Paediatric injuries around the knee: Soft tissue injuries.

We review the diagnosis, management and potential pitfalls of acute soft tissue injuries in the skeletally immature knee, including anterior cruciate ligament (ACL) injuries, meniscal injuries, patellar dislocation and patellofemoral instability (PFI). There has been an increasing incidence of such injuries in the paediatric population, and controversy remains regarding their treatment. We summarise evidence-based treatments for these injuries and discuss strategies to minimise complications as the child reaches skeletal maturity.

An analysis of national variance in coding for patellofemoral instability.

BACKGROUND: We sought to identify which specific set of codes are used by each acute NHS trust in England to document the diagnosis and management of patellofemoral instability (PFI). METHODS: All acute NHS Trusts in England were sent freedom of information (FOI) requests regarding their use of International Statistical Classification of Diseases and Related Health Problems version 10 (ICD-10) codes for the diagnoses related to PFI, and Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures 4th revision (OPCS-4) codes for surgical management of PFI. RESULTS: 106 of 132 (80%) relevant trusts who manage patients with PFI responded with information. Coding for diagnosis of patellar dislocation and recurrent dislocation were largely consistent with 96% of the trusts using the same code. However, coding of patellar instability varied widely with 10 different codes being used, the most common of which was being used by only 34% of trusts. Coding for operative management exhibited greater variety with the number of different codes being used by trusts for each of the eight surgical treatments ranging from 11 to 19 and the range for the most common code being used by trusts from 34% to 64%. Furthermore, a large number of trusts used multiple different codes for the same diagnosis or treatment of PFI. CONCLUSION: There is a lack of uniformity in how trusts code PFI diagnosis and treatment. Standardisation will enable further research involving focused analysis of trust databases to facilitate a better understanding of the epidemiology of this condition.

Paediatric injuries around the knee: Bony injuries.

The aim of this article is to discuss the diagnosis, management and pitfalls of bony injuries around the skeletally immature knee. Each within their own right is a relatively uncommon injury but associated with potential complications. Distal femoral physeal fractures can result in growth arrest and vascular injury. Tibial spine avulsions can result in an unstable knee. Tibial tubercle fractures can be associated with compartment syndrome and pose a risk to the extensor mechanism of the knee. Fixation can be complicated by growth arrest and subsequent recurvatum deformity. Finally, patella sleeve injuries are often missed and this can also threaten the extensor mechanism. We discuss the approach to clinical and radiological assessment of these injuries, and evidence based recommendations as to how they are best managed to avoid complications.

Epidemiology and outcomes of burn injuries at a tertiary burn care center in Bangladesh.

Globally, burns are among some of the most devastating injuries and account for more than 265,000 deaths worldwide. In Bangladesh alone, nearly 3000 people die annually from burn-related injuries. This study was conducted at the National Institute of Burn and Plastic Surgery in Dhaka, Bangladesh in June of 2016. Data included conducting surveys of hospitalized burn patients (N=66) and a chart review of deceased burn patients (N=88). In addition to reporting on the demographic profile of patients, information was also obtained on clinical measures during hospitalization. For non-fatal burns, high risk groups included young adult males (early 30s) of lower socioeconomic status. Among children, the most vulnerable group was found to be children less than eight years old. The most common non-fatal types of burn injuries were flame (35%), electrical (31%) and scald (24%). Discharged patients had an average hospital stay of around 30days with half of all patients requiring surgical intervention, thus indicating the severity of those cases and the need for resource-intensive care. Among the discharged patient population, factors significantly associated with a longer duration of hospital stay included severity of injury, not having received prior treatment before admission and whether or not patients required surgery during hospitalization. Among the mortality cases, the high-risk groups also included young adult males and children of around eight years of age. The average total body surface area (TBSA) sustained in these cases was 46.4%, with 65% of deaths attributable to complications from flame burns. These findings highlight the frequency and severity of burn injuries, identify vulnerable population groups and list common causes of burns in this large developing country of 160 million people. Furthermore, these findings may be applicable to the epidemiology and outcome of burns in similar low and middle income countries.

Tobacco exposure and sleep disturbance in 498 208 UK Biobank participants.

