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The present model on two-cell tornadoes generalizes the one-cell model of Baker and Sterling (2017) by introducing a sharpness parameter. However, we model only the outer cell. The idea was derived from Vatistas et al. (1991) model which showed that larger values of the sharpness parameter increase the sharpness of azimuthal velocity near the periphery of maximum azimuthal velocity. This generalization brings about the cherished change, which helps better fit to tornado motion. Natural tornadoes can fit different values of the sharpness parameter, indicating the limitations of Baker and Sterling's model. The fluid is considered Newtonian, incompressible, and non-viscous while the motion is steady. Major changes concerning the sharpness parameter are observed in the axial velocity component which behaves differently for one-cell and two-cell tornadoes in two cases, i.e., parameter less than one and parameter greater than or equal to one. A remarkable observation is that the strongest updraft shifts towards the periphery of the maximum radial velocity. Moreover, the radial profile of pressure difference at the reference height behaves quite differently for two-cell tornadoes. Furthermore, sharpness parameter affects the distance traveled by flying debris and the time taken by falling debris to reach the ground. • It is a two-cell model for tornado dynamics discussing outer cells. • Different values of the sharpness parameter provide a better fit for real tornadoes. • Maximum updraft shifts towards the radius of maximum radial velocity. • The lesser the sharpness parameter, the greater the radial pressure gradient. • Sharpness parameter hugely affects the trajectory of the debris particles. [ABSTRACT FROM AUTHOR]

To investigate the relation of different factors with recovery from dyspnea after COVID-19. A questionnaire based observational study. The SGRQ is a health and related quality of life related questionnaire. It is validated for using in post COVID patients. The modified BORG scale for dyspnea is a categorical scale starting from 0 (nothing at all) to ending at10 (maximal). Modified MRC scale for dyspnea is a 5-point scale with scores ranging from 0-4, it measures dyspnea during daily activities. Patients were assessed at the day of discharge and on 30th day after discharge. This study was conducted in a tertiary care center of Eastern India and study population was all discharged Patients of COVID-19 with presence of dyspnea. Total 48 patients were included in this prospective observational study. Patients having dyspnea during discharge are selected for this study. Only those patients who were having dyspnea after discharge and not admitted to another department for concomitant illness were studied. HRQoL was assessed by St George's Respiratory Questionnaire (SGRQ) and dyspnea during daily activity was assessed by modified Medical Research Council (mMRC) scale and we used modified BORG scale for dyspnea during exertion. HRQoL, dyspnea during daily activity and dyspnea during exertion. The mean mMRC, modified Borg and SGRQ at D0 were 2.38±0.98, 3.15±2.12 and 45.36±27.32 respectively which were improved to 0.94±0.86, 0.94±1.27 and 19.22±18.96. Age showed significant positive correlations with initial modified Borg (r=0.292, p=0.044) and SGRQ (r=0.332, p=0.021). Body mass Index showed significant positive correlations with initial mMRC (r=0.352, p=0.014) and SGRQ (r=0.419, p=0.003). Our study showed on discharge many COVID patients have impaired HRQoL and also have dyspnea on exertion. With early institution of standard pulmonary rehabilitation protocol symptoms and HRQoL improves rapidly in a month. There is no conflict of interest. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests the antiangiogenic potential of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) among the anticancerous properties of this drug. In the present studies, we investigated the antiangiogenic effects of dietary 2-DG on tumour (Lewis lung carcinoma [LLC]) as well as ionising radiation–induced angiogenesis in mouse models. Dietary 2-DG reduced the serum vascular endothelial growth factor levels (∼40%) in LLC-bearing mice along with a significant inhibition of tumour growth and metastases. In vivo Matrigel plug assays showed significant decrease in vascularisation, Fluorescein isothiocyanate (FITC)-dextran fluorescence and factor VIII–positive cells in the plugs from 2-DG–fed mice, supporting the notion that dietary 2-DG significantly suppresses the tumour-associated and radiation-induced angiogenesis. 2-DG inhibited the glucose usage and lactate production as well as ATP levels of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner, accompanied by growth inhibition and loss of viability in vitro. Furthermore, 2-DG inhibited the capillary-like tube formation in Matrigel as well as migration and transwell invasion by HUVECs, which are functional indicators of the process of angiogenesis. These results suggest that dietary 2-DG inhibits processes related to angiogenesis, which can impair the growth and metastasis of tumours. • Dietary 2-deoxy- d -glucose (2-DG) inhibits Lewis lung carcinoma primary tumour growth and lung metastasis. • 2-DG administration inhibits tumour-associated and radiation-induced angiogenesis. • Inhibition of glucose metabolism in activated endothelial cells underlies the mechanisms of antiangiogenic potential of 2-DG. [ABSTRACT FROM AUTHOR]

