Congenital Myasthenic Syndromes with COLQ mutations: Long term follow-up

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagenlike tail subunit gene (ColQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We report the time course of clinical manifestations in 15 COLQ-mutated patients followed from 1987 to 2010. All patients suffered from a muscle weakness with onset at birth or in childhood. Ocular and bulbar signs were found in 60% of the patients and delayed pupillary light response in 20% of our patients. EMG study demonstrated a decrement on repetitive nerve stimulation and repetitive compound muscle action potential in all patients. Clinical symptoms strongly fluctuated daily, weekly, monthly or even yearly. Severe relapses were characterized by a general motor weakness associated with pain which resolved spontaneously after a few months whereas the relapses with these symptoms and bulbar signs could last up to several years. Genetic analyses identified 16 different mutations including 9 novel ones. There was no genotype-phenotype correlation. Our study confirms the predominance of oculobulbar signs and the frequency of respiratory distress in COLQrelated CMS. At the end of the follow up of 23 years, interesting findings were (i) the spontaneous reversibility of severe relapses, some of them lasting for up to 5 years (ii) the good prognosis of COLQ-related CMS, since at the end of the follow-up 80% of patients were ambulant and 87% of patients had no respiratory trouble (iii) the efficacy of Ephedrine and, to a lesser extend, of 3-4 DAP. The triggering factors of relapses were esterase inhibitors, effort, puberty, pregnancy and delivery highlighting the importance of hormonal factors in CMS. In conclusion, patients diagnosed with unknown congenital myopathy should undergo an electrophysiological study of neuromuscular junction to identify ColQ-related CMS.

Axillary Lymph Node Dissection for Sentinel Lymph Node Micrometastases May Be Safely Omitted in Early-Stage Breast Cancer Patients: Long-Term Outcomes of a Prospective Study.

OBJECTIVES: To evaluate the long-term disease-free and overall survival of patients with sentinel lymph node (SLN) micrometastases, in whom a completion axillary lymph node dissection (ALND) was systematically omitted. BACKGROUND: The use of step sectioning and immunohistochemistry for SLN analysis results in a more accurate histopathologic examination and a higher detection rate of micrometastases. However, the clinical relevance and therapeutic implications of SLN micrometastases remain a matter of debate. METHODS: In this prospective study, 236 SLN biopsies were performed in 234 consecutive early-stage breast cancer patients (T1, T2 </= 3 cm, cN0 M0) between 1998 and 2002. The SLN were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry. None of the patients with negative SLN or SLN micrometastases (International Union Against Cancer classification, >.2 mm to </=2 mm) underwent a completion ALND or radiation to the axilla. Long-term overall and disease-free survivals were compared between patients with negative SLN and those with SLN micrometastases by log rank tests. RESULTS: The SLN was negative in 55% of patients (123 of 224). SLN micrometastases were detected in 27 patients (27 of 224, 12%). After a median follow-up of 77 months (range, 24-106 months), neither locoregional recurrences nor distant metastases occurred in any of the 27 patients with SLN micrometastases. There were no statistically significant differences for overall (P = .656), locoregional (P = .174), and axillary and distant disease-free survival (P = .15) between patients with negative SLN and SLN micrometastases. CONCLUSIONS: This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early-stage breast cancer patients with SLN micrometastases.

Partial cricotracheal resection for pediatric subglottic stenosis: long-term outcome in 57 patients.

OBJECTIVE: We sought to assess the long-term outcome of 57 pediatric patients who underwent partial cricotracheal resection for subglottic stenosis. METHODS: Eighty-one pediatric partial cricotracheal resections were performed in our tertiary care institution between 1978 and 2004. Fifty-seven patients had a minimal follow-up time of 1 year and were included in this study. Evaluation was based on the last laryngotracheal endoscopy, the responses to a questionnaire, and a retrospective review of the patient's data. The following parameters were analyzed: decannulation rates, breathing, voice quality, and deglutition. RESULTS: A single-stage partial cricotracheal resection was performed in 38 patients, and a double-stage procedure was performed in 19 patients. Sixteen patients underwent an extended partial cricotracheal resection (ie, partial cricotracheal resection combined with another open procedure). At a median follow-up time of 5.1 years, the decannulation rates after a single- or double-stage procedure were 97.4% and 95%, respectively. Two patients remained tracheotomy dependent. One patient had moderate exertional dyspnea, and all other patients had no exertional dyspnea. Voice quality was found to improve after surgical intervention for 1 +/- 1.34 grade dysphonia (P < .0001) according to the adapted GRBAS grading system (Grade, Roughness, Breathiness, Asthenia, and Strain). CONCLUSIONS: Partial cricotracheal resection provides good results for grades III and IV subglottic stenosis as primary or salvage operations. The procedure has no deleterious effects on laryngeal growth and function. The quality of voice significantly improves after surgical intervention but largely depends on the preoperative condition.

