ATP1A3 related disease manifesting as rapid onset dystonia-parkinsonism with prominent myoclonus and exaggerated startle.

We report ATP1A3-associated rapid-onset dystonia-parkinsonism with an atypical presentation including myoclonus and exaggerated startle in four patients. Their prominence over parkinsonism prompted consideration of a syndromic diagnosis of myoclonus dystonia. ATP1α3 dysfunction in GABAergic neurons could explain these examination findings. The spectrum of ATP1A3-associated movement disorders includes myoclonus-dystonia.

The Impact of the New State Body for Transplantation on Lung Transplantation Waiting List Mortality.

Introduction Organ Donation Transplant Ireland (ODTI) was established in 2014 to provide leadership and governance of the transplant programme in Ireland. We aim to establish if the implementation of ODTI translates into a decrease in waiting list mortality. Methods A retrospective analysis of all patients listed for lung transplantation on the Irish Heart and Lung Transplant Programme, between January 2011 and December 2016, was performed. We compared mortality on the waiting list before and after the establishment of ODTI. Results During the study period, a total of 259 patients were on the lung transplant list. Sixty percent of patients underwent lung transplantation. Following establishment of ODTI, there was a statistically significant reduction of waiting list mortality from 46% in the era prior to ODTI to 33% after ODTI formation (p=0.02). Conclusion This study demonstrates the establishment of the governing body ODTI reduced mortality on the lung transplant waiting list.

Giant desmoid tumour of the thorax following latissimus dorsi and implant breast reconstruction: case report and review of the literature.

The case of a giant thoracic desmoid tumour in a 44-year-old woman, who presented two years following a breast reconstruction with a latissimus dorsi (LD) flap and implant, is reported. Clinical findings included a rapidly growing, painless mass. Computed tomography (CT) suggested skin and intercostal soft tissue invasion. The tumour was resected en bloc with the LD muscle, implant capsule and underlying rib segments. The resultant thoracic and abdominal wall defects were reconstructed with Dualmesh® and polypropylene meshes respectively. There was no evidence of recurrence at thirty-six months follow-up.

Renal transplantation outcomes following heart and heart-lung transplantation.

BACKGROUND: Chronic kidney disease is a frequent complication following heart and combined heart-lung transplantation. The aim of this study was to analyse the outcome of a subsequent renal transplant in heart, lung and heart-lung transplantation recipients. METHODS: All heart, lung and heart-lung transplant recipients who received a subsequent renal transplant over a 27-year period in a national heart and lung transplant centre were included in this study. RESULTS: A total of 18 patients who had previously undergone heart (n = 6), lung (n = 7) and heart-lung (n = 5) transplantation received a renal transplant. The mean duration to development of end-stage kidney disease (ESKD) was 115 ± 45.9 months. The most common contributor to ESKD was calcineurin inhibitor nephrotoxicity. The 5-year patient survival and graft survival rates were 91.7 and 85.6%, respectively. The median creatinine level at the most recent follow-up was 123 µmol/L, IQR 90.8-147.5. CONCLUSIONS: The overall outcome of renal transplantation following previous non-renal solid organ transplantation is excellent considering the medical complexity and co-morbidities of this patient population. Renal transplantation represents an important treatment option for ESKD in non-renal solid organ transplant recipients.

Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland.

