CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5' and 3' ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. METHODS: In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. RESULTS: Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. CONCLUSIONS: This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

Is a fractured mandible an emergency?

We retrospectively audited the records of 708 patients who presented with the diagnosis of fractured mandible between January 2009 and July 2013 at the Queen Elizabeth Hospital, Birmingham. We assessed the different factors that may have altered their outcomes, and found that delay before definitive fixation caused no harm in either the short or the long term.

Prescription of antibiotics: does it alter the outcome for patients who have fractures of the angle of the mandible?

We retrospectively studied 708 consecutive patients at the Queen Elizabeth Hospital, Birmingham, to find out whether one of the four antibiotic protocols in use conferred any advantage (or disadvantage) on a patient who had a fractured angle of the mandible, and there was none. However, the time from initial injury until the time of the first dose of antibiotic was important. Clinically, if patients waited more than 72hours after the injury before the first dose of antibiotic was given, they had a three times higher rate of postoperative infection than patients who were given their first dose between 24 and 72hours after the injury. Morbidity was more than five times higher during the postoperative period if the patient had waited for three days before their first dose, compared with those given the first dose within eight hours of injury. The overall rate of malunion or non-union of the fracture was between five and 10 times higher if the patient had waited more than 72hours after injury compared with all the other groups. There was a considerable difference in cost between the intravenous and oral versions of the antibiotics used (Augmentin® and metronidazole) so, if it could be shown that the oral doses are as efficacious as intravenous doses, a great deal of money could be saved.

Microarterial anastomoses: A parameterised computational study examining the effect of suture position on intravascular blood flow.

This study investigates the extent to which individual aspects of suture placement influence local haemodynamics within microarterial anastomoses. An attempt to physically quantify flow characteristics of blood past microvascular sutures is made using computational fluid dynamics (CFD) software. Particular focus has been placed on increased shear strain rate (SSR), a known precipitant of intravascular platelet activation and thrombosis. Measurements were taken from micrographs of sutured anastomoses in chicken femoral vessels, with each assessed for bite width, suture angle and suture spacing. Computational geometries were then created to represent the anastomosis. Each suture characteristic was parameterised to allow independent or simultaneous adjustment. Flow rates were obtained from anonymised Doppler ultrasound scans of analogous vessels during preoperative assessment for autologous breast reconstruction. Vessel simulations were performed in 2.5mm ducts with blood as the working fluid. Vessel walls were non-compliant and a continuous Newtonian flow was applied, in accordance with current literature. Suture bite angle and spacing had significant effects on local haemodynamics, causing notably higher local SSRs, when simulated at extremes of surgical practice. A combined simulation, encompassing subtle changes of each suture parameter simultaneously i.e. representing optimum technique, created a more favourable SSR profile. As such, haemodynamic changes associated with optimum suture placement are unlikely to influence thrombus formation significantly. These findings support adherence to the basic principles of good microsurgical practice.

Regulation of splicing-associated SR proteins by HPV-16.

HPV-16 (human papillomavirus type 16) is a small dsDNA (double-stranded DNA) virus which infects mucosal epithelial tissue of the cervix. Epithelial tissue is composed of a basal layer of cells, capable of division, and a number of suprabasal layers, wherein the cells become more differentiated the closer to the surface of the epithelium they become. Expression of viral proteins is dependent upon epithelial differentiation status, and, within the HPV-16 genome, several elements have been found which control expression both transcriptionally and post-transcriptionally. Expression of the highly immunogenic capsid proteins, L1 and L2, is restricted to only the most differentiated cells, where immune surveillance is limited. However, L1 and L2 transcripts can be detected in less differentiated cells, suggesting post-transcriptional mechanisms exist to prevent their expression in these cells. Indeed, a number of cis-acting RNA elements have been observed within the HPV-16 late region which may be involved in control of capsid gene expression. Mechanisms controlling HPV-16 capsid gene expression and the cellular RNA-processing factors involved will be the focus of this article.

Brd4 is required for e2-mediated transcriptional activation but not genome partitioning of all papillomaviruses.

