Cell-cell adhesion proteins in melanocytic pilomatrix carcinoma

Tumors of the matrix of rigid structures include matrical tumors of the hairs, nails, and teeth. These tumors share similar phenotypical and signaling features. Although benign matrical hair tumors are among the most common of these tumors, hair matrix tumors containing pigmented melanocytes are very rare. The malignant variant called melanocytic pilomatrix carcinoma contains benign colonizing dendritic melanocytes admixed with the carcinomatous follicular matrical cells

Genetic variability and ontogeny predict microbiome structure in a disease-challenged montane amphibian

Amphibian populations worldwide are at risk of extinction from infectious diseases, including chytridiomycosis caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd). Amphibian cutaneous microbiomes interact with Bd and can confer protective benefits to the host. The composition of the microbiome itself is influenced by many environment- and host-related factors. However, little is known about the interacting effects of host population structure, genetic variation and developmental stage on microbiome composition and Bd prevalence across multiple sites. Here we explore these questions in Amietia hymenopus, a disease-affected frog in southern Africa. We use microsatellite genotyping and 16S amplicon sequencing to show that the microbiome associated with tadpole mouthparts is structured spatially, and is influenced by host genotype and developmental stage. We observed strong genetic structure in host populations based on rivers and geographic distances, but this did not correspond to spatial patterns in microbiome composition. These results indicate that demographic and host genetic factors affect microbiome composition within sites, but different factors are responsible for host population structure and microbiome structure at the between-site level. Our results help to elucidate complex within- and among- population drivers of microbiome structure in amphibian populations. That there is a genetic basis to microbiome composition in amphibians could help to inform amphibian conservation efforts against infectious diseases

Biological-effective versus conventional dose volume histograms correlated with late genitourinary and gastrointestinal toxicity after external beam radiotherapy for prostate cancer: a matched pair analysis

BACKGROUND: To determine whether the dose-volume histograms (DVH's) for the rectum and bladder constructed using biological-effective dose (BED-DVH's) better correlate with late gastrointestinal (GI) and genitourinary (GU) toxicity after treatment with external beam radiotherapy for prostate cancer than conventional DVH's (C-DVH's). METHODS: The charts of 190 patients treated with external beam radiotherapy with a minimum follow-up of 2 years were reviewed. Six patients (3.2%) were found to have RTOG grade 3 GI toxicity, and similarly 6 patients (3.2%) were found to have RTOG grade 3 GU toxicity. Average late C-DVH's and BED-DVH's of the bladder and rectum were computed for these patients as well as for matched-pair control patients. For each matched pair the following measures of normalized difference in the DVH's were computed: (a) δ(AUC )= (Area Under Curve [AUC] in grade 3 patient – AUC in grade 0 patient)/(AUC in grade 0 patient) and (b) δ(V60 )= (Percent volume receiving = 60 Gy [V60] in grade 3 patient – V60 in grade 0 patient)/(V60 in grade 0 patient). RESULTS: As expected, the grade 3 curve is to the right of and above the grade 0 curve for all four sets of average DVH's – suggesting that both the C-DVH and the BED-DVH can be used for predicting late toxicity. δ(AUC )was higher for the BED-DVH's than for the C-DVH's – 0.27 vs 0.23 (p = 0.036) for the rectum and 0.24 vs 0.20 (p = 0.065) for the bladder. δ(V60 )was also higher for the BED-DVH's than for the C-DVH's – 2.73 vs 1.49 for the rectum (p = 0.021) and 1.64 vs 0.71 (p = 0.021) for the bladder. CONCLUSIONS: When considering well-established dosimetric endpoints used in evaluating treatment plans, BED-DVH's for the rectum and bladder correlate better with late toxicity than C-DVH's and should be considered when attempting to minimize late GI and GU toxicity after external beam radiotherapy for prostate cancer

Gene expression differences between stroke-associated and asymptomatic carotid plaques

Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2-fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization

Sarcomere Formation Occurs by the Assembly of Multiple Latent Protein Complexes

The stereotyped striation of myofibrils is a conserved feature of muscle organization that is critical to its function. Although most components that constitute the basic myofibrils are well-characterized biochemically and are conserved across the animal kingdom, the mechanisms leading to the precise assembly of sarcomeres, the basic units of myofibrils, are poorly understood. To gain insights into this process, we investigated the functional relationships of sarcomeric protein complexes. Specifically, we systematically analyzed, using either RNAi in primary muscle cells or available genetic mutations, the organization of myofibrils in Drosophila muscles that lack one or more sarcomeric proteins. Our study reveals that the thin and thick filaments are mutually dependent on each other for striation. Further, the tension sensor complex comprised of zipper/Zasp/α-actinin is involved in stabilizing the sarcomere but not in its initial formation. Finally, integrins appear essential for the interdigitation of thin and thick filaments that occurs prior to striation. Thus, sarcomere formation occurs by the coordinated assembly of multiple latent protein complexes, as opposed to sequential assembly

Child and parent predictors of picky eating from preschool to school age

Background: Picky eating is prevalent in childhood. Because pickiness concerns parents and is associated with nutrient deficiency and psychological problems, the antecedents of pickiness need to be identified. We propose an etiological model of picky eating involving child temperament, sensory sensitivity and parent-child interaction. Methods: Two cohorts of 4-year olds (born 2003 or 2004) in Trondheim, Norway were invited to participate (97.2% attendance; 82.0% consent rate, n = 2475) and a screen-stratified subsample of 1250 children was recruited. We interviewed 997 parents about their child’s pickiness and sensory sensitivity using the Preschool Age Psychiatric Assessment (PAPA). Two years later, 795 of the parents completed the interview. The Children’s Behavior Questionnaire (CBQ) was used to assess children’s temperament. Parent- child interactions were videotaped and parental sensitivity (i.e., parental awareness and appropriate responsiveness to children’s verbal and nonverbal cues) and structuring were rated using the Emotional Availability Scales (EAS). Results: At both measurement times, 26% of the children were categorized as picky eaters. Pickiness was moderately stable from preschool to school age (OR = 5.92, CI = 3.95, 8.86), and about half of those who displayed pickiness at age 4 were also picky eaters two years later. While accounting for pickiness at age 4, sensory sensitivity at age 4 predicted pickiness at age 6 (OR = 1.25, CI = 1.08, 2.23), whereas temperamental surgency (OR = 0.88, CI = 0.64, 1.22) and negative affectivity (OR = 1.17, CI = 0.75, 1.84) did not. Parental structuring was found to reduce the risk of children’s picky eating two years later (OR = 0.90, CI = 0.82, 0.99), whereas parental sensitivity increased the odds for pickiness (OR = 1.10, CI = 1.00, 1.21). Conclusions: Although pickiness is stable from preschool to school age, children who are more sensory sensitive are at higher risk for pickiness two years later, as are children whose parents display relatively higher levels of sensitivity and lower levels of structuring. Our findings suggest that interventions targeting children’s sensory sensitivity, as well as parental sensitivity and structuring, might reduce the risk of childhood pickiness. Health care providers should support parents of picky eaters in repeatedly offering unfamiliar and rejected foods to their children without pressure and acknowledging child autonomy

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred

Dementia as a determinant of social and health service use in the last two years of life 1996-2003

<p>Abstract</p> <p>Background</p> <p>Dementia is one of the most common causes of death among old people in Finland and other countries with high life expectancies. Dementing illnesses are the most important disease group behind the need for long-term care and therefore place a considerable burden on the health and social care system. The aim of this study was to assess the effects of dementia and year of death (1998-2003) on health and social service use in the last two years of life among old people.</p> <p>Methods</p> <p>The data were derived from multiple national registers in Finland and comprise all those who died in 1998, 2002 or 2003 and 40% of those who died in 1999-2001 at the age of 70 or over (n = 145 944). We studied the use of hospitals, long-term care and home care in the last two years of life. Statistics were performed using binary logistic regression analyses and negative binomial regression analyses, adjusting for age, gender and comorbidity.</p> <p>Results</p> <p>The proportion of study participants with a dementia diagnosis was 23.5%. People with dementia diagnosis used long-term care more often (OR 9.30, 95% CI 8.60, 10.06) but hospital (OR 0.33, 95% CI 0.31, 0.35) and home care (OR 0.50, 95% CI 0.46, 0.54) less often than people without dementia. The likelihood of using university hospital and long-term care increased during the eight-year study period, while the number of days spent in university and general hospital among the users decreased. Differences in service use between people with and without dementia decreased during the study period.</p> <p>Conclusions</p> <p>Old people with dementia used long-term care to a much greater extent and hospital and home care to a lesser extent than those without dementia. This difference persisted even when controlling for age, gender and comorbidity. It is important that greater attention is paid to ensuring that old people with dementia have equitable access to care.</p

Epidemiology, Molecular Characterization and Antibiotic Resistance of Neisseria meningitidis from Patients ≤15 Years in Manhiça, Rural Mozambique

BACKGROUND: The epidemiology of meningococcal disease in Mozambique and other African countries located outside the "meningitis belt" remains widely unknown. With the event of upcoming vaccines microbiological and epidemiological information is urgently needed. METHODS: Prospective surveillance for invasive bacterial infections was conducted at the Manhiça District hospital (rural Mozambique) among hospitalized children below 15 years of age. Available Neisseria meningitidis isolates were serogrouped and characterized by Multilocus Sequence Typing (MLST). Antibiotic resistance was also determined. RESULTS: Between 1998 and 2008, sixty-three cases of confirmed meningococcal disease (36 meningitis, 26 sepsis and 1 conjunctivitis) were identified among hospitalized children. The average incidence rate of meningococcal disease was 11.6/100,000 (8/100,000 for meningitis and 3.7/100,000 for meningococcemia, respectively). There was a significant rise on the number of meningococcal disease cases in 2005-2006 that was sustained till the end of the surveillance period. Serogroup was determined for 43 of the 63 meningococcal disease cases: 38 serogroup W-135, 3 serogroup A and 2 serogroup Y. ST-11 was the most predominant sequence type and strongly associated with serogroup W-135. Two of the three serogroup A isolates were ST-1, and both serogroup Y isolates were ST-175. N. meningitidis remained highly susceptible to all antibiotics used for treatment in the country, although the presence of isolates presenting intermediate resistance to penicillin advocates for continued surveillance. CONCLUSIONS: Our data show a high rate of meningococcal disease in Manhiça, Mozambique, mainly caused by serogroup W-135 ST-11 strains, and advocates for the implementation of a vaccination strategy covering serogroup W-135 meningococci in the country

Comparative genomics of the type VI secretion systems of Pantoea and Erwinia species reveals the presence of putative effector islands that may be translocated by the VgrG and Hcp proteins

<p>Abstract</p> <p>Background</p> <p>The Type VI secretion apparatus is assembled by a conserved set of proteins encoded within a distinct locus. The putative effector proteins Hcp and VgrG are also encoded within these loci. We have identified numerous distinct Type VI secretion system (T6SS) loci in the genomes of several ecologically diverse <it>Pantoea </it>and <it>Erwinia </it>species and detected the presence of putative effector islands associated with the <it>hcp </it>and <it>vgrG </it>genes.</p> <p>Results</p> <p>Between two and four T6SS loci occur among the <it>Pantoea </it>and <it>Erwinia </it>species. While two of the loci (T6SS-1 and T6SS-2) are well conserved among the various strains, the third (T6SS-3) locus is not universally distributed. Additional orthologous loci are present in <it>Pantoea </it>sp. aB-valens and <it>Erwinia billingiae </it>Eb661. Comparative analysis of the T6SS-1 and T6SS-3 loci showed non-conserved islands associated with the <it>vgrG </it>and <it>hcp</it>, and <it>vgrG </it>genes, respectively. These regions had a G+C content far lower than the conserved portions of the loci. Many of the proteins encoded within the <it>hcp </it>and <it>vgrG </it>islands carry conserved domains, which suggests they may serve as effector proteins for the T6SS. A number of the proteins also show homology to the C-terminal extensions of evolved VgrG proteins.</p> <p>Conclusions</p> <p>Extensive diversity was observed in the number and content of the T6SS loci among the <it>Pantoea </it>and <it>Erwinia </it>species. Genomic islands could be observed within some of T6SS loci, which are associated with the <it>hcp </it>and <it>vgrG </it>proteins and carry putative effector domain proteins. We propose new hypotheses concerning a role for these islands in the acquisition of T6SS effectors and the development of novel evolved VgrG and Hcp proteins.</p