BACKGROUND: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder. AIM: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland. METHODS: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed. RESULTS: On the prevalence date there were 592 individuals in Ireland with adult onset idiopathic isolated focal dystonia, a point prevalence of 17.8 per 100 000 (95% confidence interval 16.4-19.2). Phenotype numbers were cervical dystonia 410 (69.2%), blepharospasm 102 (17.2%), focal hand dystonia 39 (6.6%), spasmodic dysphonia 18 (3.0%), musician's dystonia 17 (2.9%) and oromandibular dystonia six (1.0%). Sixty-two (16.5%) of 375 consenting index cases had a relative with clinically confirmed adult onset idiopathic isolated focal dystonia (18 multiplex and 24 duplex families). Marked variations in the proportions of patients with tremor, segmental spread, sensory tricks, pain and psychiatric symptoms by phenotype were documented. CONCLUSIONS: The prevalence of adult onset idiopathic isolated focal dystonia in Ireland is higher than that recorded in many similar service-based epidemiological studies but is still likely to be an underestimate. The low proportion of individuals with blepharospasm may reflect reduced environmental exposure to sunlight in Ireland. This study will serve as a resource for international comparative studies of environmental and genetic factors in the pathogenesis of the disorder.

First bilateral lobar lung transplant in Ireland: advanced operative strategies in lung transplantation.

Lobar lung transplantation is an option that provides the possibility of transplantation of small size recipients with size-mismatch donor lungs by surgically reducing the size of donor lungs. We report our first experience of bilateral lobar lung transplantation of big donor lungs, in a small size urgently listed recipient, after size reduction. A 24 years old girl with end stage cystic fibrosis received the bilateral lobar lung transplant. She made very good recovery postoperatively and was discharged home two weeks following surgery.

A film of patients with movement disorders made in Queen Square, London in the Mid-1920s by Samuel Alexander Kinnier Wilson.

BACKGROUND: Through Edward Reynolds' collaboration with Samuel Alexander Kinnier Wilson's (SAKW) son, James, on Babylonian neurology and psychiatry, and his contact with James' nephew, Jim, grandson of SAKW, a remarkable film of patients with movement disorders, made by SAKW in the mid-1920s, has come to light. METHODS/RESULTS: The 20-min silent film with captions by SAKW includes patients with senile tremor, Parkinson's disease and postencephalitic parkinsonism, hemiballismus, Huntington's chorea, Sydenham's chorea, hysterical palsy and tremor, multiple sclerosis, and progressive lenticular degeneration. Most of the patients are filmed in the square outside the National Hospital. The British Film Institute dates the film to 1924 and the captions to 1925. The case records of 6 of the 14 patients, who were admitted to the National Hospital, Queen Square, under the care of Dr. SAKW have been identified and summarized. DISCUSSION: SAKW may have been stimulated and facilitated to make this film through his personal contact with Charlie Chaplin with whom he stayed at his Californian estate, probably in the summer of 1924. The first films of neurological patients were made in Europe and USA at the beginning of the 20th century, although most have perished. This may be one of the oldest examples from UK. It is also notable for the inclusion of Wilson's disease and a brief shot of SAKW himself.

Neutrophil immunosurveillance for heart transplant rejection: a prospective study.

Immunologic surveillance for rejection detection in human heart transplantation offers many potential advantages. To date, investigative efforts have focused primarily on the acquired immune system, particularly the lymphocyte. Little attention has been given to aspects of innate immune function. We have previously reported that perioperative neutrophil adhesion molecule expression is associated with early rejection episodes after human cardiac transplantation. Herein we have investigated the utility of neutrophil immunosurveillance in human heart transplant recipients at later time points. We recruited patients more than 3 months after transplantation. Neutrophil assessment was performed simultaneously with an endomyocardial biopsy that showed rejection. No significant relationship was seen between neutrophil maturity (P = .622; n = 34), adhesion marker expression (P = .567; n = 34), respiratory burst (P = .604; n = 34), or apoptosis rates (P = .662; n = 34) and contemporary rejection status at >3 months after transplantation. However, interesting relationships were noted between neutrophil adhesion markers at this late stage and historical rejection status. Higher levels of the adhesion protein CD11b observed at this late stage were significantly associated with a history of higher rejection grades in the first postoperative biopsy (Spearman rank coefficient 0.359; R = 0.304; P = .005; n = 62). Other aspects of neutrophil function and persistence were not significantly associated with rejection history. This finding, combined with the previously reported findings, supports a role for an individual phenotype in neutrophil function in early rejection episodes after transplantation.