A Framework for Quality in Long-Term Residential Care for Older People in Ireland

The National Council on Ageing and Older People has long been concerned about the quality of long-term residential care for older people in Ireland. In 1986, its predecessor, the National Council for the Aged published “It’s Our Home”. The Quality of Life in Private and Voluntary Nursing Homes. In 1999 the Council commissioned a postal survey of all long-term residential care facilities in the country to determine whether facilities had quality initiatives in operation; providers’ views and aspirations for future provision of long-term care; providers’ views on the introduction of a national quality monitoring policy Download the Report here

Long-term azithromycin therapy in patients with severe chronic obstructive pulmonary disease and repeated pulmonary exacerbations

L’objectiu es determinar si el tractament amb azitromicina a llarg termini redueix la freqüència d’exacerbacions respiratòries en pacients amb malaltia pulmonar obstructiva crònica (MPOC) greu. Estudi retrospectiu observacional que avalua els beneficis clínics del tractament amb azitromicina a llarg termini (500 mg per via oral tres vegades per setmana) durant 12 mesos en pacients amb MPOC greu amb un mínim de 4 exacerbacions agudes (EAMPOC) per any o colonitzats per Pseudomonas aeruginosa. Es comparen amb els 12 mesos previs a l’introducció de l’azitromicina: nombre de EAMPOC, hospitalitzacions i dies d'estada hospitalària. L’azitromicina a llarg termini s’associa a una reducció significativa de EAMPOC, hospitalitzacions i dies d’estada hospitalària en pacients amb EPOC greu independentment de la colonització basal.

