Clinical and genetic factors involved in Porto-sinusoidal vascular disorder after oxaliplatin exposure.

BACKGROUND AND AIMS: Oxaliplatin (OX) has been described as a potential etiologic agent for porto-sinusoidal vascular disorder (PSVD). Our aim was to describe the natural history of PSVD due to OX in colon cancer (CRC) and identify risk factors for its development. METHODS: We made a multicenter retrospective case-control (ratio 1:3) study with patients diagnosed of PSVD-OX. Baseline data, end of treatment, years of follow-up and diagnosis of PSVD were collected and compared to controls (without PSVD). Besides, 16 different SNPs were selected from bibliography and analyzed by genotyping in the case group to identify potential genetic risk factors. RESULTS: 41 cases were identified, with a median time to PSVD diagnosis after the end of OX of 34 months. Spleen diameter was the strongest predictor of PSVD during treatment (OR 43.94 (14.48-133.336); p < 0.0001). Additionally, thrombocytopenia (<150 × 10^9) at one year was a significant disease risk marker (OR 9.35; 95% CI: 3.71-23.58; p = 0.001). We could not establish any significant association between the selected SNPs and PSVD diagnosis. CONCLUSION: The increase of spleen diameter is the strongest predictor of PSVD in patients treated with OX for CRC. These patients could be candidates for a specific follow-up of portal hypertension-related complications.

Caregiver knowledge of obstructive sleep apnoea in Down syndrome.

BACKGROUND: Down syndrome (DS) population has a very high prevalence of obstructive sleep apnoea (OSA), but this remains underdiagnosed. Hence, we aimed to evaluate caregiver's knowledge of OSA and related sociodemographic factors that could contribute to OSA screening patterns in this population. METHODS: An online survey though the LuMind IDSC Foundation focused on OSA diagnosis, treatments and the number of sleep studies performed. Data were compared between subjects born before and after the American Academy of Pediatrics (AAP) recommendations for OSA screening. RESULTS: Of the caregivers, 724 (parents 96.3%), responded to the survey. The median [interquartile (IQR)] age of the subjects with DS was 12 [20;7] years. The majority (84.3%) had sleep apnoea diagnosis, and half of them were initially referred for a sleep study due to disturbed sleep symptoms. Only 58.7% of the responders were aware of the AAP recommendations. This was linked to higher socioeconomic and/or educational level and to an earlier OSA diagnosis. The median (IQR) age of OSA diagnosis was lowered after the AAP guidelines publication compared with before its publication (3 [4;2] years vs. 10 [18;5] years, P < 0.000). Adenotonsillectomy (81.9%) and continuous positive airway pressure (61.5%) were the most commonly prescribed treatments. Few had discussed other new therapies such as hypoglossal nerve stimulation (16.0%). Only 16.0% of the subjects repeated the sleep study to monitor OSA with ageing, and 30.2% had to wait more than 4 years between studies. CONCLUSIONS: This study reinforces the need to improve OSA knowledge of caregivers and clinicians of individuals with DS to promote an earlier diagnosis and optimal treatment of OSA in this population.

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders.

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

Epidemiology and clinical course of hepatitis A in Cantabria before and after the epidemic outbreak of June 2016. / Epidemiología y curso clínico de la hepatitis A en Cantabria antes y después del brote epidémico de junio 2016.

BACKGROUND AND OBJECTIVES: Since June 2016, there have been outbreaks of hepatitis A in various European countries, mainly affecting men who have sex with men (MSM). The aim of this study was to assess their clinical and epidemiological impact in Cantabria, Spain. MATERIAL AND METHODS: We retrospectively collected all cases of hepatitis A diagnosed in Cantabria between January 2013 and September 2018. We compared 2 periods: January 2013-May 2016 and June 2016-September 2018. RESULTS: A total of 156 cases were diagnosed, observing an increase in the incidence starting in October 2016. With regard to 2013-2016, we observed a higher proportion of men (50.0% vs. 84.5%; p=.012) with a predominance of the homosexual orientation (80.6%) and a higher rate of sexual transmission (0% vs. 48.3%; p=.061) for the patients in the 2016-2018 period. From the clinical standpoint, all cases of severe hepatitis occurred during this latter period. CONCLUSIONS: Our results reaffirm the high clinical and epidemiological impact of the epidemic outbreak in Cantabria and emphasizes the need for optimising the current prevention measures against hepatitis A.