Transplantation, multi-organ donation & presumed consent: a 3 year survey of university students.

We profile the practises and attitudes of university students in Ireland towards consent for organ donation. 1103 students were surveyed. Only 34.6% (382/1103) carried organ donor consent cards, although the majority were favourably disposed towards donation. Only 9% (96/1103) were against donation. In regard to presumed consent only 38% (177/470) were in favour of changing the current "opt-in" consent methodology to presumed consent. These findings show a favourable opinion towards donation among Irish university students. However this may result in few actual donations in the event of brain death, as the majority do not carry donor cards and do not want to change to a presumed consent regime. The most common answer for not carrying a card was that the individual had not formalised a decision. Mandated choice at a fixed point could significantly reduce this ambivalence.

Characterisation of a novel NR4A2 mutation in Parkinson's disease brain.

OBJECTIVE: We performed a mutation screen of NR4A2 (also known as NURR1) in 409 Parkinson's disease (PD) patients. We identified a novel single base substitution in the 5'UTR of the NR4A2 (also known as NURR1) gene (c.-309C>T). RESULTS: We have performed expression studies in neuronal cell lines showing that the c.-309C>T mutation reduces NR4A2 mRNA expression in vitro. We have confirmed this finding in vivo by performing allele specific real-time PCR from brain tissue harbouring the 309C>T mutation and show a 3.48+/-1.62 fold reduction in mRNA expression of the mutant allele compared to wild-type. In addition we have undertaken genome wide expression analysis of the mutant NR4A2 brain and shown underexpressed genes were significantly enriched for gene ontology categories in nervous system development and synaptic transmission and overexpressed genes were enriched for unfolded protein response and morphogenesis. Lastly we have shown that the c.-309C>T mutation abrogates the protective effect of wild-type NR4A2 against apoptopic stress. CONCLUSIONS: Our findings indicate the c.-309C>T mutation reduces NR4A2 expression resulting in the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission. These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation.

Test for LRRK2 mutations in patients with Parkinson's disease.

LRRK2-associated Parkinson's disease is common enough to raise clinical questions such as which patients should be tested and what advice should be given. We discuss practical issues in the light of our experiences with real life Parkinson's disease patients. Neurologists should consider testing LRRK2 in Parkinson's disease patients with affected first degree relatives where the onset is over the age of 40 years. A common G2019S mutation makes genetic testing straightforward and cost-effective. Age-related or reduced genetic penetrance means that LRRK2 mutations are also found in sporadic Parkinson's disease patients; however, at present, there is little to support the widespread testing of these patients except in high-risk ethnic groups such as North African Arabs and Ashkenazi Jews. Incomplete penetrance also complicates presymptomatic testing, which is best undertaken in the context of appropriate genetic counselling.

Multiple mitochondrial DNA deletions in monozygotic twins with OPMD.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is caused by expansions of the poly (A) binding protein 2 (PABP2) gene. Previous histological analyses have revealed mitochondrial abnormalities in the muscles of OPMD patients but their significance remains uncertain. OBJECTIVE: We had the rare opportunity to study monozygotic twins with identical expansions of the PABP2 gene but with markedly different severities of OPMD. Both had histological features of mitochondrial myopathy. We determined whether mitochondrial DNA abnormalities underlay these changes. METHODS: Clinical information was obtained by history and examination. Muscle biopsies were obtained from each subject and genetic analysis was performed using long-range PCR and Southern blotting. RESULTS: We demonstrate, for the first time, the presence of mitochondrial DNA (mtDNA) deletions by Southern blotting in individuals with OPMD. This correlates with the presence of mitochondrial myopathy in both twins. Moreover, both twins had different mtDNA deletions, which might explain their phenotypic differences. CONCLUSION: We hypothesise that mitochondrial dysfunction may occur as a consequence of PABP2 gene mutations, and that this dysfunction may affect the phenotypic manifestations of OPMD.

