations were also notably preserved with Br-NCs. Thus, preclinical studies distinctly manifested that Br-NCs formulation opens new avenue for development of novel effective therapeutic modality for rheumatoid arthritis management.

Objective As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, TLR9 promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression. Design Therefore, the TLR9 SNPs and the interferon lambda 4 ( IFNL4 ) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) ‘anti-D’ cohorts. Functional analyses were done with promoter reporter constructs of human TLR9 in B cells and assessing TLR9 mRNA levels in whole blood of healthy volunteers. Results The TLR9 rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both ‘anti-D’ cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both TLR9 variants and an association of the C allele of rs5743836 with allele-specific TLR9 mRNA regulation by oestrogens in women. Conclusions TLR9 promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.

Purpose:To describe the outcome of phacoaspiration with intraocular lens implantation in children with unilateral congenital cataract in the first 4 years of life.Methods:A retrospective chart review of children with visually significant unilateral congenital cataract presenting in the first 4 years of life was done. Children with a minimum postsurgical follow-up of 1 year were included. Outcome measures were mean spherical equivalent, visual axis clarity, visual acuity and complications till the last follow-up.Results:Ninety-three children met the inclusion criteria. The mean age of surgery was 13.23 ± 11.89 months and the mean follow-up period was 24.37 ± 17.35 months. Nearly 40% of children presented during their first year of life. No difference was noted between the subgroups in terms of age ( p = 0.310), sex ( p = 0.475) or laterality ( p = 0.349). Surgical membranectomy was performed in 22 eyes (23.6%) after an average period of 4.85 ± 2.58 months after surgery. One eye underwent piggy back intraocular lens and four eyes underwent intraocular lens exchange after a mean duration of 50 months (range 40–60 months). The mean visual acuity was 0.79 ± 0.11 (log MAR chart). A total of 60.7% of these children ( n = 31) achieved best corrected visual acuity or 20/80 or better.Conclusion:The results of our study suggest that primary intraocular lens implantation in children with unilateral congenital cataract gives good structural and functional results. Besides a meticulous surgery, visual outcome is affected by the time of presentation and postoperative compliance to amblyopia therapy.

Lung cancer is one of the most abundant causes of the cancerous deaths worldwide. It has low survival rate mainly due to the late diagnosis. With the hardware advancements in computed tomography (CT) technology, it is now possible to capture the high resolution images of lung region. However, it needs to be augmented by efficient algorithms to detect the lung cancer in the earlier stages using the acquired CT images. To this end, we propose a two-step algorithm for early detection of lung cancer. Given the CT image, we first extract the patch from the center location of the nodule and segment the lung nodule region. We propose to use Otsu method followed by morphological operations for the segmentation. This step enables accurate segmentation due to the use of data-driven threshold. Unlike other methods, we perform the segmentation without using the complete contour information of the nodule. In the second step, a deep convolutional neural network (CNN) is used for the better classification (malignant or benign) of the nodule present in the segmented patch. Accurate segmentation of even a tiny nodule followed by better classification using deep CNN enables the early detection of lung cancer. Experiments have been conducted using 6306 CT images of LIDC-IDRI database. We achieved the test accuracy of 84.13%, with the sensitivity and specificity of 91.69% and 73.16%, respectively, clearly outperforming the state-of-the-art algorithms.

α-Synuclein physiologically chaperones SNARE-complex assembly at the synapse but pathologically misfolds into neurotoxic aggregates that are characteristic for neurodegenerative disorders, such as Parkinson's disease, and that may spread from one neuron to the next throughout the brain during Parkinson's disease pathogenesis. In normal nerve terminals, α-synuclein is present in an equilibrium between a cytosolic form that is natively unfolded and monomeric and a membrane-bound form that is composed of an α-helical multimeric species that chaperones SNARE-complex assembly. Although the neurotoxicity of α-synuclein is well established, the relationship between the native conformations of α-synuclein and its pathological aggregation remain incompletely understood; most importantly, it is unclear whether α-synuclein aggregation originates from its monomeric cytosolic or oligomeric membrane-bound form. Here, we address this question by introducing into α-synuclein point mutations that block membrane binding and by then assessing the effect of blocking membrane binding on α-synuclein aggregation and neurotoxicity. We show that membrane binding inhibits α-synuclein aggregation; conversely, blocking membrane binding enhances α-synuclein aggregation. Stereotactic viral expression of wild-type and mutant α-synuclein in the substantia nigra of mice demonstrated that blocking α-synuclein membrane binding significantly enhanced its neurotoxicityin vivo. Our data delineate a folding pathway for α-synuclein that ranges from a physiological multimeric, α-helical, and membrane-bound species that acts as a SNARE-complex chaperone over a monomeric, natively unfolded form to an amyloid-like aggregate that is neurotoxicin vivo.