Supporting advanced dementia in people with Down syndrome and other intellectual disability: consensus statement of the International Summit on Intellectual Disability and Dementia.

BACKGROUND: The International Summit on Intellectual Disability and Dementia (Glasgow, Scotland; October 2016) noted that advanced dementia can be categorised as that stage of dementia progression characterised by significant losses in cognitive and physical function, including a high probability of further deterioration and leading to death. METHOD: The question before the Summit was whether there were similarities and differences in expressions of advanced dementia between adults with intellectual disability (ID) and adults in the general population. RESULTS: The Summit noted challenges in the staging of advanced dementia in people with ID with the criteria in measures designed to stage dementia in the general population heavily weighted on notable impairment in activities of daily living. For many people with an ID, there is already dependence in these domains generally related to the individuals pre-existing level of intellectual impairment, that is, totally unrelated to dementia. Hence, the Summit agreed that as was true in achieving diagnosis, it is also imperative in determining advanced dementia that change is measured from the person's prior functioning in combination with clinical impressions of continuing and marked decline and of increasing co-morbidity, including particular attention to late-onset epilepsy in people with Down syndrome. It was further noted that quality care planning must recognise the greater likelihood of physical symptoms, co-morbidities, immobility and neuropathological deterioration. CONCLUSIONS: The Summit recommended an investment in research to more clearly identify measures of person-specific additional decline for ascertaining advanced dementia, inform practice guidelines to aid clinicians and service providers and identify specific markers that signal such additional decline and progression into advanced dementia among people with various levels of pre-existing intellectual impairment.

Señales de alarma precoces del trastorno del espectro autista en personas con síndrome de Down / Early warning signs of autism spectrum disorder in people with Down syndrome

Introducción. En la población general, el diagnóstico de trastornos del espectro autista (TEA) se realiza generalmente en una etapa temprana, mejorándose así el pronóstico. En las personas con síndrome de Down (SD), la falta de instrumentos específicos y adaptados para el diagnóstico, y la falta de experiencia de los profesionales, hace que el diagnóstico de TEA suela pasar desapercibido. Objetivo. Identificar señales de alarma «tempranas» de un posible diagnóstico de TEA en niños con SD en los primeros años de vida (de 0 a 4 años). Métodos. Estudio retrospectivo de cohortes: niños con SD y TEA (SD-TEA) y niños con SD y sin TEA (SD-noTEA) emparejados por sexo y edad. Se identificaron las siguientes señales de alarma tempranas: 1) ausencia de sonrisa social; 2) falta atención compartida; 3) falta de búsqueda de consuelo/protección; 4) ausencia de queja; 5) poco interés por el otro; 6) no señala; 7) no imita; 8) ausencia de balbuceo, vocalización; 9) expresión facial inapropiada; 10) rituales verbales o acciones repetitivas; 11) manierismos manos/dedos; 12) estereotipias; 13) interés sensorial, y 14) no integración de la mirada y la conducta. Seis investigadores, quienes no participaron en la identificación de las señales de alarma tempranas, seleccionaron aquellas que orientarían a un diagnóstico de TEA (análisis cualitativo). Se solicitó a los padres videos de las personas con SD en «actividad» entre los 0 y 4 años. Los mismos investigadores, cegados al diagnóstico de TEA y tras visualizar los videos, puntuaron las señales de alarma tempranas en 3 categorías: presencia/ausencia/no evaluable (análisis cuantitativo). Resultados. Durante el año 2013, se obtuvieron 12 videos de 12 personas con SD: 6 del grupo SD-TEA y 6 del grupo SD-noTEA. El análisis cualitativo identificó como señales de alarma temprana relacionadas con el diagnóstico de TEA: «no integración de la mirada», «no imita», «rituales verbales o acciones repetitivas» y «estereotipias»; y el análisis cuantitativo identificó: «falta de atención compartida» y «falta de interés por el otro». Conclusión. Ciertas «señales de alarma» pueden orientar hacia un diagnóstico de TEA en los primeros años de vida en niños con SD (AU)