Background: Mutations in PRKN (PARK2) are commonly encountered in early-onset Parkinson disease (PD).Objectives: To screen for PRKN mutations in a clinically well-characterized cohort of early-onset PD patients with a family history (FEOPD; ≤50 years at onset) or sporadic (SEOPD; ≤50 years at onset) and late-onset familial patients (FLOPD; >50 years at onset).Methods: A total of 97 patients including 52 SEOPD and 45 familial PD (FEOPD: 23; FLOPD: 22) were screened for variants in PRKN by PCR- Sanger sequencing. PRKN dosage and variants in known PD genes were screened by qPCR and whole-exome sequencing in a subset of samples.Results: A total of 25 (25.77%) patients (SEOPD: 12, FEOPD: 6, and FLOPD: 7) were positive for PRKN variants. Of these, two patients manifested homozygous variants; while one patient was carrying three PRKN variants and two patients were carrying two PRKN variants. But, we could not examine their parents or relatives and their genotypes remain unknown. The remaining 20 (80%) patients were carrying heterozygous variants only. 32% of these variants were in exon 2, including a novel truncating homozygous variant (c.97C > T:p.Arg33Ter) in a SEOPD patient.Conclusion: In our cohort, a novel homozygous variant (c.97C > T:p.Arg33Ter) in a patient with hyperhidrosis expands the spectrum of PRKN associated mutations. Furthermore, ~80% of the PRKN variants being heterozygous in this study cohort, implies the utility of the cohort for identification of additional novel/known causative PD gene(s). [ABSTRACT FROM AUTHOR]

Keywords: Dystonia deafness syndrome; CAPOS syndrome; ATP1A3 mutation EN Dystonia deafness syndrome CAPOS syndrome ATP1A3 mutation 192 194 3 11/23/20 20200901 NES 200901 CAPOS syndrome (Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is one of the three overlapping clinical conditions caused by heterozygous mutations in the ATP1A3 gene, while other two include "Alternating Hemiplegia of Childhood" (AHC) and "Rapid-onset Dystonia Parkinsonism" (RDP) [1]. Dystonia deafness syndrome, CAPOS syndrome, ATP1A3 mutation. [Extracted from the article]

Keywords: Dystonia; Gene EN Dystonia Gene 33 35 3 06/16/20 20200501 NES 200501 KMT2B-related dystonia is characterized by childhood-onset and progressive disease course with prominent lower-limb, cervical, cranial, and laryngeal involvement [1]. The onset of dystonia in this patient was at the age of 43 years and the most dominant symptoms were cervical dystonia, dysarthria, dysphonia, upper limb dystonia, and dystonic camptocormia. Our case highlights the fact that dystonia secondary to KMT2B mutation should also be considered as one of the differentials in patients presenting with dystonia opisthotonus. [Extracted from the article]

Introduction Patent vitellointestinal duct occurs in about 2% of the population which unusually leads to small intestinal obstruction associated with high morbidity and mortality. Here we are reporting an unusual case of patent vitellointestinal duct causing small intestinal obstruction in an adult patient. Presentation of case A 22-year-old male without any medical illness presented as an emergency with a 3 day hystory of abdominal pain, multiple episode of vomiting and abdominal distention. Distended abdomen and sign of peritonitis were found on abdominal examination. Abdominal X-rays revealed multiple small intestinal air-fluid levels. A patent vitellointestinal duct extending from distal ileum to the posterior wall of the umbilicus was found causing closed loop ileal obstruction during laparotomy. Resection of a vitellointestinal duct along with gangrenous distal ileum and cecum with ileocolostomy was performed. He was discharged on the 8 th postoperative day. Discussion Diagnosing and management of cause of intestinal obstruction in patients without history of abdominal surgery is very challenging. Early resuscitation and timely surgical intervention of intestinal obstruction due to a rare patent vitellointestinal duct can be life-saving measure. Conclusion The patent vitellointestinal duct is an uncommon entity in adults and moreover this disorder leading to intestinal obstruction is very rare. Surgeons should be aware of this infrequent cause of small bowel obstruction to allow for early diagnosis and to facilitate better patient outcomes. [ABSTRACT FROM AUTHOR]

‘Meige's syndrome’ is a type of cranial dystonia characterized by blepharospasm and oromandibular dystonia and can be associated with complex movement of lower facial muscles, mouth, jaw, tongue, pharyngeal and cervical muscles. Frequently, blepharospasm is the earliest clinical manifestation, which spreads over a period of time to involve other cranial and extra-cranial muscles. Common characteristics of this syndrome are well known, but their variety is wide. Different eponyms such as “Breughel syndrome”, “Wood syndrome”, “Blepharospasm plus”, “Segmental cranial dystonia” and “Segmental cranio-cervical dystonia” have been used to describe this entity with numerous anatomical variations. In the majority of the patients Meige's syndrome is primary or idiopathic, where the cause of spasm is not known, however secondary cases can occur following prolonged use of neuroleptics or secondary to underlying brain disorders. This syndrome has also been described in patients with essential tremor, Parkinson's disease and atypical Parkinsonism. Neurophysiological features are similar to other focal dystonia characterized by abnormal plasticity and impaired inhibition. Most of the patients are successfully treated with injection of botulinum toxin, however deep brain stimulation has emerged as a good therapeutic option in intractable patients. The objective of this review is to understand whether patients who develop Meige's syndrome are different from patients who manifest blepharospasm or oromandibular dystonia alone. [ABSTRACT FROM AUTHOR]

Study Design: Exploratory case-control study. Introduction: Writer's cramp (WC) is a type of focal hand dystonia. The central nervous system plays a role in its pathophysiology, but abnormalities in the affected musculoskeletal components may also be relevant. Purpose of the Study: We compared the active range of motion (ROM) in patients with WC and healthy volunteers (HVs) and correlated the findings with disease duration and severity. Methods: Affected limb joints were measured with goniometers. Patients were assessed at least 3 months after their last botulinum toxin (botulinum neurotoxin) injection, and strength was clinically normal, t tests were used to compare the ROMs of WC with matched HVs. The Spearman correlation coefficient assessed the relationship of active ROMs to the disease duration and handwriting subscore of the Dystonia Disability Scale. Results: ROMs of D1 metacarpophalangeal (MCP) joint extension as well as D2 and D5 MCP flexion were significantly smaller in WC, and distal interphalangeal joint extension in D3 and D5 was significantly greater compared with HVs. There were negative correlations between D2 MCP flexion and disease duration and with Dystonia Disability Scale. Discussion. Abnormalities in ROMs in WC were found. Severity and disease duration correlated with reduced D2 MCP flexion. This may be related to intrinsic biomechanical abnormalities, co-contraction of muscles, or a combination of subclinical weakness and atrophy from repeated botulinum neurotoxin injections. Conclusions: Hand biomechanical properties should not be ignored in the pathophysiology of WC. Level of Evidence: 2c. [ABSTRACT FROM AUTHOR]

Tremor has been recognized as an important clinical feature in dystonia. Tremor in dystonia may occur in the body part affected by dystonia known as dystonic tremor or unaffected body regions known as tremor associated with dystonia. The most common type of tremor seen in dystonia patients is postural and kinetic which may be mistaken for familial essential tremor. Similarly familial essential tremor patients may have associated dystonia leading to diagnostic uncertainties. The pathogenesis of tremor in dystonia remains speculative, but its neurophysiological features are similar to dystonia which helps in differentiating it from essential tremor patients. Treatment of tremor in dystonia depends upon the site of involvement. Dystonic hand tremor is treated with oral pharmacological therapy and dystonic head, jaw and voice tremor is treated with injection botulinum toxin. Neurosurgical interventions such as deep brain stimulation and lesion surgery should be an option in patients not responding to the pharmacological treatment. [ABSTRACT FROM AUTHOR]