New insights into the long-term evolutionary history of the avian MHC

SummaryGene duplication and neofunctidnalization are important processes in the evolution of phenotypic complexity. They account for important evolutionary novelties that confer ecological adaptation, such as the major histocompatibility complex (MHC), a multigene family with a central role in vertebrates' adaptive immune system. Multigene families, which evolved in large part through duplication, represent promising systems to study the still strongly depbated relative roles of neutral and adaptive processes in the evolution of phenotypic complexity. Detailed knowledge on ecological function and a well-characterized evolutionary history place the mammals' MHC amongst ideal study systems. However mammalian MHCs usually encompass several million base pairs and hold a large number of functional and non-functional duplicate genes, which makes their study complex. Avian MHCs on the other hand are usually way more compact, but the reconstruction of. their evolutionary history has proven notoriously difficult. However, no focused attempt has been undertaken so far to study the avian MHC evolutionary history in a broad phylogenetic context and using adequate gene regions.In the present PhD, we were able to make important contributions to the understanding of the long-term evolution of the avian MHC class II Β (MHCI1B). First, we isolated and characterized MHCIIB genes in barn owl (Tyto alba?, Strigiformes, Tytonidae), a species from an avian lineage in which MHC has not been studied so far. Our results revealed that with only two functional MHCIIB genes the MHC organization of barn owl may be similar to the 'minimal essential' MHC of chicken (Gallus gallus), indicating that simple MHC organization may be ancestral to birds. Taking advantage of the sequence information from barn owl, we studied the evolution of MHCIIB genes in 13 additional species of 'typical' owls (Strigiformes, Strigidae). Phylogenetic analyses revealed that according to their function, in owls the peptide-binding region (PBR) encoding exon 2 and the non-PBR encoding exon 3 evolve by different patterns. Exon 2 exhibited an evolutionary history of positive selection and recombination, while exon 3 traced duplication history and revealed two paralogs evolving divergently from each other in owls, and in a shorebird, the great snipe {Gallinago media). The results from exon 3 were the first ever from birds to demonstrate gene orthology in species that diverged tens of millions of years ago, and strongly questioned whether the taxa studied before provided an adequate picture of avian MHC evolution. In a follow-up study, we aimed at explaining a striking pattern revealed by phylogenetic trees analyzing the owl sequences along with MHCIIB sequences from other birds: One owl paralog (termed DAB1) grouped with sequences of passerines and falcons, while the other (DAB2) grouped with wildfowl, penguins and birds of prey. This could be explained by either a duplication event preceding the evolution of these bird orders, or by convergent evolution of similar sequences in a number of orders. With extensive phylogenetic analyses we were able to show, that indeed a duplication event preceeded the major avian radiation -100 my ago, and that following this duplication, the paralogs evolved under positive selection. Furthermore, we showed that the divergently evolving amino acid residues in the MHCIIB-encoded β-chain potentially interact with the MHCI I α-chain, and that molecular coevolution of the interacting residues may have been involved in the divergent evolution of the MHCIIB paralogs.The findings of this PhD are of particular interest to the understanding of the evolutionary history of the avian MHC and, by providing essential information on long-term gene history in the avian MHC, open promising perspectives for advances in the understanding of the evolution of multigene families in general, and for avian MHC organization in particular. Amongst others I discuss the importance of including protein structure in the phylogenetic study of multigene families, and the roles of ecological versus molecular selection pressures. I conclude by providing a population genomic perspective on avian MHC, which may serve as a basis for future research to investigate the relative roles of neutral processes involving effective population size effects and of adaptation in the evolution of avian MHC diversity and organization.RésuméLa duplication de gènes et leur néo-fonctionnalisation sont des processus importants dans l'évolution de la complexité phénotypique. Ils sont impliqués dans l'apparition d'importantes nouveautés évolutives favorisant l'adaptation écologique, comme c'est le cas pour le complexe majeur d'histocompatibilité long-terme du CMH aviaire classe II Β (CMH II Β). Nous avons isolé et caractérisé les gènes CMH I IB de la chouette effraie (Tyto alba; Strigiformes, Tytonidae), une espèce appartenant à une lignée aviaire dont le CMH n'avait pas été étudié jusqu'ici. Avec uniquement deux gènes CMHIIB fonctionnels, l'organisation CMH de la chouette effraie semble être comparable à celle "minimale" du poulet (Gallus gallus), ce qui suggère qu'une organisation simple du CMH pourrait être ancestrale chez les oiseaux. En se basant sur l'information obtenue pour cette espèce, nous avons ensuite étudié l'évolution des gènes CMHIIB chez 13 espèces de chouettes "typiques" (Strigiformes, Strigidae). Les analyses phylogénétiques ont révélé que chez les chouettes, selon leur fonction, l'exon 2 codant pour la 'peptide-binding region' (PBR) et l'exon 3 ne codant pas pour la région PBR évoluent de manière distincte. L'exon 2 montre une histoire évolutive de sélection positive et recombinaison, tandis que l'exon 3 retrace l'histoire de duplication et révèle deux paralogues évoluant de façon divergente chez les chouettes, ainsi que chez un limicole, la bécassine double (Gallinago media). Les résultats découlant de l'analyse de l'exon 3 ont montré pour la première fois chez les oiseaux une orthologie de gènes chez des espèces ayant divergé il y a des dizaines de millions d'années. Dans une deuxième étude, nous avons voulu expliquer le pattern surprenant révélé par les arbres phylogénétiques lorsque les séquences CMHIIB des chouettes sont analysées avec les séquences d'autres oiseaux: un paralogue de chouette (appelé DABI) forme un groupe avec les séquences de passereaux et faucons, tandis que l'autre (DAB2) se regroupe avec les gallo-ansériformes, les manchots et les rapaces diurnes. Ceci pourrait être expliqué soit par une duplication qui a précédé l'évolution de ces ordres aviaires soit par évolution convergente dans un certain nombre d'ordres. Grâce à des analyses phylogénétiques approfondies, nous avons pu montrer qu'un événement de duplication a effectivement précédé la radiation aviaire principale d'il y a environ 100 millions d'années, et qu'après cette duplication les paralogues ont évolué sous sélection positive. De plus, les résidus d'acides aminés évoluant de façon divergente dans la chaîne β codée par le CMHIIB interagissent potentiellement avec la chaîne α codée par le CMHII, et que la coévolution moléculaire de ces résidus pourrait être à la base de l'évolution divergente des paralogues CMHIIB.Dans cette thèse sont discutés entre autres l'importance d'inclure la structure des protéines dans l'étude phylogénétique des familles multigéniques, ainsi que les rôles respectifs des pressions sélectives écologique et moléculaire. La conclusion comporte une perspective sur la génomique des populations du CMH aviaire, qui pourrait servir de base pour de futures recherches sur les rôles relatifs joués par Îes processus neutres comprenant les effets de la taille efficace des populations et l'adaptation dans l'évolution de la diversité et l'organisation du MHC aviaire.