Introduction. In general population, the current trend is to make the diagnosis of Autism Spectrum Disorders (ASD) at an early stage, which it is crucial to improve the prognosis. In contrast, in Down syndrome (DS) population, the ASD diagnosis is frequently delayed, having negative consequences on the overall development of the children who suffer. Objective. To identify «early warning signals» for the detection of the ASD in DS in the first years of life (0 to 4 years). Methods. Retrospective cohort study: SD with an ASD diagnosis (SD-ASD) and healthy-DS (SD-noASD) matched by sex and age. Early warning signals were identified and selected from different questionnaires for ASD of general population: 1. Lack of social smile; 2. Shared care foul; 3. Lack of finding comfort/protection; 4. Lack of complaint; 5. Little interest for the others; 6. No pointing; 7. Non-imitation; 8. Lack of babbling/vocalization; 9. Inappropriate facial expression; 10. Presence of rituals as repetitive actions or repetitive sentences; 11. Mannerisms hands/fingers; 12. Stereotypes; 13. Lack of interest sensory; and 14. Non-integration of the look. Six investigators, who did not participate in the identification of the «early warning signals», selected those that would guide a diagnosis of ASD (qualitative analysis). Parents were asked for videos of people with DS in «activity» between 0 and 4 years. The same investigators, blinded to the diagnosis of ASD and after watching the videos, scored the «early warning signals» in three categories: presence / absence / non-evaluable (quantitative analysis). Results. During the year 2013, 12 videos of 12 people with SD were obtained: 6 from SD-ASD group and 6 from the SD-noASD group. The qualitative analysis identified as early warning signals related to the diagnosis of ASD: «non-integration of the look», «non-imitation», «presence of rituals as repetitive actions or repetitive sentences» and «stereotypies», and the quantitative analysis: «shared care foul» and «little interest for the others». Conclusion. Certain «warning signals» may lead to a diagnosis of ASD in the first years of life in children with DS (AU)

Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints.

BACKGROUND: Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS-C) are lacking. AIM: A prespecified further analysis to evaluate the efficacy and safety of linaclotide, a guanylate cyclase C agonist, in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency (EMA) submission. METHODS: Two randomised, double-blind, multicentre Phase 3 trials investigated once-daily linaclotide (290 µg) for 12 weeks (Trial 31) or 26 weeks (Trial 302) in patients with IBS-C. Prespecified primary endpoints were the EMA-recommended co-primary endpoints: (i) 12-week abdominal pain/discomfort responders [≥30% reduction in mean abdominal pain and/or discomfort score (11-point scales), with neither worsening from baseline, for ≥6 weeks] and (ii) 12-week IBS degree-of-relief responders (symptoms 'considerably' or 'completely' relieved for ≥6 weeks). RESULTS: Overall, 803 (Trial 31) and 805 patients (Trial 302) were randomised. A significantly greater proportion of linaclotide-treated vs. placebo-treated patients were 12-week abdominal pain/discomfort responders (Trial 31: 54.8% vs. 41.8%; Trial 302: 54.1% vs. 38.5%; P < 0.001) and IBS degree-of-relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; P < 0.0001). Similarly, significantly more linaclotide- vs. placebo-treated patients were responders for ≥13 weeks in Trial 302 (abdominal pain/discomfort: 53.6% vs. 36.0%; IBS degree-of-relief: 37.2% vs. 16.9%; P < 0.0001). The proportion of sustained responders (co-primary endpoint responders plus responders for ≥2 of the last 4 weeks of treatment) was also significantly greater with linaclotide vs. placebo in both trials (P < 0.001). CONCLUSION: Linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks. TRIAL REGISTRATION: ClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).

Irritable bowel syndrome with constipation: a European-focused systematic literature review of disease burden.