We evaluated the effect of combining 2′- O -[2-[2-( N , N -dimethylamino)ethoxy]ethyl] (2′- O -DMAEOE), a 2′-cationic modification, with a 2′,4′-constrained 2′- O -ethyl nucleic acid (cEt BNA) on the activity of an antisense oligonucleotide (ASO) using PTEN as a model target. Our results suggest that replacing one cEt BNA nucleotide with 2′- O -DMAEOE nucleotide at the 5′-end of a 2-10-2 gapmer ASO maintained the potency relative to parent ASO in liver. The cationic 2′- O -DMAEOE modification did not improve the activity of ASO in extra-hepatic tissues. Results from this study provide guidance to design improved antisense oligonucleotide drugs. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease causing both motor and non-motor symptoms. Drooling, an excessive pooling and spillover of saliva out of the oral cavity, is one of the non-motor symptoms in PD patients that produces various negative physical and psychosocial consequences for patients and their caregivers. At present, the pathophysiology of drooling in PD is not completely certain; however, impaired intra-oral salivary clearance is likely the major contributor. There are neither standard diagnostic criteria nor standard severity assessment tools for evaluating drooling in PD. In accordance with the possible pathophysiology, dopaminergic agents have been used to improve salivary clearance; however, these agents are not completely effective in controlling drooling. Various pharmacological and non-pharmacological treatment options have been studied. Local injection with botulinum toxin serotypes A and B into major salivary glands is most effective to reduce drooling. Future research to explore the exact pathophysiology and develop standard diagnostic criteria and standard severity assessment tools are needed to formulate specific treatment options and improve patient care. [ABSTRACT FROM AUTHOR]

Abstract: Restless legs syndrome (RLS) is a common sensorimotor neurological disorder that is diagnosed according to the revised criteria of the International RLS Study Group (IRLSSG). The pathophysiology of RLS is still unknown and its prevalence is influenced by ethnicity, age, and gender. RLS is divided into two types by etiology: primary or idiopathic and secondary. Primary RLS is strongly influenced by a genetic component while secondary RLS is caused by other associated conditions such as end-stage renal disease or peripheral neuropathy. Another common condition associated with RLS is pregnancy. The prevalence of RLS during pregnancy is two to three times higher than in the normal population and is influenced by the trimester and the number of parity. The main mechanisms that may contribute to the pathophysiology of RLS during pregnancy are hormonal changes and iron and folate status. Standard medications for treating RLS during pregnancy are not established. Most medications have been used according to the evidence from non-pregnant patients. Therefore, consideration of the medical treatment for treating RLS during pregnancy should be balanced between the benefit of relieving the symptoms and maternal and fetal risk. In general, the prognosis of RLS during pregnancy is good and symptoms are usually relieved after delivery. [Copyright &y& Elsevier]

To investigate the role of low molecular weight protein- tyrosine phosphatase (LMW-PTP) in glucose metabolism and insulin action, a specific antisense oligonucleotide (ASO) was used to reduce its expression both in vitro and in vivo. Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-β subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. The ASO-treated DIO and ob/ob animals showed improved insulin sensitivity, which was reflected by a lowering of both plasma insulin and glucose levels and improved glucose and insulin tolerance in DIO mice. The treatment did not decrease body weight or increase metabolic rate. These data demonstrate that LMW-PTP is a key negative regulator of insulin action and a potential novel target for the treatment of insulin resistance and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Focus on uncommon symptoms of COVID-19: Potential reason for spread of infection. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias (HSPs), also known as spastic paraplegias (SPGs) are a heterogeneous group of inherited neurodegenerative diseases in which the patients present with gradually progressive spasticity and weakness that predominantly tends to affect the lower limbs.[1] SPGs are classified by the phenotype (pure or complicated), the trait of inheritance, and the mutated gene.[1] SPG12 is a pure SPG-type due to RTN2 gene mutation which encodes the reticulon 2 protein.[2] We are reporting a 46-year-old female with RTN2 gene mutation, who presented with spastic quadriparesis and features suggestive of anterior horn cell involvement. Overall psychiatric symptoms are rare in HSP, and SPG4-HSP patients are more likely to be associated with underlying psychosis.[5] To conclude, our patient extends the RTN2-gene associated SPG12 and provides evidence for anterior horn cell involvement. [Extracted from the article]

Summary: Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2′-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease. [Copyright &y& Elsevier]

Internet has become a major information source, yet little is known about why women use the internet for obtaining health information. In this paper, we propose and test three exploratory models to explain internet use for obtaining health information: health and wellness model, health needs model, and search costs model. The health and wellness model is based on the notion that internet has become such an integral part of daily life that health-conscious women use the internet in a pro-active manner for health promotion. The health needs model posits that women with greater health needs or concerns are more likely to use the internet. Finally, the search costs model explores the idea that women may view the internet as a resource for reducing high information search costs. These models were tested using data collected through telephone surveys of women in three southern New Jersey counties in the USA. Consistent with expectations, our findings show that internet use to search for health information is greater among women with higher levels of income and education. There is support for all three models, with surprisingly strong support for the health and wellness model. We conclude that women increasingly rely on the internet to supplement health information received from traditional sources and discuss the implications of our findings for policymakers and health professions. [Copyright &y& Elsevier]

The article describes the case of a 64-year-old man who presented with history of severe burning paresthesias involving both hands and feet. The patient developed diminished sensation for tough and temperature in a glove and stocking pattern and non-itchy skin lesions in over legs and face. He was diagnosed with acute onset rapidly progressive distal symmetric vasculitic polyneuropathy.