Background: The prevalence of sleep disturbance is high and increasing. The study investigated whether active, former and passive smoking were associated with sleep disturbance. Methods: This cross-sectional study used data from the UK Biobank: a cohort study of 502 655 participants, of whom 498 208 provided self-reported data on smoking and sleep characteristics. Multivariable multinomial and logistic regression models were used to examine the associations between smoking and sleep disturbance. Results: Long-sleep duration (>9 h) was more common among current smokers [odds ratio (OR): 1.47; 95% confidence interval (CI): 1.17-1.85; probability value (P) = 0.001] than never smokers, especially heavy (>20/day) smokers (OR: 2.85; 95% CI: 1.66-4.89; P < 0.001). Former heavy (>20/day) smokers were also more likely to report short (<6 h) sleep duration (OR: 1.41; 95% CI: 1.25-1.60; P < 0.001), long-sleep duration (OR: 1.99; 95% CI: 1.47-2.71; P < 0.001) and sleeplessness (OR: 1.47; 95% CI: 1.38-1.57; P < 0.001) than never smokers. Among never smokers, those who lived with more than one smoker had higher odds of long-sleep duration than those not cohabitating with a smoker (OR: 2.71; 95% CI: 1.26-5.82; P = 0.011). Conclusions: Active and passive exposure to high levels of tobacco smoke are associated with sleep disturbance. Existing global tobacco control interventions need to be enforced.

Dietary fat and total energy intake modifies the association of genetic profile risk score on obesity: evidence from 48 170 UK Biobank participants.

BACKGROUND: Obesity is a multifactorial condition influenced by both genetics and lifestyle. The aim of this study was to investigate whether the association between a validated genetic profile risk score for obesity (GPRS-obesity) and body mass index (BMI) or waist circumference (WC) was modified by macronutrient intake in a large general population study. METHODS: This study included cross-sectional data from 48 170 white European adults, aged 37-73 years, participating in the UK Biobank. Interactions between GPRS-obesity and macronutrient intake (including total energy, protein, fat, carbohydrate and dietary fibre intake) and its effects on BMI and WC were investigated. RESULTS: The 93-single-nucleotide polymorphism (SNP) GPRS was associated with a higher BMI (ß: 0.57 kg m-2 per s.d. increase in GPRS (95% confidence interval: 0.53-0.60); P=1.9 × 10-183) independent of major confounding factors. There was a significant interaction between GPRS and total fat intake (P(interaction)=0.007). Among high-fat-intake individuals, BMI was higher by 0.60 (0.52, 0.67) kg m-2 per s.d. increase in GPRS-obesity; the change in BMI with GPRS was lower among low-fat-intake individuals (ß: 0.50 (0.44, 0.57) kg m-2). Significant interactions with similar patterns were observed for saturated fat intake (high ß: 0.66 (0.59, 0.73) versus low ß: 0.49 (0.42, 0.55) kg m-2, P(interaction)=2 × 10-4) and for total energy intake (high ß: 0.58 (0.51, 0.64) versus low ß: 0.49 (0.42, 0.56) kg m-2, P(interaction)=0.019), but not for protein intake, carbohydrate intake and fibre intake (P(interaction) >0.05). The findings were broadly similar using WC as the outcome. CONCLUSIONS: These data suggest that the benefits of reducing the intake of fats and total energy intake may be more important in individuals with high genetic risk for obesity.

Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Interactive effects of age and estrogen on cortical neurons: implications for cognitive aging.