OBJECTIVE: To conduct a systematic literature review to assess burden of disease and unmet medical needs in patients with irritable bowel syndrome (IBS) with constipation (IBS-C), with a focus on five European countries (France, Germany, Italy, Spain, UK). METHODS: MEDLINE, EMBASE, and grey literature searches were carried out using terms for IBS and constipation, to identify studies reporting epidemiological, clinical, humanistic, or economic outcomes for IBS-C, published between 2000 and 2010. RESULTS: Searches identified 885 unique abstracts and 33 supplementary articles, of which 100 publications and six grey literature sources met the inclusion criteria. Among patients with IBS, the prevalence estimates of IBS-C ranged from 1 to 44%. Co-morbid conditions, such as personality traits, psychological distress, and stress, were common. Patients with IBS-C had lower health-related quality-of-life (HRQoL) compared with the general population, and clinical trials suggested that effectively treating IBS-C improves HRQoL. The European societal cost of IBS-C is largely unknown, as no IBS-C-specific European cost-of-illness studies were identified. Two cost analyses demonstrated the substantial societal impact of IBS-C, including reduced productivity at work and work absenteeism. Guidelines offered similar recommendations for the diagnosis and management of IBS; however, recommendations specifically for IBS-C varied by country. Current IBS-C treatment options have limited efficacy and the risk:benefit profile of early 5-HT(4) agonists restricts clinical use. CONCLUSIONS: This systematic review indicates a clear need for European-focused IBS-C burden-of-disease and cost-of-illness studies to address identified evidence gaps. There is a need for new therapies for IBS-C that are effective, well tolerated, and have a positive impact on HRQoL.

The impact of allodynia on the efficacy of almotriptan when given early in migraine: data from the "Act when mild" study.

The objective of this study was to evaluate the impact of allodynia on treatment outcomes in the patients with acute migraine treated in the "Act when Mild" (AwM) study. AwM, a randomized placebo-controlled trial, studied almotriptan 12.5 mg in the early treatment (within 1 hr) of acute migraine when the pain was still mild, and investigated clinical outcomes in the presence or absence of allodynia, which was prospectively recorded using patient questionnaires. Of the total population, 39% (n = 404) reported allodynia that did not alter the efficacy of almotriptan administered for early/mild pain in terms of 2-hr pain-free rates (53.9% for allodynic patients vs. 52.5% for nonallodynic patients). Similarly, sustained pain-free rates were 47.2% versus 45.5%, and migraine duration 1.40 versus 1.54 hr, respectively. However, allodynia impaired the effectiveness of almotriptan in the patients with moderate/severe pain in terms of longer migraine duration, fewer patients achieving pain-free status, and more requiring rescue medication. In conclusion, the lack of effect of allodynia on the efficacy of almotriptan given for early/mild migraine pain might help explain the improved outcomes associated with the early-treatment strategy in AwM. Moreover, the data suggest that pain intensity is the main driver of triptan response, and not the presence or absence of allodynia.

PICOGEN: experiencia de 5 años de un programa de asesoramiento genético en demencia / PICOGEN: Five years experience with a genetic counselling program for dementia

Introducción: Describimos la experiencia del Programa de Información y Consejo Genético para demencias familiares (PICOGEN) en sus 5 a˜nos de funcionamiento. Métodos: Todos los sujetos fueron asesorados por un neurólogo que seleccionó los candidatos a estudio genético según la historia familiar y el diagnóstico (enfermedad de Alzheimer [EA], degeneración lobular frontotemporal [DLFT] o enfermedad priónica). Los sujetos asintomáticos que decidieron conocer su estatus genético siguieron un protocolo estructurado de evaluación antes y después de la realización del test genético. Resultados: Ochenta y siete pacientes de 72 familias fueron candidatos a estudio genético, 20 de 72 familias presentaban historia familiar autosómica dominante de inicio precoz (HADp). En 22 se detectó una mutación patogénica (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 no descritas previamente. Todos los casos con mutación, excepto uno PSEN1 (12,5%) y 4 PRNP (50%) presentaban HADp. En 3 casos con HADp (15%) no se encontró ninguna mutación. 24 de 54 sujetos asintomáticos de familias con mutación conocida decidieron realizarse el estudio presintomático, 10 resultaron portadores. En el seguimiento de los sujetos que realizaron el estudio predictivo no se observó ninguna complicación psiquiátrica mayor. Conclusiones: En nuestra serie la HADp resultó un criterio sensible para la detección de mutaciones patogénicas en EA y DLFT, pero no en enfermedades priónicas. Un 15% de los casos HADp no presentaron alteraciones genéticas causales en estudios diagnósticos convencionales. El 43% de los sujetos en riesgo que recibieron asesoramiento genético individual realizaron el estudio presintomático. El estudio presintomático resultó seguro en este contexto (AU)

Introduction: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). Methods: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. Results: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the presymptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. Conclusions: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of presymptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions (AU)

PICOGEN: five years experience with a genetic counselling program for dementia.