Abstract: We report here the use of PPh3/halogenating agents as highly efficient reagents for the ring opening of aziridines with halides. The method works effectively for both activated and non-activated aziridines, and furnishes the products in excellent yields within a short period of time. [Copyright &y& Elsevier]

Background: Genetic heterogeneity in Parkinson's disease (PD) has been unambiguously reported across different populations. Assuming a higher genetic load, we tested variant burden in PD genes to an early onset PD cohort from India.Methods: Whole exome sequencing was performed in 250 PD patients recruited following MDS-UPDRS criteria. The number of rare variants in the 20 known PD genes per exome were used to calculate average rare variant burden with the 616 non-PD exomes available in-house as a comparison group. SKAT-O test was used for gene level analysis.Results: 80 patients harboured rare variants in 20 PD genes, of which six had known pathogenic variants accounting for 2.4% of the cohort. Of 80 patients, 12 had homozygous and nine had likely compound heterozygous variants in recessive PD genes and 59 had heterozygous variants in only dominant PD genes. Of the 16 novel variants of as yet unknown significance identified, four homozygous across ATP13A2, PRKN, SYNJ1 and PARK7; and 12 heterozygous among LRRK2, VPS35, EIF4G1 and CHCHD2 were observed. SKAT-O test suggested a higher burden in GBA (punadjusted = 0.002). Aggregate rare variant analysis including 75 more individuals with only heterozygous variants in recessive PD genes (excluding GBA), with an average of 0.85 protein-altering rare variants per PD patient exome versus 0.51 in the non-PD group, revealed a significant enrichment (p < 0.0001).Conclusion: This first study in an early onset PD cohort among Indians identified 16 novel variants in known genes and also provides evidence for a high genetic burden in this ethnically distinct population. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis B can have varied extrahepatic manifestations involving the skin, renal, haematological and nervous systems. Neurological manifestations in hepatitis B may take the form of Guillain-Barré syndrome and secondary systemic vasculitis-related mononeuritis multiplex. The clinical course of hepatitis B-related, vasculitis-related neuropathy is usually subacute to chronic and clinical evolution is relatively benign. To our knowledge, acute hepatitis B-associated vasculitis manifesting as acute distal symmetric polyneuropathy has not been reported. We report a 60-year-old man who presented with fever, mild hepatomegaly, skin lesions in the form of non-palpable purpura and acute onset distal symmetric sensorimotor polyneuropathy. Serum transaminase levels were raised and viral serological markers revealed acute hepatitis B. The patient remained anicteric throughout his clinical course. Nerve conduction studies showed severe axonal sensorimotor polyneuropathy and histopathological examination of sural nerve biopsy was suggestive of vasculitic neuropathy. The patient was first given a course of intravenous immunoglobulin with the antiviral drug entecavir. The fever subsided after 1week of treatment. The patient was started on prednisolone in addition to the entecavir, and showed significant improvement in motor power and marked resolution in paresthesia after 2weeks of treatment. Thus, acute onset distal symmetric sensorimotor polyneuropathy of vasculitic etiology can be a manifestation of acute hepatitis B. [Copyright &y& Elsevier]

Vermicompost was prepared by five different treatments from relatively resistant coconut husk mixed with either pig slurry or poultry manure. The recovery of vermicompost varied from 35% to 43% and it resulted in significant increase in pH, microbial biomass carbon, macro and micro nutrients concentration. Among the treatments highest relative N (1.6) and K (1.3) recovery were observed for 20% feedstock substitution by pig slurry while poultry manure substitution recorded highest P recovery (2.4). Compost maturity parameters significantly differed and well correlated. The characteristics of different treatments established the maturity indices as C/N 15–20; Cw < 1.8; Cw/Norg < 0.55; Lignin < 10–12; CHA/CFA > 1.5 and HI > 15.0. The manurial value of the coconut husk compost was improved by feedstock substitution with pig slurry (80:20). The results revealed the technical feasibility of converting coconut husk into valuable compost by feedstock substitution with pig slurry. [ABSTRACT FROM AUTHOR]