Bromodomain protein 4 (Brd4) has been identified as the cellular binding target through which the E2 protein of bovine papillomavirus type 1 links the viral genome to mitotic chromosomes. This tethering ensures retention and efficient partitioning of genomes to daughter cells following cell division. E2 is also a regulator of viral gene expression and a replication factor, in association with the viral E1 protein. In this study, we show that E2 proteins from a wide range of papillomaviruses interact with Brd4, albeit with variations in efficiency. Moreover, disruption of the E2-Brd4 interaction abrogates the transactivation function of E2, indicating that Brd4 is required for E2-mediated transactivation of all papillomaviruses. However, the interaction of E2 and Brd4 is not required for genome partitioning of all papillomaviruses since a number of papillomavirus E2 proteins associate with mitotic chromosomes independently of Brd4 binding. Furthermore, mutations in E2 that disrupt the interaction with Brd4 do not affect the ability of these E2s to associate with chromosomes. Thus, while all papillomaviruses attach their genomes to cellular chromosomes to facilitate genome segregation, they target different cellular binding partners. In summary, the E2 proteins from many papillomaviruses, including the clinically important alpha genus human papillomaviruses, interact with Brd4 to mediate transcriptional activation function but not all depend on this interaction to efficiently associate with mitotic chromosomes.

Prevalence of persistent primary reflexes and motor problems in children with reading difficulties.

It has been shown that some children with reading difficulties have underlying developmental delay and that this may be related to the persistence of primary reflexes. This study investigated the prevalence of persistent primary reflexes in the ordinary primary school population and how this related to other cognitive and social factors. Three groups of 41 children were drawn from a representative, cross-sectional sample of 409 children (aged 9-10 years) attending 11 ordinary primary schools in N. Ireland. The three groups represented the bottom, middle and top 10% respectively of readers from the total sample population. The relative persistence (on a scale of 0 to 4) of the Asymmetrical Tonic Neck Reflex (ATNR) and the prevalence of motor difficulties were assessed for these 3 groups. The rôle of 5 predictor variables (verbal IQ, social deprivation, sex, month of birth and religious affiliation) in determining the reading level of the total sample was also investigated. It was found that the lowest reading group had a significantly higher mean level of ATNR (1.56 [95% CI 1.22-1.90]) compared with the middle reading group (0.56 [0.22-0.90]) and the top reading group (0.59 [0.25-0.92]). 17% of children in the lowest reading group had extremely high levels of the ATNR while 24% showed no presence of ATNR. This contrasted with 0% and 66%, respectively for both middle and top reading groups. It was also found that there was a significant difference between the lowest reading group and the top reading group on a standardised test of motor ability. Furthermore, there was evidence that ATNR persistence but not motor ability was associated with the sex of the child with boys, in particular, at risk. There was no evidence that ATNR persistence or motor ability was significantly associated with social deprivation. It was also found that there were no significant differences between dyslexic and non-dyslexic children with reading difficulties in motor (including balance) performance. This study highlights the high levels of primary reflex persistence in children with reading difficulties and it provides further evidence of the association between reading difficulties and movement difficulties in young children. However, while the implications for intervention are discussed, it is stressed that the persistence of primary reflexes cannot be used as a causal model for reading difficulties, including dyslexia.

Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant, inherited condition that is characterized primarily by the development of early-onset colorectal cancer and a number of other epithelial malignancies. The underlying genetic basis of the disease is associated with a breakdown of DNA-mismatch repair. There are many genes involved in DNA-mismatch repair, and five of them have been implicated in HNPCC. Two of the genes (hMSH2 and hMLH1) account for the majority of HNPCC families (approximately 60%), and it is not known what the exact contributions of the remaining three genes (hPMS1, hPMS2, and hMSH6) are in relation to this condition. In addition, a sixth gene (hEXO1) has been associated with a disease phenotype that is consistent with HNPCC. Current estimates suggest that all four of these genes, combined, may account for up to 5% of families. In this report, we examine the contribution of hPMS2 and hEXO1 to a well-defined set of families that fulfill the diagnostic criteria for HNPCC. The genes, hPMS2 and hEXO1, were studied by denaturing high performance liquid chromatography (DHPLC) analysis in 21 families that have previously been determined not to have mutations in hMSH2 or hMLH1. hPMS2 accounts for a small proportion of HNPCC families, and none were deemed to be associated with hEXO1. Mutations in hPMS2 appear to account for a small proportion of families adhering to the Amsterdam II criteria, whereas hEXO1 does not appear to be associated with HNPCC.

Cerebral atrophy following shaken impact syndrome and other non-accidental head injury (NAHI).

PURPOSE OF THE STUDY: To determine the frequency of cerebral atrophy and microcephaly in a group of children with sequential MRI brain scans after surviving a non-accidental head injury (n = 16). METHODS: Serial head circumference measurements (OFC) were extracted and plotted on standard growth charts for each child retrospectively to determine the frequency of secondary microcephaly. Cerebral atrophy was diagnosed and quantified by measurement of the ventricular/cortical ratio on coronal images of the sequential scans. RESULTS: Acquired microcephaly was found in 15 children (93.8%) over a median follow-up period of 67.93 weeks. There was a significant reduction in the median Z-score for the OFC at the most recent follow-up when compared with that at presentation (p < 0.001, Wilcoxon Signed Rank Test). Cerebral atrophy was found to be the cause of the microcephaly in eight of the 15 children and was evident as early as 9 days after presentation. CONCLUSION: A large proportion of the cohort (93.8%) develops acquired microcephaly after an inflicted head injury and cerebral atrophy is responsible in half of these cases.

Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients.

Peutz-Jeghers syndrome (PJS) is a rare cancer predisposition, which is characterized by the presence of hamartomatous polyposis and mucocutaneous pigmentation. A significant proportion of both familial and sporadic forms of this disorder are associated with mutations in the STK11 (serine/threonine kinase 11)/LKB1 gene. In this report we present a series of Australian PJS cases, which suggest that mutations in the STK11 gene do not account for many families or patients without a family history. The most likely explanation is either the presence of another susceptibility gene or genetic mosaicism in the non-familial patients.

Comorbid non-alcohol substance misuse among people with schizophrenia: epidemiological study in central London.

BACKGROUND: Few epidemiological studies have assessed the extent and nature of comorbid non-alcohol substance misuse in people with schizophrenia in the community in the UK. AIMS: To study the extent and nature of comorbid non-alcohol substance misuse in people with schizophrenia in central London. METHOD: Subjects were identified in an epidemiological census survey of South Westminster. Standardised assessment of each subject included demographic data, ratings of mental state and movement disorder and questioning about drug and alcohol misuse. RESULTS: Individuals with schizophrenia or related psychoses were identified (n=352) and 57 (16%) reported a lifetime history of non-alcohol substance misuse. Age and gender were the main variables relevant to the extent and pattern of misuse. Self-reported non-alcohol substance misuse showed no significant relationship with a range of outcome measures. CONCLUSIONS: The high proportion of subjects reporting non-alcohol substance misuse is comparable with figures from the USA. The reports of lifetime misuse most commonly referred to cannabis, psychostimulants, LSD, opiates and anticholinergics. Misuse was concentrated in those younger than 36 years and was reported more often by males.

Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds.

Hereditary nonpolyposis colorectal cancer (HNPCC) describes the condition of a disparate group of families that have in common a predisposition to colorectal cancer in the absence of a premalignant phenotype. The genetic basis of this disease has been linked to mutations in genes associated with DNA mismatch repair. A large proportion of families harbor changes in one of two genes, hMSH2 and hMLH1. Approximately 35% of families in which the diagnosis is based on the Amsterdam criteria do not appear to harbor mutations in DNA-mismatch-repair genes. In this report we present data from a large series of families with HNPCC and indicate that there are subtle differences between families that harbor germline changes in hMSH2 and families that harbor hMLH1 mutations. Furthermore, there are differences between the mutation-positive group (hMSH2 and hMLH1 combined) of families and the mutation-negative group of families. The major findings identified in this study focus primarily on the extracolonic disease profile observed between the mutation-positive families and the mutation-negative families. Breast cancer was not significantly overrepresented in the hMSH2 mutation-positive group but was overrepresented in the hMLH1 mutation-positive group and in the mutation-negative group. Prostate cancer was not overrepresented in the mutation-positive groups but was overrepresented in the mutation-negative group. In age at diagnosis of colorectal cancer, there was no difference between the hMSH2 mutation-positive group and the hMLH1 mutation-positive group, but there was a significant difference between these two groups and the mutation-negative group.

Effects of replicating primary-reflex movements on specific reading difficulties in children: a randomised, double-blind, controlled trial.

BACKGROUND: Children with specific reading difficulties have problems that extend beyond the range of underlying language-related deficits (eg, they have difficulties with balance and motor control). We investigated the role of persistent primary reflexes (which are closely linked in the earliest months of life to the balance system) in disrupting the development of reading skills. METHODS: We assessed the efficacy of an intervention programme based on replicating the movements generated by the primary-reflex system during fetal and neonatal life. A randomised, individually matched, double-blind, placebo-controlled design was used and children (aged 8-11 years) with persistent primary reflexes and a poor standard of reading were enrolled into one of three treatment groups: experimental (children were given a specific movement sequence); placebo-control (children were given non-specific movements); and control (no movements). FINDINGS: From an initial sample of 98 children, 60 children, 20 in each group were matched on age, sex, verbal intelligence quotient (IQ), reading ability, and persistent asymmetrical tonic neck reflex. For asymmetrical tonic neck-reflex levels there was a significant (group by time) interaction (p<0.001). The experimental group showed a significant decrease in the level of persistent reflex over the course of the study (mean change -1.8 [95% CI -2.4 to -1.2], p<0.001), whereas the changes in the placebo-control and control groups were not significant (-0.2 [-0.9 to 0.6] and -0.4 [-0.9 to 0.2]). INTERPRETATION: This study provides further evidence of a link between reading difficulties and control of movement in children. In particular, our study highlights how the educational functioning of children may be linked to interference from an early neurodevelopmental system (the primary-reflex system). A new approach to the treatment of children with reading difficulties is proposed involving assessment of underlying neurological functioning, and appropriate remediation.

