TRPA1 is selected as a semi-conserved channel during vertebrate evolution due to its involvement in spermatogenesis.

TRPA1 is a non-selective cation channel originated in invertebrates. The genomic locus containing TRPA1 gene remains highly conserved and retained in all vertebrates. TRPA1 gene is evolutionarily selected, yet maintained as a highly diverged protein. Throughout the vertebrate evolution, the extracellular loops of TRPA1 become most diverged indicating that TRPA1 may be involved in detecting large spectrum and uncertain stimulus which is critical for adaptive benefit. We tested the expression of TRPA1 in mature sperm from different vertebrates. This is the first report demonstrating that TRPA1 is expressed endogenously in mature spermatozoa of multiple species representing entire vertebrate phyla. However, its specific localization within sperm remains species-specific. Accordingly, we report that in rodents TRPA1 expression correlates with different stages of spermatogenesis. We propose that presence of endogenous TRPA1 in testes and in mature sperm provides reproductive benefit.

Cognitive behavioural impairment with irreversible sensorineural deafness as a complication of West Nile encephalitis.

Despite common clinical features to suggest encephalitis, different viral encephalitides are known to have some specific clinical features, which if present, may suggest infection by a particular virus. West Nile viral (WNV) encephalitis has not been described with any specific diagnostic feature so far. In this context, we describe three patients of West Nile encephalitis (WNE) who had behavioural and cognitive impairment with acute irreversible bilaterally symmetrical sensorineural deafness. Clinical profiles of these cases suggest that the patients who present with prominent behavioural and cognitive changes and have in addition features of bilateral sensorineural deafness may be considered as the possible case of WNE.

Reverse triiodothyronine (rT3) attenuates ischemia-reperfusion injury.

Hypothyroidism has been associated with better recovery from cerebral ischemia-reperfusion (IR) injury in humans. However, any therapeutic advantage of inducing hypothyroidism for mitigating IR injury without invoking the adverse effect of whole body hypothyroidism remains a challenge. We hypothesize that a deiodinase II (D2) inhibitor reverse triiodothyronine (rT3) may render brain specific hypometabolic state to ensue reduced damage during an acute phase of cerebral ischemia without affecting circulating thyroid hormone levels. Preclinical efficacy of rT3 as a neuroprotective agent was determined in rat model of middle cerebral artery occlusion (MCAO) induced cerebral IR and in oxygen glucose deprivation/reoxygenation (OGD/R) model in vitro. rT3 administration in rats significantly reduced neuronal injury markers, infarct size and neurological deficit upon ischemic insult. Similarly, rT3 increased cellular survival in primary cerebral neurons under OGD/R stress. Based on our results from both in vivo as well as in vitro models of ischemia reperfusion injury we propose rT3 as a novel therapeutic agent in reducing neuronal damage and improving stroke outcome.

Role of corrected-assisted-synchronized-periodic therapy in post-stroke rehabilitation.

BACKGROUND: Stroke is one of the common causes of chronic disability among neurological disorders. The role of various physiotherapy techniques has been extensively described in the literature. Here, we introduce a new physiotherapy technique, "Corrected-Assisted-Synchronized-Periodic (CASP) therapy." In this study, we aimed to compare CASP therapy with conventional physiotherapies. MATERIALS AND METHODS: This was a prospective, parallel, quasi-randomized, double-blind controlled intervention trial. The study was carried out at a tertiary care teaching and research centre. Sixty-one stroke affected patients with functional modified Rankin Scale (mRS) ranging from 1 to 5 suffering from post-stroke spasticity (grade 1-4) and muscle weakness were included in the study. Patients were randomly allocated into two groups. The first group followed conventional passive stretching exercises and the second group was offered CASP therapy. They were prospectively followed up at 3 monthly intervals for 6 months. The main outcome-measures were improvement in power, reduction in spasticity, and improvement in overall functional outcome. RESULTS: Mann-Whitney U-test for statistical significance was applied. At follow-up, CASP recipients reported improvement on functional scales such as Barthel index of activity of daily living, and modified Rankin scale (mRS), along with reduction in post-stroke spasticity and improvement in muscle power at 3 and 6 months of follow-up. CONCLUSION: CASP therapy has a major role in post-stroke rehabilitation particularly in limiting disability, reducing post-stroke spasticity, and providing an improvement in major functional outcomes.

Clinical characterization of neck pain in migraine.