Parkinson’s disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson’s disease, a common mechanism underlying especially sporadic Parkinson’s disease is still largely unknown. In order to gain further insight into the etiology of Parkinson’s disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson’s disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson’s disease, into a molecular interaction landscape. The molecular Parkinson’s disease landscape harbors four main biological processes—oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation—that interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson’s disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron-specific signaling cascades. Furthermore, we validate the Parkinson’s disease -lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson’s disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson’s disease and highlight a key role for lipids and lipoproteins in Parkinson’s disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson’s disease., Molecular interactions: the importance of fats Lipids and lipoproteins play a central role in four key biological processes underlying Parkinson’s disease (PD). Using bioinformatics and other extensive analyses of previously published data, Geert Poelmans, Cornelius Klemann and colleagues in The Netherlands, Germany and the USA have mapped the interactions of proteins that are encoded by genes associated with both familial and sporadic forms of PD. They identify the oxidative stress response, lysosomal function, endoplasmic reticulum stress response and immune response activation as the main mechanisms leading to the death of dopaminergic neurons. Lipid signaling is implicated in all four of these processes and the authors find a link between the levels of particular lipids and lipoproteins and the risk of PD. These findings suggest that compounds that regulate lipid or lipoprotein levels offer a potential new treatment strategy for PD.

The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen speci es are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies.

Huntington's Disease (HD) is an autosomal dominant progressive degenerative disorder of the basal ganglia characterized by motor, cognitive, and psychiatric manifestations, with an estimated prevalence of 1.75 per 100,000. It can present any time between infancy and senescence. Mood disorders, obsessive compulsive symptoms, psychosis, delirium, sexual disorders, and 'frontal' syndromes, have been reported in patients with HD. Delusions are seen in only about 5-12%. Indian data on HD has been largely through case reports. Given this background, we present an uncommon case with clinical features suggestive of HD and organic delusional disorder. This case report presents the psychiatric and neurological features of a 39-year-old male, who presented with abnormal choreiform movements since eight years, followed by a delusion of infidelity, and a family history suggestive of HD. Differential diagnosis and laboratory results, including neuroimaging and treatment, are presented. Delusions are the common manifestation of psychosis in patients with brain disorders, occurring more often than a formal thought disorder. Lesions of the temporal lobes or caudate nuclei and bilateral brain involvement are common in disorders manifesting psychosis. However, reasons for the infrequent occurrence of delusions in HD, in comparison to other neurodegenerative disorders, are unknown.

BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society (Less)

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. (C) 2016 Elsevier Inc. All rights reserved.

Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.

Contains fulltext : 167923.pdf (Publisher’s version ) (Open Access) Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease. Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p. Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

At a synapse, the synaptic vesicle protein cysteine-string protein-α (CSPα) functions as a co-chaperone for the SNARE protein SNAP-25. Knockout (KO) of CSPα causes fulminant neurodegeneration that is rescued by α-synuclein overexpression. The CSPα KO decreases SNAP-25 levels and impairs SNARE-complex assembly; only the latter but not the former is reversed by α-synuclein. Thus, the question arises whether the CSPα KO phenotype is due to decreased SNAP-25 function that then causes neurodegeneration, or due to the dysfunction of multiple as-yet uncharacterized CSPα targets. Here, we demonstrate that decreasing SNAP-25 levels in CSPα KO mice by either KO or knockdown of SNAP-25 aggravated their phenotype. Conversely, increasing SNAP-25 levels by overexpression rescued their phenotype. Inactive SNAP-25 mutants were unable to rescue, showing that the rescue was specific. Under all conditions, the neurodegenerative phenotype precisely correlated with SNARE-complex assembly, indicating that impaired SNARE-complex assembly due to decreased SNAP-25 levels is the ultimate correlate of neurodegeneration. Our findings suggest that the neurodegeneration in CSPα KO mice is primarily produced by defective SNAP-25 function, which causes neurodegeneration by impairing SNARE-complex assembly.

Chlamydiae are obligate intracellular Gram-negative bacteria that cause widespread diseases in humans. Due to the intimate association between bacterium and host, Chlamydia evolved various strategies to protect their host cell against death-inducing stimuli, allowing the bacterium to complete its development cycle. An RNA interference (RNAi)-based screen was used to identify host cell factors required for apoptosis resistance of human epithelial cells infected with Chlamydia trachomatis serovar L2. Among the 32 validated hits, the anti-apoptotic Bcl-2 family member Mcl-1 was identified as a target. Protein network analyses implicated the transcription factor hypoxia-induced factor 1 alpha (HIF-1α) to be central to the regulation of many of the identified targets. Further mechanistic investigations showed that HIF-1α was stabilized within the host cell cytoplasm during early infection time points, followed by its translocation to the nucleus and eventual transcriptional activation of Mcl-1. siRNA-mediated depletion of HIF-1α led to a drastic decrease in Mcl-1, rendering the cell sensitive to apoptosis induction. Taken together, our findings identify HIF-1α as responsible for upregulation of Mcl-1 and the maintenance of apoptosis resistance during Chlamydia infection.

We report a case of congenital tuberculosis, a rare entity itself; complicated by pulmonary interstitial emphysema, thus leading to air entrapment in lungs and prolonged oxygen dependence. The diagnosis of congenital tuberculosis is often missed and under-reported due to low index of suspicion and less sensitivity of diagnostic tools.