In the past few decades it has become clear that estrogen signaling plays a much larger role in modulating the cognitive centers of the brain than previously thought possible. We have developed a nonhuman primate (NHP) model to investigate the relationships between estradiol (E) and cognitive aging. Our studies of cyclical E treatment in ovariectomized (OVX) young and aged rhesus monkeys have revealed compelling cognitive and synaptic effects of E in the context of aging. Delayed response (DR), a task that is particularly dependent on integrity of dorsolateral prefrontal cortex (dlPFC) area 46 revealed the following: (1) that young OVX rhesus monkeys perform equally well whether treated with E or vehicle (V), and (2) that aged OVX animals given E perform as well as young adults with or without E, whereas OVX V-treated aged animals display significant DR impairment. We have analyzed the structure of layer III pyramidal cells in area 46 in these same monkeys. We found both age and treatment effects on these neurons that are consistent with behavioral data. Briefly, reconstructions of pyramidal neurons in area 46 from these monkeys showed that cyclical E increased the density of small, thin spines in both young and aged monkeys. However, this effect of E was against a background of age-related loss of small, thin spines, leaving aged V-treated monkeys with a particularly low density of these highly plastic spines, and vulnerable to cognitive decline. Our current interpretation is that E not only plays a critically important role in maintaining spine number, but also enables synaptic plasticity through a cyclical increase in small highly plastic spines that may be stabilized in the context of learning. Interestingly, recent studies demonstrate that chronic E is less effective at inducing spinogenesis than cyclical E. We have begun to link certain molecular attributes of excitatory synapses in area 46 to E effects and cognitive performance in these monkeys. Given the importance of synaptic estrogen receptor α (ER-α) in rat hippocampus, we focused our initial studies on synaptic ER-α in area 46. Three key findings have emerged from these studies: (1) synaptic ER-α is present in axospinous synapses in area 46; (2) it is stable across treatment and age groups (which is not the case in rat hippocampus); and (3) the abundance and distribution of synaptic ER-α is a key correlate of individual variation in cognitive performance in certain age and treatment groups. These findings have important implications for the design of hormone treatment strategies for both surgically and naturally menopausal women. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

DNA yield and quality of saliva samples and suitability for large-scale epidemiological studies in children.

OBJECTIVE: To evaluate two saliva collection methods for DNA yield and quality as applied to a large, integrated, multicentre, European project involving the collection of biological material from children. DESIGN: Cross-sectional multicentre comparative study in young children. METHODS: Saliva samples were collected from 14,019 children aged 2-9 years from eight European countries participating in the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study. This involved either the collection of 2 ml of saliva from children who were able to spit, or using a sponge to collect whole saliva and buccal mucosal cells from the inside of the mouth of younger children unable to spit. Samples were assembled centrally in each participating centre and subsequently despatched for DNA extraction and biobanking to the University of Glasgow. A subgroup of 4678 samples (∼33% of sampled individuals) were chosen for DNA extraction before genotyping. RESULTS: The whole-saliva collection method resulted in a higher DNA yield than the sponge collection method (mean±s.d.; saliva: 20.95±2.35 µg, sponge: 9.13±2.25 µg; P<0.001). DNA quality as measured by A (260)/A (280) was similar for the two collection methods. A minimum genotype calling success rate of 95% showed that both methods provide good-quality DNA for genotyping using TaqMan allelic discrimination assays. CONCLUSIONS: Our results showed higher DNA yield from the whole-saliva collection method compared with the assisted sponge collection. However, both collection methods provided DNA of sufficient quantity and quality for large-scale genetic epidemiological studies.

Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal.

Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X-linked gene, MECP2, has a phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype. One of the consequences of MeCP2 absence in the brain is altered functional and structural plasticity. We aimed to characterize synaptic effects related to plasticity in the hippocampus further and establish whether plasticity defects are amenable to pharmacological reversal. Using male mice in which Mecp2 expression was prevented by a stop cassette, we assessed synaptic plasticity in area CA1 at different phenotypic stages, scoring the mice weekly for overt RTT-like signs. Strongly symptomatic Mecp2(stop/y) mice displayed reduced long-term potentiation (LTP, 40.2±1.6% of wild-type), post-tetanic potentiation (PTP, 45±18.8% of wild-type) and paired-pulse facilitation (PPF, 78±0.1% of wild type) (all P<0.05), the impairment increasing with symptom severity score. These plasticity impairments were absent in presymptomatic mice. Repeated high frequency stimulation revealed pronounced LTP saturation in symptomatic Mecp2(stop/y) mice, suggesting an LTP 'ceiling' effect. Bath application of the weak NMDA receptor blocker memantine (1 µM) resulted in partial restoration of a short-term plasticity component. These data support that idea that progressive functional synaptic impairment is a key feature in the RTT brain and demonstrate the potential for the pharmacological restoration of plasticity function.

Familial Ménière's disease: clinical and genetic aspects.