Hexose transporters of tomato: molecular cloning, expression analysis and functional characterization.

A full-length (LeHT2) and two partial (LeHT1 and LeHT3) cDNA clones, encoding hexose transporters, were isolated from tomato (Lycopersicon esculentum) fruit and flower cDNA libraries. Southern blot analysis confirmed the presence of a gene family of hexose transporters in tomato consisting of at least three members. The full-length cDNA (LeHT2) encodes a protein of 523 amino acids, with a calculated molecular mass of 57.6 kDa. The predicted protein has 12 putative membrane-spanning domains and belongs to the Major Facilitator Superfamily of membrane carriers. The three clones encode polypeptides that are homologous to other plant monosaccharide transporters and contain conserved amino acid motifs characteristic of this superfamily. Expression of the three genes in different organs of tomato was investigated by quantitative PCR. LeHT1 and LeHT3 are expressed predominantly in sink tissues, with both genes showing highest expression in young fruit and root tips. LeHT2 is expressed at relatively high levels in source leaves and certain sink tissues such as flowers. LeHT2 was functionally expressed in a hexose transport-deficient mutant (RE700A) of Saccharomyces cerevisiae. LeHT2-dependent transport of glucose in RE700A exhibited properties consistent with the operation of an energy-coupled transporter and probably a H+/hexose symporter. The Km of the symporter for glucose is 45 microM.

Magnetic resonance imaging in acute non-accidental head injury.

Making the diagnosis of non-accidental head injury, particularly in the acute illness, can be difficult. The aim of this retrospective study was to evaluate the use of magnetic resonance imaging in the acute presentation of non-accidental head injury. Twelve cases admitted to the Royal Hospital for Sick Children, Edinburgh with a diagnosis of non-accidental head injury, and who had magnetic resonance imaging in the acute illness, were identified. The average age was 5.7 mo (range 1 to 34 mo). The mechanism of the primary injury was whiplash-shaking injury syndrome with impact in four cases and without evidence of impact in seven; in one case there was a compression injury. The magnetic resonance imaging findings reflected the pathological consequences of rotational acceleration-deceleration injury and did not differ between those cases with evidence of impact and those without. Subdural haematomas were identified in all cases; the commonest location for subdural blood was the subtemporal region. It is surprising and important that the most frequent location of subdural blood was in the subtemporal area. This is an area difficult to assess by computerized tomography. Evidence of repeated injuries was found in two cases. These findings confirm the value of magnetic resonance imaging in the acute phase of non-accidental head injury.

Novel antipsychotics, extrapyramidal side effects and tardive dyskinesia.

A common and serious drawback of the conventional antipsychotics is their association with a range of motor disturbances: acute extrapyramidal symptoms, including parkinsonism, acute akathisia and acute dystonia; and chronic motor problems such as tardive dyskinesia, chronic akathisia and tardive dystonia. In addition to physical disability directly related to abnormal movements, the acute movement disorders can cause considerable subjective discomfort and distress, and are frequently cited as a reason for poor compliance with medication, at least during acute treatment. They can also confound clinical assessment of mental-state phenomena because of symptom overlap with the psychotic illness being treated. The results of clinical trials of the newer antipsychotic drugs such as clozapine, risperidone, olanzapine, amisulpride, quetiapine and sertindole suggest a lower liability for acute extrapyramidal symptoms than conventional antipsychotic drugs such as haloperidol and chlorpromazine. The relative liability of each of the newer drugs to cause acute extrapyramidal side effects is not known, as they have been available for a relatively short time and there is a paucity of direct comparative studies. Evidence is accumulating that those patients exhibiting acute extrapyramidal side effects are at greater risk of developing tardive dyskinesia, which raises the hope that the newer antipsychotic drugs may also be associated with less tardive dyskinesia in the longer term. Encouraging data are already available for clozapine, which appears to have a low incidence of tardive dyskinesia, and therapeutic value in a proportion of established cases of tardive dyskinesia and tardive dystonia. Here we review the available data on atypical antipsychotics and adverse motor effects.