Variation in Exon 29 of the NOS1 Gene Does Not Contribute to Parkinson's Disease in the North Karnataka Population.

INTRODUCTION: Nitric oxide (NO) overproduction has been found to have neurotoxic effects on the brain. Moreover, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced, the suppression of the NO-synthesizing enzymes, such as neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), has neuroprotective benefits in Parkinson's disease (PD). These findings imply that NOS may have a role in regulating the nigral dopaminergic neurons' tolerance to environmental stressors in PD. OBJECTIVE: In the present study, we investigated variations in the NOS1 gene that may raise the likelihood of PD. METHODS: PD patients who visited the neurology departments of several medical colleges and hospitals in North Karnataka, India, between 2009 and 2011 were included in the study. The detailed clinic pathological details were obtained from 100 PD patients. Genomic DNA was isolated using the kit method followed by the evaluation of the quality and quantity of isolated gDNA. Polymerase chain reaction (PCR) amplification of exon 29 was performed, and sequencing was performed using the Applied Biosystems ABI 3500 Sanger sequencing platform. RESULTS: The present study is comprised of 100 PD patients, which includes 65 males and 35 females. There were 64 sporadic, 34 idiopathic, and two familial PD cases. The majority (67.1%) of PD cases were from metropolitan areas. Community-based segregation showed that the maximum cases were from Hindu Lingayat. A proportion (90.8%) of the patients had tremors, 32.7% of them displayed slowness in their daily tasks, and 8.1% of them had dyskinesia. Molecular analysis showed two untranslated region (UTR) variations g.151787 del T (rs1434015950) and g.151745 C>T (rs2682826) in our study group. CONCLUSION: The absence of mutations in the targeted NOS1 gene in the PD patients from North Karnataka shows the involvement of other genes in the molecular pathophysiology. Thus, it is crucial to screen other possible genes using cutting-edge technology to obtain a clear picture of the genetics of PD.

Outcomes of patients with chronic plaque psoriasis and hidradenitis suppurativa on biologic therapy during the Covid-19 pandemic: A UK dermatology tertiary centre experience.

Retrospective review data from 183 patients with psoriasis and/or hidradenitis suppurativa from a UK tertiary dermatology centre, suggests biologic therapy does not confer a significant increased risk of contracting severe Covid-19 in this cohort. This is in line with a growing body of evidence which indicates that it is safe to continue using biologic therapies during the pandemic.

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.

Use of the Skin Cancer Quality of Life Impact Tool (SCQOLIT) - a feasibility study in non-melanoma skin cancer.

BACKGROUND: Incidence of non-melanoma skin cancers (NMSCs) is increasing and can significantly impact on quality of life (QOL), yet there are few studies evaluating patient-reported outcome measures (PROMs) in NMSC populations. We undertook a prospective feasibility study to evaluate a skin cancer-specific PROM, the Skin Cancer Quality of Life Impact Tool (SCQOLIT), in patients with a new diagnosis of NMSC. OBJECTIVES: (i) To establish acceptability of SCQOLIT in dermatology clinics, (ii) a descriptive analysis of SCQOLIT scores in NMSC. METHODS: Patients with histologically confirmed NMSC completed SCQOLIT, EQ-5D and a transition item. Questionnaires were completed at baseline and 3 months for group 1 ('low-risk' NMSC) and group 2 ('high-risk' NMSC) with additional questionnaires at 6-9 months for group 2. Patients participated in structured interviews. Clinician experience was captured through staff evaluation forms and a focus group. Acceptability and psychometric properties of SCQOLIT were assessed. RESULTS: Overall, 318 patients consented to participate. Mean SCQOLIT score at baseline was 5.33, with 2.6% of patients scoring ≥20. No ceiling effects were observed, whilst 13.9% scored 0. Validity was demonstrated against EQ-5D. Cronbach's alpha 0.84 demonstrated internal consistency. Thirteen patients were interviewed and thought SCQOLIT was comprehensive, captured impact on health-related QOL and helped express their needs to clinicians. Most clinicians found SCQOLIT 'very useful' or 'useful to some extent' in facilitating discussions. CONCLUSIONS: This feasibility study demonstrates that SCQOLIT is acceptable to patients and staff in dermatology skin cancer clinics. The psychometric properties of SCQOLIT confirm its utility in NMSC populations.

Pasteurella multocida Septic Shock: Case Report and Literature Review.