BACKGROUND AND PURPOSE: Ménière's disease is not uncommon, with an incidence in Caucasians of about one in 2000. The incidence peaks in the fifth decade. Cases are usually isolated or sporadic, but in perhaps five per cent other family members are affected. We report here the clinical and genetic characteristics of a comprehensive set of familial Ménière's disease cases from the UK. METHODS: Forty-six affected families were studied. All cases were diagnosed using the American Academy of Otolaryngology-Head and Neck Surgery committee on hearing and equilibrium 1995, or more stringent, criteria. OUTCOMES AND RESULTS: Autosomal dominant inheritance with reduced penetrance was the most likely mode of inheritance overall. Apparent genetic anticipation was observed, but may also be a result of ascertainment bias given the collection strategy. There was also a slight tendency for cases to result from maternal transmission within the families in this set. The family pedigrees are presented, and the authors have also set up a website at which all the pedigrees may be viewed in greater detail.

Developmental changes in adiposity in toddlers and preschoolers in the GENESIS study and associations with the ACE I/D polymorphism.

OBJECTIVES: To investigate the relationship between the angiotensin I-converting enzyme 1 (ACE) I/D polymorphism and adiposity-related phenotypes in a large cohort of toddlers and preschoolers. METHODS: Body composition measurements and DNA samples were obtained from 2102 Greek children aged 1-6 years, as part of a large-scale epidemiological study (GENESIS). All children were genotyped for the ACE I/D polymorphism and gender- and age-stratified statistical analyses were performed. RESULTS: In girls aged 4-6 years, the D-allele was associated with higher measurements of body mass index (BMI) (P=0.018), waist (P=0.001) and upper arm (P=0.013) circumferences, genotype accounting for 2.5, 4 and 3% of the phenotypic variance, respectively. In boys, the D-allele showed strong associations with lower BMI (P=0.001) at the age of 1-2 years that explained 17% of the phenotypic variance and with larger suprailiac skinfold (P=0.008) at 3-4 years old that explained 2% of the variance. No other significant associations between the ACE I/D polymorphism and adiposity-related phenotypes were found. In girls, the age at which significant associations were revealed coincided with the age at which BMI was observed to increase after its developmental nadir, but this feature of the association was not observed in boys. CONCLUSIONS: The ACE I/D polymorphism is associated with developmental and physiological changes in adiposity-related traits during early childhood in a gender- and age-specific manner.

Laparoscopic extraperitoneal excision of a nerve sheath tumor of the spermatic cord.

A 60-year-old male presented with a nontender irreducible mass in the right groin. Examination revealed swelling in the inguinal canal in the region of the deep inguinal ring. He underwent laparoscopic, extraperitoneal exploration of the spermatic cord, where a soft tissue tumor was identified and excised. Histological examination confirmed a nerve sheath tumor. Nerve sheath tumors are uncommon neoplasms of peripheral nerves, which theoretically can arise from any nerve fiber but have only been described in the spermatic cord in three reports in the literature. We are not aware of any reports describing their excision either laparoscopically or by the extraperitoneal route.

Day-case laparoscopic Nissen fundoplication.

BACKGROUND: The aim was to assess the acceptability and safety of day-case laparoscopic fundoplication for gastro-oesophageal reflux disease (GORD). METHODS: This prospective study commenced in December 1999 and lasted for 18 months. All patients had proven symptomatic GORD. Inclusion criteria were American Society of Anesthesiologists grade I or II with adequate home support. A standard anaesthetic, analgesic and antiemetic protocol was used. Patients were contacted by telephone on the night of discharge and arrangements were made for a nurse to visit the following day. Postoperative pain and nausea were assessed using visual analogue scores (scale 0-10) on a self-completion questionnaire. RESULTS: Twenty patients were included. There were no postoperative complications. All patients were discharged on the day of surgery. Median time to discharge was 6 h 30 min (range 4.5 to 9 h). One patient reattended casualty the following morning but none required readmission. There was no significant difference in median pain or nausea scores the evening after surgery or the next morning. All patients were satisfied with the information given and aftercare provided. All would recommend it to a friend and 19 of 20 would undergo the procedure as a day case again. CONCLUSION: This study suggests that day-case laparoscopic fundoplication is feasible. Patients find it acceptable and it appears safe.