INTRODUCTION:: Several extracranial symptoms, including somatic pain syndormes, are known to occur in migraine. Though neck pain has been occasionally described with migraine, its precise association and nature is not yet clear. OBJECTIVE:: To study the incidence and characteristics of neck pain in migraine with particular emphasis on its occurrence as a trigger or a part of the symptom complex of migraine, as well as its association with different phases of the migraine attack. MATERIALS AND METHODS:: We interviewed 391 migraine patients for 18 months. All patients who reported neck pain anytime during the migraine phase were analyzed for their demographic profile, headache and neck pain characteristics, the associated conditions, and other clinical features. RESULTS:: One hundred and sixty-six (42.5%) patients reported neck pain anytime during the attack (61.5% were female patients and the mean age was 35.8 years). A total of 82.7% patients had migraine without aura and 75.3% had episodic migraine at the onset. In 53 patients (32%), neck pain was a trigger, and in the rest (n = 113, 68%), neck pain was a part of migraine symtomatology. Fifty-seven patients (34.3%) noticed neck pain before the onset of headache; 148 patients (89.2%) reported neck pain at the onset of headache, and 46 patients (27.7%) experienced neck pain after the resolution of headache. The characteristic feature of migraine, such as the unilateral side shifting type of headache, was seen in only 54.2% of the patients, and the throbbing pain quality was seen in 75.2% of the patients. There was no significant difference in the nonheadache symptoms (P = 0.587) and cranial autonomic symptoms (P = 0.596) between the neck pain triggered migraine patients and those having neck pain as a part of the attack. CONCLUSION:: These data indicate that neck pain is a very common feature of migraine attacks and is likely to be either a trigger or a part of the migraine attack. Contrary to the established concept, however, neck pain as a prodromal or postdromal migraine symptom was less common. Careful history taking is required to diagnose neck pain as a feature of migraine and to differentiate it from secondary headache due to a cervical pathology for avoiding unnecessary imaging or other investigations.

Ultrasound Findings in Thyroid Nodules: A Radio-Cytopathologic Correlation.

INTRODUCTION: Ultrasound (USG) can be a good screening tool to identify high-risk nodule requiring fine-needle aspiration cytology (FNAC). The study aimed to assess the association of USG characteristic of thyroid nodule with malignancy. METHODS: A cross-sectional study was performed from August 2011 to July 2012 at Tribhuvan University Teaching Hospital. Patients referred for USG of the neck with thyroid nodule more than 10 mm were offered FNAC and included in the study after taking informed consent. USG characteristics were compared with histopathologic diagnosis of benign or malignant nodule. RESULTS: USG characteristics significantly (P < 0.05) associated with malignancy were as follows: size of thyroid nodule more than 30 mm, ill-defined margin, solid echotexture, hypoechoic lesion, microcalcification, and any form of increased vascularity. High sensitivity was seen in microcalcification, hypoechoic echogenicity, and ill-defined margin and high specificity was seen in ill-defined margin and solid echotexture. Relatively high sensitivity and specificity was found in ill-defined margin. CONCLUSIONS: Texture, size, margin, echogenicity, and vascularity are important factors for discriminating benign from malignant nodule. Hypoechogenicity, vascularity of any type, ill-defined margin, and microcalcification were independent predictors of malignancy. None of the characteristics were sensitive and specific to be used independently as screening tool to identify high risk of malignancy.

Tumefactive acute disseminated encephalomyelitis.

Tumefactive demyelinating lesions are tumour-like presentations of acute demyelinating lesions. They have been described with multiple sclerosis only and not with other varieties of acquired demyelination like acute disseminated encephalomyelitis (ADEM). The uncertainty about the diagnosis at the onset of the disease in tumefactive ADEM makes it important that the physicians should be aware of this entity. Various radiological similarities with more sinister lesions like central nervous system gliomas or lymphomas may lead to this confusion. Appropriate supportive treatment with steroids and follow up is required in these cases to avoid unnecessary interventions.

Complete middle cerebral artery block without brain infarction.

We report a patient with progressive supranuclear palsy and incidentally detected the absence of right middle cerebral artery (MCA) without any old or acute infarct in its territory. The magnetic resonance angiography and computed tomography angiography failed to detect any significant collateral circulation. We discuss the embryogenesis of brain circulation and offer a possible explanation for the nonvisualization of the right MCA in our patient.

Progressive supra-nuclear palsy: frequency of cardinal extrapyramidal features at first presentation.

OBJECTIVES: Cardinal extrapyramidal features of progressive supranuclear palsy (PSP) help in clinically differentiating this condition from Parkinson's disease and other Parkinsonian syndromes. However, not all extrapyramidal features may be initially present, thus posing a difficulty in early diagnosis. We studied their frequency at the time of first presentation. METHODS: Patients diagnosed clinically with PSP using the National Institute for Neurological Disorders and Society for PSP (NINDS/SPSP) criteria and seen between August 2010 and April 2013 were examined for the presence, 'presence with deviation' or absence of six extrapyramidal features: axial rigidity, symmetry, extended posture, backward falls, absence of tremors and lack of levodopa response. RESULTS: Twenty-eight patients (mean (SD) age 64.86 (9.72) years; 16 (57%) men) met the inclusion criteria. Of these, 14% had all six extrapyramidal features associated with PSP, 39% had five, 29% had four, 14% had three and 4% had two. The most frequent extrapyramidal sign was axial rigidity (68%). Axial plus peripheral rigidity was found in 18% of patients and peripheral rigidity alone in 14%. Extrapyramidal features were symmetrical in 29% and asymmetrical beyond 1 year in 29%. Body posture was extended in 46% and flexed in 21%. Backward falls were found in 50% and forward falls in 11%. Pill-rolling tremors were observed in 29%. Response to levodopa therapy was poor in 21% and good beyond 6 months in 39%. CONCLUSIONS: Only 14% of PSP patients present with all six cardinal extrapyramidal features. Also, deviations from standard descriptions are common in the initial stages of disease.