Differential white cell count relationships with human cardiac allograft rejection.

The focus of research in allograft rejection has targeted the lymphocyte, with little attention given to the neutrophil. Recent data indicate that a perioperative neutrophil influx into the cardiac allograft influences early rejection. Factors that influence neutrophil transendothelial migration might offer predictive markers of rejection. We explored the relationship between the number of circulating neutrophils in heart transplant recipients and the development of rejection. Differential white cell counts were obtained prior to transplantation and concurrently with subsequent endomyocardial rejection surveillance biopsies for 53 heart transplant recipients undergoing 410 biopsies. Preoperative differential white cell counts had no relationship with rejection. In the first 3 months after transplantation, no relationship was found between contemporary differential white cell counts and rejection. However, more than 3 months following surgery, rejection grade positively correlated on univariate analysis with neutrophil counts and the usage of cyclosporine, prednisolone, and mycophenolate. There was no relationship with eosinophils or lymphocytes. Multivariate analysis demonstrated a persistent relationship among rejection severity, neutrophil count, and prednisolone usage. A significant positive association of higher steroid usage with higher rejection grades must reflect efforts to treat patients with rejection. The significant association of higher neutrophil counts with higher rejection severity might suggest a pathological contribution to rejection. However, given the neutrophilia response to acute steroid administration, we must conclude that the neutrophil association was related to steroid administration. The absence of a relationship between white cell counts and rejection suggests that functional rather than antiproliferative strategies may offer the greatest therapeutic potential.

A step towards being EWTD compliant: a single institution study of the cardiothoracic surgery experience.

The introduction of the European Working Time Directive has led to intensive debate regarding the working conditions, training and service delivery of Non Consultant Hospital Doctors. Surgical specialties are especially affected by the directive as they have always been associated with long working hours. These have been defended on the basis that these were required to achieve surgical competence. This study aims to survey the working hours and examine the activity of cardiothoracic surgery trainees, who traditionally worked long hours, in a single institution. Arising from the survey results, a novel working model is proposed.

PINK1 protein in normal human brain and Parkinson's disease.

Parkinson's disease is a common incurable neurodegenerative disease whose molecular aetiology remains unclear. The identification of Mendelian genes causing rare familial forms of Parkinson's disease has revealed novel proteins and pathways that are likely to be relevant in the pathogenesis of sporadic Parkinson's disease. Recently, mutations in a novel gene, PINK1, encoding a 581 amino acid protein with both mitochondrial targeting and serine/threonine kinase domains, were identified as a cause of autosomal recessive parkinsonism. This provided important evidence for the role of the mitochondrial dysfunction and kinase pathways in neurodegeneration. In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. The possible role of the PINK1 protein was also assessed in a number of neurodegenerative diseases characterized by proteinaceous inclusions. For these studies, rabbit polyclonal antibodies were raised against two peptide sequences within the N-terminal hydrophilic loops of PINK1 protein. Using immunohistochemistry and western blotting we were able to demonstrate that PINK1 is a ubiquitous protein expressed throughout the human brain and it is found in all cell types showing a punctate cytoplasmic staining pattern consistent with mitochondrial localization. Fractionation studies of human and rat brain confirm that PINK1 is localized to the mitochondrial membranes. In addition, we show that PINK1 is detected in a proportion of Lewy bodies in cases of sporadic Parkinson's disease and Parkinson's disease associated with heterozygous mutations in the PINK1 gene, which are clinically and pathologically indistinguishable from the sporadic cases. PINK1 was absent in cortical Lewy bodies, in neurofibrillary tangles in Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, and in the glial and neuronal alpha-synuclein positive inclusions in multiple system atrophy. These studies provide for the first time in vivo morphological and biochemical evidence to support a mitochondrial localization of PINK1 and underpin the significance of mitochondrial dysfunction in the pathogenesis of nigral cell degeneration in Parkinson's disease.