Pasteurella multocida is a small, Gram-negative, facultatively anaerobic coccobacillus that inhabits the normal microbiota of the respiratory tract of several animals, especially cats and dogs. By infecting humans, a wide range of clinical pictures can evolve varying from mild local cellulitis to more severe systemic diseases (e.g., meningitis, pneumonia, endocarditis, and bacteremia). Septic shock is an uncommon complication of P. multocida infection, with less than 100 cases reported in the literature. It is frequently associated with cirrhotic and immunocompromised individuals and rarely immunocompetent ones. Here, we present a case of Pasteurella multocida septic shock in an elderly man secondary to leg cellulitis with a review of the relevant literature.

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.

INTRODUCTION: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.

A Novel Homozygous Mutation in the FUCA1 Gene Highlighting Fucosidosis as a Cause of Dystonia: Case Report and Literature Review.

BACKGROUND: Fucosidosis is a rare lysosomal disorder caused by mutations in the FUCA1 gene. We describe here a novel homozygous mutation in FUCA1 in an Indian fucosidosis case. Furthermore, we summarize the clinical and genetic findings in the most recently reported individuals with fucosidosis. CASE: The proband is an 8-year-old boy born to consanguineous parents. He had generalized dystonia and bilateral spasticity as well as coarse facies, dysostosis multiplex, recurrent infections, angiokeratoma corporis diffusum, and visceromegaly. Whole exome sequencing analysis detected a homozygous canonical splice variant in the FUCA1 gene [Chr1(GRCh37):g.24172346C > T; NM_000147.4:c.1261-1G > A], not previously reported as causative of a human phenotype. Low levels of α-fucosidase in patient leukocytes and a positive qualitative urine based thin layer chromatography test for fucosidosis confirmed the diagnosis. Our literature review identified 89 cases of fucosidosis since the last major review. We show that dystonia is a rare manifestation (12%) and that only a small minority of cases receive treatment with transplantation (3.37%). CONCLUSION: We report a novel homozygous mutation in FUCA1 as the cause of severe neurological phenotype including generalized dystonia. Early recognition of fucosidosis may be important for consideration of promising treatment options, such as bone marrow transplantation.

Establishing and developing a Teenage and Young Adult dermatology clinic with embedded specialist psychological support.

Skin conditions are common in adolescence and impart considerable psychological burden. The Department of Health has identified the specialized needs of adolescents transitioning from paediatric to adult services as a priority, yet there are few dedicated transitional clinics in the UK providing appropriate psychosocial support. We have established a monthly Teenage and Young Adult (TYA) dermatology clinic dedicated to managing teenagers and young adults with skin disease alongside open-access psychological support. Demographic data and Teenagers' Quality of Life Index (T-QoL) measures were recorded for all patients in 2016. To evaluate patient experience, two online surveys were conducted. Statistically significant improvements in the T-QoL were recorded for patients with the most common skin condition (eczema) attending for repeat assessment by the psychologist. Patients reported high satisfaction rates in both patient experience surveys. These results demonstrate that specialized adolescent care both is well received and can improve outcomes for these patients.

Patient preferences for topical treatment of actinic keratoses: a discrete-choice experiment.

BACKGROUND: The treatment of actinic keratosis (AK) is a potentially effective strategy for the prevention of cutaneous squamous cell carcinoma (cSCC). However, the patient perspective on potential benefits of AK treatment in terms of skin cancer reduction has received little attention to date. OBJECTIVES: (i) To investigate patient preferences for topical treatments for AK using a discrete-choice experiment (DCE); (ii) to evaluate patient willingness to trade between clinical benefit and medical burden. METHODS: The DCE was conducted as part of a study to establish the feasibility of a phase III randomized controlled trial evaluating the prevention of cSCC using currently available topical interventions. Preferences were elicited by asking patients to make a series of choices between treatment alternatives with different hypothetical combinations of attribute levels. Willingness to trade between treatment attributes was estimated using a flexible-choice model that allows for the heterogeneity of patient preferences. RESULTS: A total of 109 patients with AK completed the DCE. The majority of patients who expressed valid preferences were willing to accept some reduction in both prophylactic and cosmetic efficacy to reduce the burden of the treatment regimen, the severity of skin reaction and other adverse effects. Patients may reject treatment if the perceived therapeutic benefit is outweighed by the subjective burden of treatment. CONCLUSIONS: Evidence of significant variation in the perceived utility of treatments across patients highlights the importance of taking individual patient preferences into account to improve AK treatment acceptability and adherence.

Cutaneous hyperpigmentation and familial gastrointestinal stromal tumour associated with KIT mutation.