Nature of Parkinsonian features in multiple system atrophy.

Objectives: For this observational study, we evaluated the clinical profile of Parkinsonian features in multiple system atrophy (MSA), as there is no clarity about the specifics of these features in this disease compared to progressive supranuclear palsy (PSP) and Parkinson's disease (PD). Materials and Methods: Here, we selected 57 patients with MSA based on standard criteria and grouped them into two categories - Parkinsonian variant of MSA (MSA-P) and cerebellar variant of MSA (MSA-C). However, researchers did not distinguish among patients based on the nature of extrapyramidal syndrome or levodopa responsiveness. Then, we examined the patients at the time of their first visit to outpatient clinics or indoor wards and recorded and analyzed the specific extrapyramidal features or their variations. Results: The extrapyramidal features including levodopa responsiveness were highly variable among MSA-C as well as MSA-P patients. A subset of patients presented with features resembling PSP (symmetry [56.1%], axial rigidity [52.6%], backward falls [28.1%], and down-gaze restriction [17.5%]), while others presented with features resembling PD (asymmetry [43.9%], tremors [71.9%], and peripheral rigidity [40.4%]). After grouping patients based on predominant extrapyramidal features, 36.8% of patients had PD-like, 19.3% had PSP-like, and 43.9 % had mixed presentation. Moreover, 86% of patients had a perceptible levodopa response, including a sustained response for more than six months in 64% of patients. Conclusion: Extrapyramidal features in MSA patients may be PD-like, PSP-like, or mixed. Moreover, an initial presentation resembling PSP or PD may be deceptive and one must follow it up for MSA.

Developmental Changes in Genome Replication Progression in Pluripotent versus Differentiated Human Cells.

DNA replication is a fundamental process ensuring the maintenance of the genome each time cells divide. This is particularly relevant early in development when cells divide profusely, later giving rise to entire organs. Here, we analyze and compare the genome replication progression in human embryonic stem cells, induced pluripotent stem cells, and differentiated cells. Using single-cell microscopic approaches, we map the spatio-temporal genome replication as a function of chromatin marks/compaction level. Furthermore, we mapped the replication timing of subchromosomal tandem repeat regions and interspersed repeat sequence elements. Albeit the majority of these genomic repeats did not change their replication timing from pluripotent to differentiated cells, we found developmental changes in the replication timing of rDNA repeats. Comparing single-cell super-resolution microscopic data with data from genome-wide sequencing approaches showed comparable numbers of replicons and large overlap in origins numbers and genomic location among developmental states with a generally higher origin variability in pluripotent cells. Using ratiometric analysis of incorporated nucleotides normalized per replisome in single cells, we uncovered differences in fork speed throughout the S phase in pluripotent cells but not in somatic cells. Altogether, our data define similarities and differences on the replication program and characteristics in human cells at different developmental states.

Genome-wide-associated variants in migraine susceptibility: a replication study from North India.

OBJECTIVE: Genome-wide association studies (GWAS) have identified various migraine susceptibility variants. We aim to replicate 5 GWAS-associated polymorphisms (rs1835740, LRP1 rs11172113, TRPM8 rs10166942, PRDM16 rs2651899, and TGFBR2 rs7640453) in the North Indian population. Furthermore, we checked the single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium (LD) with the selected variants. We also undertook to predict the functional effect (in silico) of the variants. DESIGN: The study included 340 migraineurs and 200 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), amplification-refractory mutation system (ARMS)-PCR, and Taqman. Logistic regression was used for association analysis. LD plot was prepared using genotyping data retrieved from ENCODE and HapMart. Functional effect was predicted by functional SNP (F-SNP)and FastSNP. RESULTS: We did not observe any significant effect of the variant genotype or allele of the first migraine GWAS associated marker, rs1835740. However, significance was observed in case of heterozygous genotype for total migraineurs and migraine without aura (MO). We suggest potential protective effect of LRP1 rs11172113 polymorphism in migraine susceptibility. PRDM16 rs2651899 variant genotype and allele showed a protective effect on migraine and MO susceptibility. On the other hand, TRPM8 rs10166942 and TGFBR2 rs7640543 variants did not have significant influence on migraine susceptibility in the North Indian population. Most of the selected SNPs (except LRP1 rs11172113) and some of the SNPs in strong LD were predicted to affect transcriptional regulation. Functional effect of LRP1 rs11172113 variant could not be predicted, but another SNP in the same LD block was found to affect transcription factor binding sites. CONCLUSION: We report significant influence of rs1835740, LRP1 rs11172113 and PRDM16 rs2651899 polymorphisms on migraine susceptibility in the North Indian population. Finally, we present the first replication study of GWAS-associated polymorphisms in a population other than European.