INTRODUCTION: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). METHODS: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. RESULTS: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the pre-symptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. CONCLUSIONS: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of pre-symptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions.

[New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. / Nueva mutación en el gen PSEN1 (E120G) asociada a enfermedad de Alzheimer de inicio precoz.

OBJECTIVE: To describe a novel mutation in exon 5 of the presenilin 1 gene (E120G)associated with early-onset autosomal dominant Alzheimer's disease (AD). PATIENT AND METHODS: The proband was a man who began with memory loss and progressive cognitive decline at the age of 34. His father and his sister suffered from early-onset cognitive decline. The genetic study performed on the blood sample using the single strand conformation polymorphism (SSCP) technique did not detect any abnormality suggestive of the presence of a mutation in PSEN1, PSEN2, and APP. In the last stage of the disease the patient had seizures and gait alteration. He died at the age of 44. Coding exons 3-12 of PSEN1 were studied by direct sequencing using isolated DNA from frozen brain tissue of the proband. RESULTS: The neuropathological examination showed the presence of frequent amyloid plaques and neurofibrillary tangles and severe amyloid angiopathy. The direct sequencing of the PSEN1 gene disclosed the presence of the E120G mutation. CONCLUSIONS: E120G is a novel mutation in PSEN1 that probably causes early-onset autosomal dominant AD. Absence of genetic alterations in screening techniques (SSCP) does not rule out the presence of mutations. We recommend direct sequencing for the genetic study of patients with early-onset autosomal dominant AD.

A novel PSEN1 mutation (K239N) associated with Alzheimer's disease with wide range age of onset and slow progression.

OBJECTIVE: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer's disease (AD). METHODS AND RESULTS: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. CONCLUSION: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.

Nueva mutación en el gen PSEN1 (E120G) asociada a enfermedad de Alzheimer de inicio precoz / New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease

Objetivo: Describir una nueva mutación en el exón 5 del gen PSEN1 (E120G) asociada a enfermedad de Alzheimer (EA) de inicio precoz y patrón de herencia autosómico dominante. Paciente y métodos: El probando era un varón en el que se inició la enfermedad a los 34 años con problemas de memoria y deterioro cognitivo progresivo. Su padre y una hermana presentaron deterioro cognitivo de inicio precoz. El estudio genético por single strand conformation polymorphism (SSCP) de una muestra sanguínea del probando no detectó anormalidades que indicaran mutaciones en PSEN1, PSEN2 y APP. En los estadios finales de la enfermedad, el paciente presentó crisis epilépticas y alteración de la marcha. El paciente falleció a los 44 años. Los exones 3-12 del gen PSEN1 fueron analizados por secuenciación directa utilizando ADN aislado del tejido cerebral congelado del probando. Resultados: El examen neuropatológico reveló abundantes placas seniles y ovillos neurofibrilares, junto con una angiopatía amiloidea severa. El nuevo estudio genético del gen PSEN1 realizado mediante secuenciación directa detectó la mutación E120G. Conclusiones: E120G es una nueva mutación en PSEN1, probable causa de EA de inicio precoz con patrón autosómico dominante. La ausencia de mutaciones en estudios genéticos de cribado (SSCP) no descarta que haya mutaciones. Se recomienda el estudio genético mediante secuenciación directa en los casos de EA de inicio precoz y patrón de herencia autosómico dominante (AU)

Objective: To describe a novel mutation in exon 5 of the presenilin 1 gene (E120G)associated with early-onset autosomal dominant Alzheimer’s disease (AD). Patient and methods: The proband was a man who began with memory loss and progressive cognitive decline at the age of 34. His father and his sister suffered from early-onset cognitive decline. The genetic study performed on the blood sample using the single strand conformation polymorphism (SSCP) technique did not detect any abnormality suggestive of the presence of a mutation in PSEN1, PSEN2, and APP. In the last stage of the disease the patient had seizures and gait alteration. He died at the age of 44. Coding exons 3-12 of PSEN1 were studied by direct sequencing using isolated DNA from frozen brain tissue of the proband. Results: The neuropathological examination showed the presence of frequent amyloid plaques and neurofibrillary tangles and severe amyloid angiopathy. The direct sequencing of the PSEN1 gene disclosed the presence of the E120G mutation. Conclusions: E120G is a novel mutation in PSEN1 that probably causes early-onset autosomal dominant AD. Absence of genetic alterations in screening techniques (SSCP) does not rule out the presence of mutations. We recommend direct sequencing for the genetic study of patients with early-onset autosomal dominant AD (AU)

Early vs. non-early intervention in acute migraine-'Act when Mild (AwM)'. A double-blind, placebo-controlled trial of almotriptan.

The study was designed to compare the response to almotriptan in migraine patients who take medication early in the course of the attack with that when medication is taken after pain has become moderate or severe. A randomized, four-arm, multicentre, multinational, double-blind, placebo-controlled trial of almotriptan (12.5 mg) comparing treatment administration when pain intensity was mild and within 1 h of headache onset vs. pain that had become moderate or severe was conducted. Of 491 migraineurs enrolled, 403 were evaluable [intention-to-treat population (ITT)]. Their mean age was 38 years, 84% were female and they had a mean of 3.7 attacks/month. Of these patients, 10% did not take medication according to their randomly allocated basal pain intensity (mild or moderate/severe) and were subsequently reassigned to that group for this analysis-'Act when Mild (AwM)' group. In the almotriptan arms, 53% of mild basal pain and 38% of moderate/severe basal pain patients were pain free at 2 h (P = 0.03; primary end-point). Corresponding proportions in the placebo groups were 25% and 17% (statistically significant vs. respective almotriptan arms). Secondary end-points (ITT) were also significantly in favour of early intervention with almotriptan, both between and across treatment groups, such as sustained pain free: 45.6% vs. 30.5% (P = 0.02). Adverse events were reported in < 5% of treated patients in all groups (NS), with no serious events. Treatment with almotriptan while migraine pain is still mild provides statistically significant and clinically relevant enhancements in efficacy compared with treatment when pain has reached higher severity levels.

Ebastine fast-dissolving tablets versus regular tablets: acceptability and preference in patients with allergic rhinitis.

A new fast-dissolving tablet (FDT) formulation of ebastine has been developed that dissolves rapidly in the mouth without the need for water. This new formulation of ebastine FDT offers an opportunity to tailor prescribing in a way that meets patient's preferences. The aim of the reported study was to evaluate the preferences of allergic rhinitis patients who were given either a placebo version of ebastine FDT or a placebo version of ebastine regular tablet (RT). Allergic rhinitis patients from Germany, Italy and Mexico, who were regular consumers of oral antihistamines, were recruited to a randomized, crossover study comparing placebo forms of ebastine FDT and ebastine RT. Patients were interviewed at home and were given both a FDT and RT (10 and 20 mg doses were used with a 1:1 ratio). Data on patient preferences were recorded by an interviewer and analyzed using descriptive statistics. A total of 420 individuals participated (140 in each country), 70% with intermittent and 24% with persistent allergic rhinitis. Using a rating scale of 0-10 and comparing mean values, ebastine FDT was statistically significantly better than RT for: sensation on dissolving (8.30 FDT vs 6.79 RT); taste it leaves in the mouth (8.10 FDT vs 6.60 RT); initial taste (8.07 FDT vs 6.63 RT); and texture (7.85 FDT vs 7.20 RT). Rapidity of dissolution was rated 8.67 for FDT. With the same scale, RT rated statistically significantly better than ebastine FDT for: appearance (7.46 RT vs 6.85 FDT); size (7.38 RT vs 7.06 FDT); and shape (7.55 RT vs 7.24 FDT). General evaluation was statistically significantly better for ebastine FDT (8.21 FDT vs 7.05 RT). Overall, 83% of patients preferred ebastine FDT to RT, 92% considered it to be more innovative, 90% that it was suitable to be taken without water and that it was technologically advanced, and 87% that it was suitable for taking at any time and anywhere, and that it had a refreshing taste. Ebastine FDT formulation is preferred to the RT by the majority of allergic rhinitis patients, rating most highly for dissolution, taste and texture.