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours arising in the gastrointestinal tract. Early detection, before metastasis occurs, is important as complete surgical excision achieves cure. Approximately 85% of GISTs are associated with mutations in the KIT gene, and although the majority of GISTs are sporadic, familial GISTs have been identified. Several families with multiple GIST tumours have also been described with various cutaneous findings including hyperpigmentation, multiple lentigines, vitiligo and urticaria pigmentosa. We discuss a 6-year-old boy who presented with an unusual pattern of hyperpigmentation in association with a family history of GIST. A causative KIT mutation was identified in DNA from the pigmented skin and from the resected GIST, and the patient was referred to the Paediatric Gastroenterology department for GIST screening. The term 'GIST cutaneous hyperpigmentation disease' has been suggested previously for the association of familial GIST with cutaneous hyperpigmentation caused by a germline KIT mutation.

Management of naevus sebaceous: a national survey of UK dermatologists and plastic surgeons.

Naevus sebaceous (NS) is a congenital cutaneous hamartoma, which typically occurs on the head and neck. Historically, the treatment of choice was excision in infancy because of the potential for malignant transformation; however, recent studies suggest that this risk is < 1% and unlikely in childhood. We sent a questionnaire to UK dermatologists and plastic surgeons to investigate current management practice of NS. We found that almost a third of dermatologists still recommend excision for malignancy prevention, while over 90% of plastic surgeons consider excision, with 64% citing malignancy prevention as the reason. Plastic surgeons most commonly recommended excision in childhood, whereas dermatologists waited until adulthood. We have shown there is significant variation in practice across the UK in the management of naevus NS. It is important that patients across the UK receive the same standard of care, and therefore we advocate the development of evidence-based guidance for treatment of naevus NS.

Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing.

We performed whole genome sequencing (WGS) in nine families from India with early-onset hereditary spastic paraplegia (HSP). We obtained a genetic diagnosis in 4/9 (44 %) families within known HSP genes (DDHD2 and CYP2U1), as well as perixosomal biogenesis disorders (PEX16) and GM1 gangliosidosis (GLB1). In the remaining patients, no candidate structural variants, copy number variants or predicted splice variants affecting an extended candidate gene list were identified. Our findings demonstrate the efficacy of using WGS for diagnosing early-onset HSP, particularly in consanguineous families (4/6 diagnosed), highlighting that two of the diagnoses would not have been made using a targeted approach.

Operative management of displaced acetabular fractures: an institutional experience with a midterm follow-up.

BACKGROUND: Operative management is considered to be the treatment of choice in acetabular fractures as this is the unique way of achieving precise anatomical reduction, stable internal fixation, and early mobilization of joint. With this background in mind we undertook a prospective study with an aim to assess the outcome of surgery in displaced acetabular fractures at our general orthopedic centre as a first experience. MATERIAL AND METHODS: This study was conducted on 59 patients (45 Males, 14 Females ) with mean age of 38.35 years (range 18-60 years) with displaced acetabular fractures who were admitted consecutively at our centre from May 2008 through November 2011. Nine patients (7 Male, 2 Female) were lost during follow up. The average follow up was 3.5 years (range 2-5 years). Prophylaxis for deep venous thrombosis and heterotopic ossification was used routinely in all patients. RESULTS: Clinical evaluation was based on modified Merle-d'Aubigne and Postel scoring system. Radiological evaluation was done according to criteria developed by Matta. It was graded as excellent in 16% hips, good in 54% hips, fair in 20% hips and poor in 10% hips. Good to excellent results were achieved in 42 cases (70%). The complications included were implant backout, postoperative dislocation, iatrogenic nerve palsy, superficial wound infection, intraoperative bleeding and osteoarthritis. There is a positive relationship between quality of reduction and functional outcome. In our series, radiographic congruity (75%) correlated well with the function (70%). CONCLUSIONS: 1. We conclude that operative treatment is a safe and effective method of managing displaced acetabular fractures even in general orthopedic centres. 2. Time spent on a thorough study of the radiographs/CT scan for a proper preoperative plan is worthwhile and helps to outline an appropriate surgical approach and avoid complications.

Molecular analysis of α-synuclein gene in Parkinson's disease in North Karnataka, India.

BACKGROUND: Parkinson's disease (PD) is a disabling neurological disorder characterized by progressive degeneration of dopaminergic neurons. Mutations analysis within the α-synuclein gene (SNCA) on chromosome 4 has been reported in the last decade. OBJECTIVE: To elucidate the possible role of SNCA gene in the pathogenesis of PD in Indian population specifically in north Karnataka. MATERIALS AND METHODS: The study subjects included 100 clinically diagnosed PD patients and 100 ethnically matched healthy controls. Isolated deoxyribonucleic acid (DNA) samples from both were subjected to exon-specific polymerase chain reaction (PCR) amplification and amplicons were subjected to capillary-based direct DNA sequencing. RESULT: No mutations were observed in SNCA gene of PD samples in comparison with control samples. CONCLUSION: These findings support the hypothesis that the SNCA gene mutations might be population specific and may not be playing role in causing PD in all the populations.

Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin.

BACKGROUND: Catheter ablation is an effective treatment for symptomatic individuals with atrial fibrillation (AF) but is associated with a risk of periprocedual stroke. Recent data suggest that this risk may be abolished if catheter ablation is performed with uninterrupted warfarin (UW). We sought to compare the incidence, severity and timing of periprocedural stroke between 2 periprocedural anticoagulation protocols: bridging low-molecular-weight heparin (LMWH) and UW. METHODS AND RESULTS: Periprocedural stroke (≤14 days) was assessed in 2,855 ablations performed in 1,813 patients. Thromboembolic stroke occurred in 11/1,653 (0.7%) procedures with bridging LMWH and in 5/1,202 (0.4%) procedures on UW (P = 0.5). Four of the 5 strokes (80%) on UW occurred despite a therapeutic INR and a mean activated clotting time of ≥300 seconds and 4/5 strokes (80%) occurred in patients with a CHADS2 score of 0. Eleven of 16 (69%) strokes overall occurred within 24 hours of the procedure. All 4 strokes resulting in major neurological deficit occurred in the LMWH group. Major bleeding complications occurred in 6.0% of patients in the bridging LMWH group compared to 4.0% in the UW group (P = 0.02). CONCLUSIONS: In contrast to existing data, periprocedural stroke still occurs despite therapeutic anticoagulation throughout the operative period. The optimal strategy to protect patients against thromboembolic stroke remains unclear.

Midterm functional outcome after operative management of midfoot injuries.

Background. Injuries of the midfoot are often missed and therefore underestimated. Early diagnosis and treatment are crucial for the final outcome. The primary aim of this study was to assess the pattern and results of early operative management of mid-foot injuries after a midterm follow up. Material and methods. This study was conducted on 25 patients (19 Males, 6 Females ) with mean age of 34.6 years (range 18-60 years) with mid-foot fracture dislocations who were admitted consecutively at our centre from May 2008 through November 2010. 25 patients fulfilling our inclusion criteria with mid-foot fracture dislocations were included in this study. Mechanism of injury, its pattern and results of operative management of midfoot injuries were assessed after acute management of these fractures on urgent basis. Evaluation of results was done by AOFAS Score. Results. Most common mode of injury was indirect trauma due to fall (n=12) followed by road traffic accident (n=9). Males (n=19) outnumbered females (n=6). The pattern of injuries requiring operative treatment as per our criteria were Lisfranc fracture dislocations (n=22) and navicular fractures (n=3). The mean follow up was 3.2 years and mean AOFAS score at 3.2 years was 78.36, with most patients losing points to pain and decreased recreational function. Conclusion. The Lisfranc fracture dislocations are the most common injuries around midfoot requiring operative treatment, and we believe that operative treatment considerably improves functional outcome in these injuries.

Varix of the retromandibular vein within the parotid gland: case study.

OBJECTIVE: To report a case of varix of the retromandibular vein within the parotid gland. METHODS: Case report, and discussion of the appropriate selection and use of radiological investigation techniques. RESULTS: A 64-year-old lady who presented with unilateral tinnitus underwent a magnetic resonance imaging scan to exclude a vestibular schwannoma. The magnetic resonance scout images revealed an incidental finding of a hyperechoic mass within the parotid gland. The mass was most consistent with a pleomorphic adenoma. Ultrasound-guided fine needle aspiration cytology was arranged; the ultrasound identified the mass as a varix of the retromandibular vein and fine needle aspiration cytology was not performed. CONCLUSION: A varix of the retromandibular vein is a very rare cause of a parotid mass. Appropriate radiological investigations can prevent unnecessary invasive investigations or procedures.

PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.

OBJECTIVE: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). METHODS: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. RESULTS: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. CONCLUSIONS: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Mutation analysis of the sodium/hydrogen exchanger gene (NHE5) in familial paroxysmal kinesigenic dyskinesia.

Familial Paroxysmal Kinesigenic Dyskinesia (PKD) is an autosomal dominant condition characterized by attacks of dystonia or chorea triggered by sudden movements. Recently two separate loci for PKD, Episodic Kinesigenic Dyskinesia 1 (EKD1) and Episodic Kinesigenic Dyskinesia 2 (EKD2), have been mapped to chromosome 16 but the causative genes have not been identified. The Na(+)/H(+) exchanger gene (NHE5) involved in regulating intracellular pH lies in the EKD2 region. The coding region of the NHE5 gene in familial PKD was sequenced. We did not identify any mutations in the exons, intron/exon boundaries or the 5' and 3'UTR. This excludes mutations in the coding region of the NHE5 gene as a cause for familial PKD, but does not rule out a possible role of sequence variants in introns or regulatory regions.