IKB kinase (IKK) catalytic subunits play a key role in cytokine-mediated nuclear factor (NF)-κB signaling, and a loss of NF-κB function appears to inhibit inflammation and oncogenesis. Manumycin A is a potent and selective farnesyltransferase inhibitor with antitumor activity. We found that manumycin A caused a rapid and potent inhibition of IKK activity induced by tumor necrosis factor in a number of cell types. Most unexpectedly, other classes of farnesyltransferase inhibitors had no inhibitory effect. To identify the molecular mechanisms of manumycin A action, cultured human HepG2 hepatoma cells were transiently transfected with various IKKα and IKKβ constructs, and a striking difference in manumycin A sensitivity was observed. Furthermore, cells expressing wild-type IKKβ and IKKβ mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKKβ in response to manumycin A, whereas substitution of Cys-662 and -716 conferred protection against dimer formation. Direct inhibition of IKK activity and formation of stable IKKβ dimers were observed in the presence of manumycin A that could be blocked by dithiothreitol. IKK interaction with the adaptor protein IKKγ/NEMO was disrupted in manumycin A-treated cells. Most importantly, administration of manumycin A to mice xenografted with routine B16F10 tumors caused potent IKK-suppressive effects. Thus, manumycin A with its epoxyquinoid moieties plays an important regulatory function in IKK signaling through pathways distinct from its role as a protein farnesylation inhibitor. [ABSTRACT FROM AUTHOR]

Background: Knowledge of genetic determinants in Parkinson's disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach is exploited in this study.Methods: Informative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of Parkinson's disease were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of variant(s) segregating with the phenotype were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest.Results: Two compound heterozygous variants, a rare missense (c.1139C > T:p.P380L) and a novel splice variant (c.1456 + 2 delTAGA, intron10) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and two affected siblings. WASL, a gene not previously linked to a human Mendelian disorder is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased reactive oxygen species tolerance in mutation carrying cells on Tetrabutylphosphonium hydroxide induction and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants.Conclusion: WASL, with demonstrated functional relevance in neurons may be yet another strong candidate gene for autosomal recessive PD encouraging assessment of its contribution across populations. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus (HIV) causes movement disorders in persons living with HIV (PLH). We conducted a systematic review on the spectrum of movement disorders in PLH using standard terms for each of the phenomenologies and HIV. Movement disorders in PLH were commonly attributed to opportunistic infections (OI), dopamine receptor blockade reactions, HIV-associated dementia (HAD), presented during seroconversion, developed due to drug reactions or antiretroviral therapy (ART) itself and lastly, movement disorders occurred as a consequence of the HIV-virus. Parkinsonism in ART naïve PLH was associated with shorter survival, however when Parkinsonism presented in PLH on ART, the syndrome was indistinguishable from Idiopathic Parkinson's disease and responded to therapy. Tremor was often postural due to HAD, drugs or OI. Generalized chorea was most frequent in HIV encephalopathy and toxoplasmosis gondii caused most cases of hemichorea. Ataxia was strongly associated with JCV infection, ART efavirenz toxicity or due to HIV itself. Dystonia was reported in HAD, secondary to drugs and atypical facial dystonias. Both cortical/subcortical and segmental/spinal origin myoclonus were noted mainly associated with HAD. In patients with HIV related opsoclonus-myoclonus-ataxia-syndrome, seroconversion illness was the commonest cause of followed by IRIS and CSF HIV viral escape phenomenon. Aetiology of movement disorders in PLH depend on the treatment state. Untreated, PLH are prone to develop OI and HAD and movement disorders. However, as the number of PLH on ART increase and survive longer, the frequency of ART and non-AIDS related complications are likely to increase. • Movement disorders due to OI and HAD have declined in the post-ART era. • OI and HIV infection are important causes of movement disorders in untreated patients. • Movement disorders in PLH may also associated with ART and DRB drugs. • Parkinson's disease in PLH present at an earlier age and responds well to levodopa and DBS. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGA Ti and DGA T2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because we have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase Cϵ activation, we next sought to understand the paradoxical reduction in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were associated with reduced expression of lipogenic genes (SREBP1c, ACC1, SCDJ, and mtGPAT) and increased expression of oxidative/thermogenic genes (CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase Cϵ activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Highlights from the article: The first report identifying GNAL mutation included 28 dystonia patients from eight families who had predominantly craniocervical form of dystonia with onset of symptom typically in the neck [[1]]. Recently, Sarva et al. also published a study describing three dystonia patients with GNAL mutation and all had amelioration of severe cervical dystonia symptoms after DBS; although cranial (including speech) and limb dystonia did not improve [[5]].