The Guildford MATTU TEP hernia model.

BACKGROUND: The totally extraperitoneal technique (TEP) is a well-established method for repairing inguinal hernias laparoscopically. It has a low recurrence rate with minimal morbidity. Good training is necessary to decrease the length of the learning curve. Laparoscopic training courses at the Guildford Minimal Access Therapy Training Unit (MATTU) include lectures, live demonstrations, and practical training. In the absence of a commercially available TEP hernia model, the Guildford MATTU, along with Limbs and Things, has developed a realistic artificial model. OBJECTIVE: The aim was to develop a model that would familiarize course participants with the different anatomical perspective and the steps needed to complete the TEP repair, in an effort to shorten their learning curve. EVALUATION: The MATTU model has been evaluated in terms of anatomic accuracy, realism, versatility, cost effectiveness, and ease of use. CONCLUSIONS: The MATTU model accurately replicates TEP repair. It is robust, easy to use, cost effective, and easy to maintain. It will be widely available.

Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2.

Vertebrate genes with sequence similarity to the Drosophila homeobox gene, sine oculis (so), constitute the SIX family. There is notable expression of members of this family in anterior neural structures, and several SIX genes have been shown to play roles in vertebrate and insect development, or have been implicated in maintenance of the differentiated state of tissues. Mutations in three of these genes in man (SIX5, SIX6 and SIX3) are associated with severe phenotypes, and therefore, the cloning of other human genes from this family is of interest. We have cloned and characterised the gene that encodes human SIX2, elucidated its gene structure and conducted expression studies in a range of tissues. SIX2 is widely expressed in the late first-trimester fetus, but has a limited range of expression sites in the adult. The expression pattern of SIX2 and its localisation to chromosome 2p15-p16 will be of use in assessing its candidacy in human developmental disorders.

Mutation screening in Rett syndrome patients.

Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir et al reported that mutations in the MECP2 gene were detected in around 50% of RTT patients. In this study, we have screened the MECP2 gene for mutations in our RTT material, including nine familial cases (19 Rett girls) and 59 sporadic cases. A total of 27 sporadic RTT patients were found to have mutations in the MECP2 gene, but no mutations were identified in our RTT families. In order to address the possibility of further X chromosomal or autosomal genetic factors in RTT, we evaluated six candidate genes for RTT selected on clinical, pathological, and genetic grounds: UBE1 (human ubiquitin activating enzyme E1, located in chromosome Xp11.23), UBE2I (ubiquitin conjugating enzyme E2I, homologous to yeast UBC9, chromosome 16p13.3), GdX (ubiquitin-like protein, chromosome Xq28), SOX3 (SRY related HMG box gene 3, chromosome Xq26-q27), GABRA3 (gamma-aminobutyric acid type A receptor alpha3 subunit, chromosome Xq28), and CDR2 (cerebellar degeneration related autoantigen 2, chromosome 16p12-p13.1). No mutations were detected in the coding regions of these six genes in 10 affected subjects and, therefore, alterations in the amino acid sequences of the encoded proteins can be excluded as having a causative role in RTT. Furthermore, gene expression of MECP2, GdX, GABRA3, and L1CAM (L1 cell adhesion molecule) was also investigated by in situ hybridisation. No gross differences were observed in neurones of several brain regions between normal controls and Rett patients.

Genetic linkage and radiation hybrid mapping of the three human GABA(C) receptor rho subunit genes: GABRR1, GABRR2 and GABRR3.

GABA(C) receptors mediate rapid inhibitory neurotransmission in retina. We have mapped, in detail, the human genes which encode the three polypeptides that comprise this receptor: rho1 (GABRR1), rho2 (GABRR2) and rho3 (GABRR3). We show that GABRR1 and GABRR2 are located close together, in a region of chromosome 6q that contains loci for inherited disorders of the eye, but that GABRR3 maps to chromosome 3q11-q13.3. Our mapping data suggest that the rho polypeptide genes, which are thought to share a common ancestor with GABA(A) receptor subunit genes, diverged at an early stage in the evolution of this gene family.