Report of the Interdepartmental Working Group on Long Term Care, 2006

Report of the Interdepartmental Working Group on Long Term Care, 2006 This report was finalised by the working group at the end of 2005 and submitted to Government in January 2006. While the reportâ?Ts proposals were not formally endorsed by Government, its analysis and recommendations have informed subsequent decisions, including the Fair Deal policy on Long-Term Nursing Home Care.The principles underpinning the report formed the basis for discussions about long term care with the Social Partners prior to the new national programme negotiations leading to a clear vision articulated in Towards 2016 on a number of priority actions to support older people to participate in society in a full and meaningful way. Click here to download PDF 693kb

Improving care for people with long term conditions: 'at a glance' information sheets for healthcare professionals

The Department has produced a series of information sheets for doctors,nurses, those delivering personal health budgets, allied health professionals, health trainers and anyone supporting individuals with long term conditions. The information sheets cover a range of topics including care planning, care co-ordination, managing need and assessment of risk, motivating people to self care, goal setting and action planning and end of life care.Download information sheet 1: Personalised care planning (PDF, 2514K)Download information sheet 2: Personalised care planning diagram (PDF, 2213K)Download information sheet 3: Care co-ordination (PDF, 1967K.

Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.

PURPOSE: We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. PATIENTS AND METHODS: Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). RESULTS: At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. CONCLUSION: An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.

Long-term transcutaneous monitoring of oxygen tension and carbon dioxide at 42 degrees C in critically ill neonates: improved performance of the tcpo2 monitor with topical metabolic inhibition.

Whereas during the last few years handling of the transcutaneous PO2 (tcPO2) and PCO2 (tcPCO2) sensor has been simplified, the high electrode temperature and the short application time remain major drawbacks. In order to determine whether the application of a topical metabolic inhibitor allows reliable measurement at a sensor temperature of 42 degrees C for a period of up to 12 h, we performed a prospective, open, nonrandomized study in a sequential sample of 20 critically ill neonates. A total of 120 comparisons (six repeated measurements per patient) between arterial and transcutaneous values were obtained. Transcutaneous values were measured with a control sensor at 44 degrees C (conventional contact medium, average application time 3 h) and a test sensor at 42 degrees C (Eugenol solution, average application time 8 h). Comparison of tcPO2 and PaO2 at 42 degrees C (Eugenol solution) showed a mean difference of +0.16 kPa (range +1.60 to -2.00 kPa), limits of agreement +1.88 and -1.56 kPa. Comparison of tcPO2 and PaO2 at 44 degrees C (control sensor) revealed a mean difference of +0.02 kPa (range +2.60 to -1.90 kPa), limits of agreement +2.12 and -2.08 kPa. Comparison of tcPCO2 and PaCO2 at 42 degrees C (Eugenol solution) showed a mean difference of +0.91 (range +2.30 to +0.10 kPa), limits of agreement +2.24 and -0.42 kPa. Comparison of tcPCO2 and PaCO2 at 44 degrees C (control sensor) revealed a mean difference of +0.63 kPa (range 1.50 to -0.30 kPa), limits of agreement +1.73 and -0.47 kPa. CONCLUSION: Our results show that the use of an Eugenol solution allows reliable measurement of tcPO2 at a heating temperature of 42 degrees C; the application time can be prolongued up to a maximum of 12 h without aggravating the skin lesions. The performance of the tcPCO2 monitor was slightly worse at 42 degrees C than at 44 degrees C suggesting that for the Eugenol solution the metabolic offset should be corrected.

Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis.

BACKGROUND: Anti-TNFα agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. METHODS: We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFα agents. Appropriateness of the first-line anti-TNFα treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. RESULTS: Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. CONCLUSION: Appropriateness of first-line anti-TNFα therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFα agents.

An evaluation of the inappropriate prescribing in older residents in long term care facilities in the greater Cork and Northern Ireland regions using the STOPP and Beers' criteria.

This work has highlighted a number of areas of prescribing concern, for example, the long term use of both benzodiazepines and hypnotics, in older residents residing in long term care facilities. Each of these individual areas should be further investigated to determine the underlying reason(s) for the prescribing concerns in these areas and strategic methods of addressing and preventing further issues should be developed on a national level.This resource was contributed by The National Documentation Centre on Drug Use.

A framework for quality in long-term residential care for older people in Ireland / National Council on Ageing and Older People

In 1999 the National Council on Ageing and Older People commissioned a postal survey of all long-term residential care facilities in the country to determie: - whether facilities had quality initiatives in operation - providers' views and aspirations for future provision of long-term care - providers' views on the introduction of a national quality monitoring policy This report is the outcome of the programme of work conducted by the Council on the quality of long-term residential care provision for older people in Ireland. The aim of the report is to provide a framework for developing quality in long-term residential care settings with a focus on the well-being, dignity and autonomy of older residents.