Clinical Utilities of Peripheral Blood Gene Expression Profiling in the Management of Cardiac Transplant Patients

Cardiac allografts induce host immune responses that lead to endomyocardial tissue injury and progressive graft dysfunction. Inflammatory cell infiltration and myocyte damage characterize acute cellular rejection (ACR) that presents episodically in either a subclinical or symptom-associated manner. Sampling of the endomyocardium by transvenous biopsy enables pathologic grading using light microscopic criteria to distinguish severity based on the focality or diffuseness of inflammation and associated myocyte injury. Monitoring for ACR utilizes endomyocardial biopsy in conjunction with history and physical examination and assessment of allograft function by echocardiography. However, procedural and interpretive issues limit the diagnostic certainty provided by endomyocardial biopsy. The dynamic profiling of genes expressed by peripheral blood mononuclear cells (PBMCs) enables quantitative assessments of intracellular mRNA whose levels fluctuate during systemic alloimmune responses. Gene expression profiling of PBMCs using a multi-gene ACR classifier enables the AlloMap® molecular expression test to distinguish moderate to severe ACR (p = 0.0018) in heart transplant patients. The AlloMap test provides molecular insights into a patient's risk for ACR by distilling the aggregate expression levels of its informative genes into a single score on a scale of 0 to 40. The selection of a score as a threshold value for clinical decision-making is based on its associated negative predictive value (NPV), which ranges from 98 to 99% for values in three post-transplant periods: >2 to ≤6 months, > 6to ≤ 12 months, and >12 months. Scores below the threshold value rule out ACR, while those above suggest increased ACR risk. Incorporating the AlloMap test into immunomonitoring protocols provides an opportunity for clinicians to enhance patient care and to define its role in immunodiagnostic strategies to optimize the clinical outcomes of heart transplant recipients. This summary highlights the concepts presented in an invited presentation at a conference focused on Immunodiagnostics and Immunomonitoring: From Research to Clinic, in San Diego, CA on November 7, 2006

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Body mass index, functional fitness and nutritional behaviours of senior women from the Kraków population

Background. Body Mass Index (BMI) is dependent on, among others, diet and level of physical activity. Seniors are more prone to nutritional disorders than other population groups. Objective. The aim of the study was to analyse the relationship between BMI and nutritional behaviours as well as the functional fitness level of senior women. Materials and methods. The research was carried out among a group of 120 women aged 60-84, using the TANITA SC-330ST body composition analyser, the HOLTAIN anthropometer, the Fullerton Functional Fitness Test and the authordesigned nutritional behaviour questionnaire for seniors. Statistical analyses were conducted using the IBM SPSS 21 statistical package, applying the Kruskal-Wallis ANOVA tests with comparisons of z tests at the significance level p<0.05. Results. In terms of the relationship between BMI and functional fitness indices, it was shown that women with normal weight obtained higher results for the lower body (p=0.043) and upper body agility tests than obese women (p<0.001). Females with normal BMI also obtained higher results in the endurance test than the overweight women (p=0.038). In terms of the correlation between BMI and nutritional behaviours, it was demonstrated that women with a healthy body mass more often ate varied, low-volume meals than those overweight (p=0.026). Women with correct weight ate fish, eggs and lean meat more often than obese women (p=0.036). Obese women consumed 3-5 portions of fruit and vegetables less frequently during the day than women with normal body mass (p=0.029) and those overweight (p=0.015). Obese women were less likely to eat sea fish at least 1-2 times a week than overweight females (p=0.040) and those with normal BMI (p<0.001). At the same time, women with a normal BMI indicated a higher degree of performed daily physical activity than the overweight women (p=0.028) and those with obesity (p=0.030). Conclusions. Women with normal BMI presented more rational nutrition habits and higher functional fitness than overweight and obese senior women.Wprowadzenie. Wskaźnik masy ciała BMI jest uzależniony m.in. od sposobu żywienia i poziomu aktywności fizycznej. Osoby starsze bardziej niż inne grupy populacyjne są narażone na zaburzenia stanu odżywienia. Cel. Celem badań była analiza zależności pomiędzy BMI a zachowaniami żywieniowymi i sprawnością funkcjonalną kobiet w wieku senioralnym. Materiał i metody. Badania przeprowadzono w grupie 120 kobiet w wieku 60-84 lata, z zastosowaniem analizatora składu ciała TANITA SC-330ST, antropometru HOLTAIN, testu Fullertona sprawności funkcjonalnej oraz autorskiego kwestionariusza zachowań żywieniowych dla osób starszych. Analizy statystyczne przeprowadzono za pomocą pakietu statystycznego IBM SPSS 21, z zastosowaniem testów ANOVA Kruskala-Wallisa wraz z porównaniami testami z na poziomie istotności p<0,05. Wyniki. W zakresie związków BMI ze wskaźnikami sprawności funkcjonalnej wykazano, że kobiety z normowagą uzyskały wyższe wyniki w próbie gibkości dolnej (p=0.043) i górnej części ciała niż kobiety z otyłością (p<0,001). Kobiety z prawidłowym BMI uzyskały także wyższe wyniki w próbie wytrzymałości niż kobiety z nadwagą (p=0,038). W zakresie związków BMI z zachowaniami żywieniowymi wykazano, że kobiety z prawidłową masą ciała częściej spożywały urozmaicone, mało objętościowe posiłki niż kobiety z nadwagą (p=0,026), częściej także spożywały ryby, jaja i chude mięso niż kobiety z otyłością (p=0,036). Kobiety z otyłością rzadziej spożywały 3-5 porcji warzyw i owoców w ciągu dnia niż kobiety z prawidłową masą ciała (p=0,029) oraz z nadwagą (p=0,015). Rzadziej także spożywały ryby morskie przynajmniej 1-2 razy w tygodniu niż kobiety z nadwagą (p=0,040) i z prawidłowym BMI (p<0,001). Zarazem kobiety z normatywnym wskaźnikiem BMI w wyższym stopniu deklarowały codzienne podejmowanie aktywności fizycznej niż kobiety z nadwagą (p=0,028) i otyłością (p=0,030). Wnioski. Kobiety w wieku senioralnym z prawidłowym wskaźnikiem masy ciała BMI wykazywały bardziej racjonalne zachowania żywieniowe i większą sprawność funkcjonalną niż kobiety z nadwagą i otyłością

Mästerligt om hantverk: Recension av Hantverk i Sverige. Om bagare, kopparslagare, vagnmakare och 286 andra hantverksyrken, LT, 1989

MEIS2 is a homeodomain-containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause cleft palate [Crowley et al. (2010); Am J Med Genet 152A:1326-1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions. (c) 2014 Wiley Periodicals, Inc

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression

In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient's autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint

ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation

OBJECTIVE: We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations. METHODS: Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features. RESULTS: A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy. CONCLUSIONS: ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy

Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype

The Rab GTPase family comprises approximately 70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization