Exploring naturally occurring clinical subgroups of post-traumatic headache.

OBJECTIVE: To explore naturally occurring clinical subgroups of post-traumatic headache. BACKGROUND: Persistent post-traumatic headache (PTH) is defined as a headache developing within 7 days of an injury that lasts for greater than 3 months. However, there is no evidence available from the International Classification of Headache Disorders (ICHD) based classification between persistent and acute PTH based on clinical phenotypes. METHODS: We conducted a retrospective study using the Stanford Research Repository Cohort Discovery Tool. We reviewed 500 electronic patient charts between January 2015 to September 2019 using inclusion criteria of adults older than 18 years with a diagnosis of PTH. The following variables were extracted from each patient's chart: diagnosis of PTH as dependent variable, and predictor variables as age, sex, history of migraine, loss of consciousness during head injury, pre-existing psychological history, duration of PTH and new PTH-associated comorbidities (e.g. new onset vertigo, post-traumatic stress disorder). Logistic regression was employed to identify clinical phenotypes predicting persistent PTH. All predictor variables were tested in one block to determine their predictive capacity while controlling for other predictors in the model. Two-step cluster analysis was conducted to identify naturally occurring PTH subgroups. RESULTS: A total of 300 patients were included (150 acute, 150 persistent PTH) with a median age of 47 years (IQR 31, 59) and female: male ratio of 2.7:1. Two hundred patients were excluded due to misdiagnoses. Pre-existing psychological history (standardized beta 0.16), history of migraine (0.20), new PTH-associated comorbidities (0.23) and medication overuse (0.37) statistically significantly predicted the presence of persistent PTH (p <  0.0001). Clustering analysis revealed PTH subgrouping comparable to ICHD-based classification: 140 patients in Cluster 1 (76% persistent PTH) and 160 patients in Cluster 2 (83% acute PTH). Four distinct clusters were found within persistent PTH. CONCLUSION: Pre-existing psychological history, history of migraine, new PTH-associated comorbidities and medication overuse predicted the occurrence of persistent PTH as well as two naturally occurring PTH clusters correlating to acute and persistent PTH. Management emphasis should focus on these phenotypes.

High-dose corticosteroids for acute cytomegalovirus-associated transverse myelitis in the immunocompetent patient: a case report and systematic review.

We present an immunocompetent patient with transverse myelitis (TM) during acute cytomegalovirus (CMV) infection, as evidenced by a reactive serum CMV IgM and CMV viremia. The patient had an excellent outcome after receiving only high-dose methylprednisolone. Given concerns that practitioners may have around the use of immunosuppressive therapy for this potentially infectious myelopathy, we systematically reviewed the literature to assess outcomes after administration of high-dose corticosteroids to this population. Despite severe disease at clinical nadir with inability to ambulate, immunocompetent patients with acute CMV-associated TM who received high-dose corticosteroids had good clinical outcomes 1 month to 1 year after presentation.

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

database.bio: a web application for interpreting human variations.

UNLABELLED: Rapid advances of next-generation sequencing technology have led to the integration of genetic information with clinical care. Genetic basis of diseases and response to drugs provide new ways of disease diagnosis and safer drug usage. This integration reveals the urgent need for effective and accurate tools to analyze genetic variants. Due to the number and diversity of sources for annotation, automating variant analysis is a challenging task. Here, we present database.bio, a web application that combines variant annotation, prioritization and visualization so as to support insight into the individual genetic characteristics. It enhances annotation speed by preprocessing data on a supercomputer, and reduces database space via a unified database representation with compressed fields. AVAILABILITY AND IMPLEMENTATION: Freely available at https://database.bio.

Regioselectivity control of graphene functionalization by ripples.

Ripples naturally occur in graphene sheets. First-principles calculations reveal that, by altering the pyramidalization angles of the carbon atoms, these ripples can be used to direct the chemical reactivity of graphene towards hydrogenation. A fraction of the carbon atoms of a rippled graphene, located around the crests and troughs, show significantly increased reactivity. The remaining carbon atoms have comparable reactivity to those in a flat graphene. To illustrate the increased reactivity, we show that hydrogenation becomes exothermic when the characteristic ratio between the amplitude and wavelength reaches ~0.55. This finding offers a practical chemical venue for regioselectivity control of graphene functionalization. While the rippling does not directly affect the band gap of the graphene, the rippling-induced hydrogenation does.

Morphology and texture evolution of nanostructured CaF2 films on amorphous substrates under oblique incidence flux.