Presynaptic nerve terminals release neurotransmitters repeatedly, often at high frequency, and in relative isolation from neuronal cell bodies. Repeated release requires cycles of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly and disassembly, with continuous generation of reactive SNARE-protein intermediates. Although many forms of neurodegeneration initiate presynaptically, only few pathogenic mechanisms are known, and the functions of presynaptic proteins linked to neurodegeneration, such as α-synuclein, remain unclear. Here, we show that maintenance of continuous presynaptic SNARE-complex assembly required a nonclassical chaperone activity mediated by synucleins. Specifically, α-synuclein directly bound to the SNARE-protein synaptobrevin-2/vesicle-associated membrane protein 2 (VAMP2) and promoted SNARE-complex assembly. Moreover, triple-knockout mice lacking synucleins developed age-dependent neurological impairments, exhibited decreased SNARE-complex assembly, and died prematurely. Thus, synucleins may function to sustain normal SNARE-complex assembly in a presynaptic terminal during aging.

Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease.Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers.All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations.Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Chlamydia has long been studied as an intracellular pathogen causing widespread diseases. In the last three decades, the field of apoptosis has rapidly emerged, and as a consequence, research on infectious diseases in general and on Chlamydia-host interaction in particular shifted to apoptosis modulation. Ten years ago, the first paper describing the drastic inhibition of apoptosis in Chlamydia-infected cells was published. In a reversal of roles, here was a pathogen that was strongly protecting cells in an organism against destruction by the organism's immune system. Since then, numerous studies have described apoptosis inhibition by Chlamydia and the mechanisms involved, but still there is a lack of general consensus on the subject. With a section of studies even reporting the induction of cell death by Chlamydia and not its inhibition, the field became even more diverse and complicated. In this review, an attempt is made to discuss the recent findings on apoptosis modulation by chlamydial species.

To date, there are few reports of paroxysmal exercise-induced dystonia associated with familial epilepsy. We describe a family with 4 affected members spanning 3 generations, suggestive of autosomal-dominant inheritance, who exhibited typical exercise-induced dystonia, different types of epilepsy (absence and primary generalized seizures), developmental delay, and migraine in variable combinations. Linkage of the disease to loci on chromosome 2 (paroxysmal nonkinesigenic dyskinesia) and chromosome 16 (paroxysmal kinesigenic choreoathetosis, infantile convulsions with choreoathetosis) was excluded, suggesting an as yet unidentified underlying genetic basis.

The chemopreventive effect of Lantana camara. L. (Verbenaceae) methanol leaf extract (LCLE) on 7,12-dimethylbenz[a.]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. The skin lesions were induced by the twice-weekly topical application of DMBA (100 nmol/100 µL acetone) for 8 weeks on the shaved backs of mice. LCLE was administered at the maximal tolerated dose of 400 mg/kg twice a week, 1 week before DMBA application, and continued for 20 weeks thereafter. The results of the study revealed a significant decrease in incidence of skin papillomas in mice, slight weight gain in mice, and reduced death rate in comparison with DMBA alone at the end of 20 weeks. These results were supported by histopathologic studies. The skin section of LCLE-treated mice showed hyperplastic papillomatous lesions without the evidence of infiltration or cytological atypia. From the current study, it can be inferred that LCLE possesses potential chemopreventive activity in this experimental model...

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the widely used medications all over the world, indicated for pain, fever, and inflammation. It is now well established that inflammation and cancer are closely linked with each other. Inflammatory mediators, like cyclooxygenase (COX), vascular endothelial growth factor (VEGF), tumor growth factor (TGF), fibroblast growth factor (FGF), chemokines, and cytokines and related genes, such as inhibitor of nuclear factor-kappa B kinase (IKK) and nuclear factor-kappa B (NF-κB) have been shown to be up-regulated in various cancers. Till date, numerous anticancer agents of different classes have been discovered to treat and eradicate various forms of cancer; though, limitations like cytotoxicity to normal cells and acquired tumor resistance restrict the scope of present cancer therapeutics. NSAIDs have shown to decrease the incidence, recurrence, and proliferation of various cancers, viz. colon, breast, lung, and pancreatic, etc. Therefore, the developing agents, such as NO-and Hlt;subgt;2lt;/subgt;S-releasing NSAIDs, NSAID-metal complexes, natural product-NSAID conjugates, phospho-NSAIDs, and various other NSAIDs derivatives represent the next generation therapeutics to treat both inflammation and cancer.

Genetic discoveries have lent support to the growing consensus that protein aggregation, impairment in oxidative stress, and mitochondrial dysfunction are important pathways in Parkinson’s disease. 1 In agreement with this hypothesis, Funayama and colleagues 2 report an association of CHCHD2, which is suggested to be involved in mitochondrial respiration, with Parkinson’s disease in the Japanese population. 2

© 2015 Macmillan Publishers Limited We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10-7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration.Molecular Psychiatry advance online publication, 17 February 2015; doi:10.1038/mp.2015.6.