The morphology and biaxial texture of vacuum evaporated CaF(2) films on amorphous substrates as a function of vapour incident angle, substrate temperature and film thickness were investigated by scanning electron microscopy, x-ray pole figure and reflection high energy electron diffraction surface pole figure analyses. Results show that an anomalous [220] out-of-plane texture was preferred in CaF(2) films deposited on Si substrates at < 200 °C with normal vapour incidence. With an increase of the vapour incident angle, the out-of-plane orientation changed from [220] to [111] at a substrate temperature of 100 °C. In films deposited with normal vapour incidence, the out-of-plane orientation changed from [220] at 100 °C to [111] at 400 °C. In films deposited with an oblique vapour incidence at 100 °C, the texture changed from random at small thickness (5 nm) to biaxial at larger thickness (20 nm or more). Using first principles density functional theory calculation, it was shown that [220] texture formation is a consequence of energetically favourable adsorption of CaF(2) molecules onto the CaF(2)(110) facet.

Biochemical and ultrastructural properties of a mitochondrial inner membrane fraction deficient in outer membrane and matrix activities.

Treatment of the inner membrane matrix fraction of rat liver mitochondria with the nonionic detergent Lubrol WX solubilized about 70% of the total protein and 90% or more of the following matrix activities: malate dehydrogenase, glutamate dehydrogenase, and isocitrate dehydrogenase (NADP). The Lubrol-insoluble fraction was enriched in cytochromes, phospholipids, and a Mg(++)-stimulated ATPase activity. Less than 2% of the total mitochondrial activity of monoamine oxidase, an outer membrane marker, or adenylate kinase, an intracristal space marker could be detected in this inner membrane fraction. Electron micrographs of negatively stained preparations showed vesicles (

Algorithms for the electronic and vibrational properties of nanocrystals.

Solving the electronic structure problem for nanoscale systems remains a computationally challenging problem. The numerous degrees of freedom, both electronic and nuclear, make the problem impossible to solve without some effective approximations. Here we illustrate some advances in algorithm developments to solve the Kohn-Sham eigenvalue problem, i.e. we solve the electronic structure problem within density functional theory using pseudopotentials expressed in real space. Our algorithms are based on a nonlinear Chebyshev filtered subspace iteration method, which avoids computing explicit eigenvectors except at the first self-consistent-field iteration. Our method may be viewed as an approach to solve the original nonlinear Kohn-Sham equation by a nonlinear subspace iteration technique, without emphasizing the intermediate linearized Kohn-Sham eigenvalue problems. Replacing the standard iterative diagonalization at each self-consistent-field iteration by a Chebyshev subspace filtering step results in a significant speed-up, often an order of magnitude or more, over methods based on standard diagonalization. We illustrate this method by predicting the electronic and vibrational states for silicon nanocrystals.

Real space method for the electronic structure of one-dimensional periodic systems.

We present a real space pseudopotential method for calculating the electronic structure of one-dimensional periodic systems such as nanowires. As an application of this method, we examine H-passivated Si nanowires. The band structure and heat of formation of the Si nanowires are presented and compared to plane wave methods. Our method is able to offer the same accuracy as the traditional plane wave methods but offers a number of computational advantages such as faster convergence for heteropolar nanowires.

Experimental investigation on the performance, gaseous and particulate emissions of a methanol fumigated diesel engine.

Experiments were conducted on a 4-cylinder direct-injection diesel engine with fumigation methanol injected into the air intake of each cylinder. The fumigation methanol was injected to top up 10%, 20% and 30% of the power output under different engine operating conditions. The effects of fumigation methanol on engine performance, gaseous emissions and particulate emission were investigated. The experimental results show that there is a decrease in the brake thermal efficiency when fumigation methanol is applied, except at the highest load of 0.67 MPa. At low loads, the brake thermal efficiency decreases with increase in fumigation methanol; but at high loads, it increases with increase in fumigation methanol. The fumigation method results in a significant increase in hydrocarbon (HC), carbon monoxide (CO), and nitrogen dioxide (NO(2)) emissions. The concentration of nitrogen oxides (NOx) is significantly reduced except at close to full load condition. There is also a reduction in the smoke opacity and the particulate matter (PM) mass concentration. For the submicron particles, the total number of particles decreases at low and medium loads but increases at high loads. In all cases, there is a shift of the particles towards smaller geometrical mean diameter, especially at high loads. The increase in nano-sized particles and the increase in NO(2) emission could have serious impact on human health.

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group.

PURPOSE: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. METHODS: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. RESULTS: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. CONCLUSION: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer.

BACKGROUND: The incidence of colorectal cancer in persons under 46 years of age is substantially higher in Hong Kong than in Scotland and many other countries. Consequently, we examined whether there is a hereditary predisposition for colorectal cancer in this Southern Chinese population. METHODS: We investigated the incidence of microsatellite instability (MSI) at 10 DNA sites in 117 colorectal cancer specimens from Chinese patients of various ages. Those tumors with new alleles at 40% or more of the sites investigated were identified as highly unstable MSI (MSI-H). In young patients, we also searched for germline mutations in three mismatch repair genes (hMSH2, hMLH1, and hMSH6). RESULTS: The incidence of MSI-H varied statistically significantly with age, being observed in more than 60% of those younger than age 31 years at diagnosis and in fewer than 15% of those age 46 years or older. In 15 patients (<46 years old) whose colorectal cancers showed MSI-H, eight possessed germline mutations in either hMSH2 or hMLH1. When mutations in hMSH6 were included, more than 80% of Chinese colorectal cancer patients younger than 31 years had germline mutations in mismatch repair genes. We found a novel germline missense mutation in hMSH6 in a 29-year-old man whose tumor showed no MSI. Two patients had a 4-base-pair insertion in exon 10 causing a truncated protein; this insertion is a common polymorphism with a population allele frequency in Chinese of 5.6%. CONCLUSIONS: Our results indicate that germline mutations in mismatch repair genes contribute substantially to the pathogenesis and high incidence of colorectal cancer in young Hong Kong Chinese. However, because young Chinese and Caucasians show similar proportions of colorectal cancers with MSI-H, despite the higher incidence in the former, additional factors may underlie the high susceptibility of young Chinese to colorectal cancer.

Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome.

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.

A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population.

We have previously reported that there is a high incidence of microsatellite instability (MSI) and germline mismatch repair gene mutation in colorectal cancer arising from young Hong Kong Chinese. Most of the germline mutations involve hMSH2, which is different from the mutation spectrum in the Western population. It is well known that alternative splicing is common in hMLH1, which complicates RNA based mutation detection methods. In contrast, large deletions in hMLH1, commonly observed in some ethnic groups, tend to escape detection by exon-by-exon direct DNA sequencing. Here we report the detection of a novel germline 1.8 kb deletion involving exon 11 of hMLH1 in a local hereditary non-polyposis colorectal cancer family. This mutation generates a mRNA transcript with deletion of exons 10-11, which is indistinguishable from one of the most common and predominant hMLH1 splice variants. A diagnostic test based on PCR of the breakpoint region led to the identification of an additional young colorectal cancer patient with this mutation. Haplotype analysis suggests that they may share a common ancestral mutation. Our results caution investigators in the interpretation of alternative splicing and have important implications for the design of hMLH1 mutation detection strategy in the Chinese population.

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation.

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbetaRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 - 4083.

Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes.

Colorectal cancer has been described in terms of genetic instability selectively affecting either microsatellite sequences (MIN) or chromosome number and structure (CIN). A subgroup with apparently stable, near-diploid chromosomes and stable microsatellites (MACS) also exists. These distinctions are important, partly because of their value in highlighting different pathways of carcinogenesis, and partly because of their direct relevance to prognosis. Study of early-onset cancer has often proved a fruitful resource for the identification of the nature and function of cancer susceptibility genes. In a study of colorectal cancer with stable microsatellite DNA, we describe 22 early-onset tumours (mean age=33), compared with 16 late-onset tumours (mean age=68). Both groups contained carcinomas with the MACS phenotype, characterized by near diploid DNA content, as defined by flow cytometry, and minimal chromosome arm deletion or amplification (six or less events per genome), determined by comparative genomic hybridization (CGH). Minimal chromosome imbalance correlated strongly with diploid DNA content (P<0.001). The proportion of MACS cancers was significantly greater in early-onset as compared to late-onset tumours (64 vs 13%, P=0.005). Of the chromosome arm imbalances commonly observed in late-onset tumours, only 18q- was observed more than twice amongst the 14 early-onset MACS tumours. Seventy-nine per cent of these MACS tumours were located in the distal colon, and 69% were at advanced clinico-pathological stages (with lymph node or distant metastasis). A positive family history of colorectal or other cancers was elicited in seven patients in the MACS early-onset group, and one additional patient in this group had a metachronous ovarian cancer. The results suggest that MACS cancer may have a genetic basis different from either MIN or CIN, and further studies of these cancers may lead to discovery of new mechanisms of colorectal carcinogenesis and cancer susceptibility.

BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs.

BACKGROUND: Malignant melanoma arising from different body compartments may be associated with differing aetiological factors and clinical behaviour, and may manifest diverse molecular genetic profiles. Although many studies have focused on cutaneous melanoma, little is known of mucosal and other types of melanoma. In particular, malignant melanoma of soft parts is different from other melanomas in many respects, yet manifests a common melanocytic differentiation. Mutation of BRAF is now known to be common in cutaneous melanomas, and raises possible new therapeutic options of anti-RAF treatment for these patients. Few data are available for non-cutaneous melanomas. AIMS: To study the incidence of BRAF and NRAS mutations in melanomas arising in diverse internal organs. METHODS: Fifty one melanomas from various internal organs were investigated for BRAF and NRAS mutation by direct DNA sequencing. RESULTS: BRAF and NRAS mutations were found in two and five mucosal melanomas arising from the aerodigestive and female genital tracts (n = 36). Their occurrence is mutually exclusive, giving a combined mutation incidence rate of 19.4% in mucosal melanomas. Both BRAF and NRAS mutations were absent in malignant melanoma of soft parts (n = 7). BRAF mutation was also absent in uveal melanoma (n = 6), but was seen in two of five cutaneous melanomas. The incidence of BRAF or combined BRAF/NRAS mutations in all non-cutaneous groups was significantly lower than published rates for cutaneous melanomas. CONCLUSION: Each melanoma subtype may have a unique oncogenetic pathway of tumour development, and only a small fraction of non-cutaneous melanomas may benefit from anti-RAF treatment.

Horizontal cell connections with short wavelength-sensitive cones in the retina: a comparison between New World and Old World primates.

Recent studies in the Old World macaque monkey have shown that the two horizontal cell types H1 and H2 differ with respect to their connections to short wavelength-sensitive (SWS) cones. We wanted to establish whether this pattern of connectivity is common to all primates. The connections of horizontal cells with SWS cones were studied in the retinas of two species of New World (marmoset and tamarin) and two species of Old World (orangutan and chimpanzee) primates by using a double-labelling technique. Horizontal cells were labelled with DiI and then photoconverted; SWS cones were labelled immunocytochemically. The marmoset shows a sex-linked polymorphism of colour vision: All males are dichromats, whereas most females are trichromats. In contrast, Old World primates are usually trichromats. Our results show that the horizontal cells of both New World and Old World primates have a comparable pattern of connectivity with SWS cones and thus indicate that the wiring of horizontal cells with SWS cones does not differ between dichromats and trichromats and is common to all primates. The H1 cells make no or only sparse contact with SWS cones. In marmoset, H1 cells have on average 0.8% of their dendritic terminals at SWS cones. The H2 cells contact all SWS cones in their dendritic field. In marmoset, H2 cells have on average 11.8% of their dendritic terminals at SWS cones. The axon of H2 cells contacts SWS cones but presumably also contacts other cones.

Bipolar cell diversity in the primate retina: morphologic and immunocytochemical analysis of a new world monkey, the marmoset Callithrix jacchus.

The aim of this study was to identify the bipolar cell types in the retina of a New World monkey, the common marmoset, and compare them with those found in the Old World macaque monkey. Retinal whole-mounts, sections, or both, were stained by using DiI labeling and immunohistochemical methods. Semithin sections were analyzed by using quantitative methods. We show that the same morphologic types of bipolar cell as described for the Old World macaque monkey by Boycott and Wässle (Boycott and Wässle [1991] Eur. J. Neurosci. 3:1069-1088) are present in marmoset retina: two types of midget bipolar cells, six type of diffuse bipolar cells, a blue cone bipolar cell, and one type of rod bipolar cell. The pattern of staining with different immunohistochemical markers ("fingerprint") of each bipolar cell type in marmoset was also the same as described for macaque, with one exception: the flat midget bipolar cell (FMB) class is labeled by antibodies to recoverin in macaque but is labeled by antibodies to CD15 in marmoset. The labeled FMB cells in marmoset make contact with multiple cone photoreceptors throughout most of the extrafoveal retina. The spatial density of bipolar cells in marmoset is shown to be sufficient to support one-to-one connectivity of midget bipolar and ganglion cells in the fovea and to allow for parallel pathways to ganglion cells throughout the retina. Quantitative differences in the morphology and receptor connectivity between marmoset and macaque can be related to differences in cone and rod photoreceptor density between the species. We conclude that bipolar cell diversity is a preserved feature of the primate retina.