Evolving practice: X-linked agammaglobulinemia and lung transplantation.

X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD).

Oxygen therapy in preterm infants.

Despite being the most widely used and vital therapy in neonatology, optimal strategies for the use of oxygen in preterm infants remain controversial. Achieving the balance between attaining adequate tissue oxygenation and avoiding oxygen toxicity is challenging. There remains a paucity of clear evidence based guidance for clinicians on safe oxygen saturation targets. What does seem apparent is that these targets vary over time in the life of a preterm infant. This article summarises the evidence behind current practice of oxygen monitoring and administration from the first few minutes after birth, through to the acute neonatal and later convalescent periods. Finally, we review the use of home oxygen for preterm infants with bronchopulmonary dysplasia including administration and weaning from domically home oxygen.

Coeliac disease is more common in children with high socio-economic status.

AIM: There are a number of genetic and environmental factors that are associated with an increased risk of developing coeliac disease. Our aim was to determine whether socio-economic deprivation increases or reduces the development of the disease. METHODS: A cross-sectional study identified all children <16 years old diagnosed with coeliac disease in the same tertiary paediatric centre between January 1995 and December 2011. Data, including age at diagnosis and postcode, were collected and linked with the quintile rank of the Welsh Index of Multiple Deprivation score 2008, a measure of socio-economic status. RESULTS: We included 232 patients and identified a graded association between the prevalence of coeliac disease and socio-economic deprivation, which showed a higher rate in children living in more affluent areas. The largest difference was between the lowest deprivation level (rate/1000 = 1.16) and the highest deprivation level (rate/1000 = 0.49). CONCLUSION: In our population, coeliac disease was more common in children in the higher socio-economic groupings. The reasons for this are not clear, but perhaps both the 'hygiene hypothesis' and the health seeking behaviours of parents with high socio-economic status are possible factors in the more frequent diagnosis of coeliac disease in this group.

Congenital diaphragmatic hernia.

Infants with congenital diaphragmatic hernia (CDH) have significant mortality and long-term morbidity. Only 60-70% survive and usually those in high-volume centres. The current Task Force, therefore, has convened experts to evaluate the current literature and make recommendations on both the antenatal and post-natal management of CDH. The incidence of CDH varies from 1.7 to 5.7 per 10,000 live-born infants depending on the study population. Antenatal ultrasound scanning is routine and increasingly complemented by the use of magnetic resonance imaging. For isolated CDH, antenatal interventions should be considered, but the techniques need vigorous evaluation. After birth, management protocols are often used and have improved outcome in nonrandomised studies, but immediate intubation at birth and gentle ventilation are important. Pulmonary hypertension is common and its optimal management is crucial as its severity predicts the outcome. Usually, surgery is delayed to allow optimal medical stabilisation. The role of minimal invasive post-natal surgery remains to be further defined. There are differences in opinion about whether extracorporeal membrane oxygenation improves outcome. Survivors of CDH can have a high incidence of comorbidities; thus, multidisciplinary follow-up is recommended. Multicentre international trials are necessary to optimise the antenatal and post-natal management of CDH patients.

Antenatal and postnatal management of congenital cystic adenomatoid malformation.

Congenital thoracic malformations (CTMs) are a heterogeneous group of rare disorders that may involve the airways or lung parenchyma. The authors have focused on the condition that causes the most controversy, namely, congenital cystic adenomatoid malformation (CCAM). The reported incidence is 3.5 and 0.94 per 10,000 live births for CTMs and CCAMs respectively. Ultrasound is the antenatal imaging modality of choice for screening for CCAMs whilst magnetic resonance imaging is complimentary for morphological and volumetric evaluation of the foetal lung. Most CCAMs are detected antenatally with only a small proportion presenting postnatally. Only a few CCAMs cause foetal problems, with foetal hydrops being the best predictor of death. Although many CCAMs regress during pregnancy, most remain detectable postnatally by CT scans. Surgical excision of symptomatic lesions is relatively straightforward, but management of asymptomatic lesions is controversial. Some surgeons adopt a "wait and see" approach operating only on those patients who develop symptoms, but others operate on asymptomatic patients usually within the first year of life. Due to the potential of malignant transformation, children should have long term follow up. There is an urgent need to delineate the natural history of antenatally detected CCAMs to guide future management.

Role of pulmonary infection in the development of chronic lung disease of prematurity.

We studied the role of ante- and post-natal infection in the development of chronic lung disease (CLD) of prematurity. 192 newborn infants (61 term and 131 pre-term of <34 weeks gestation: 88 with respiratory distress syndrome, 35 developed CLD and eight died) were recruited. 16S ribosomal RNA (rRNA) genes were identified by PCR of DNA isolated from 840 gastric and lung fluid samples. Ureaplasma spp. were also cultured. Presence of 16S rRNA genes (OR 1.6, 95% CI 1.2-2.2) and Ureaplasma spp. (OR 3.6, 95% CI 1.7-7.7) was significantly associated with the development of CLD. This association remained if the 16S rRNA genes and Ureaplasma spp. were first identified within the first 3 days of life (OR 2.4 (95% CI 1.4-4.1) and 3.8 (95% CI 1.4-10.0), respectively) or if first identified after 3 days of age (OR 1.7 (95% CI 1.1-2.8) and OR 5.1 (95% CI 1.3-19.8), respectively). Peak lung fluid interleukin (IL)-6 and IL-8 were significantly associated with presence of microbes (p<0.0001 and p=0.0001, respectively) and development of CLD (p=0.003 and 0.001, respectively). Both early and late microbial presence in neonatal lung fluid samples was significantly associated with the development of CLD suggesting that both ante- and post-natal infection play a role in the development of CLD.

Systematic review and meta-analysis of tracheostomy outcomes in COVID-19 patients.

A systematic review and meta-analysis of the entire COVID-19 Tracheostomy cohort was conducted to determine the cumulative incidence of complications, mortality, time to decannulation and ventilatory weaning. Outcomes of surgical versus percutaneous and outcomes relative to tracheostomy timing were also analysed. Studies reporting outcome data on patients with COVID-19 undergoing tracheostomy were identified and screened by 2 independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Outcome data were analysed using a random-effects model. From 1016 unique studies, 39 articles reporting outcomes for a total of 3929 patients were included for meta-analysis. Weighted mean follow-up time was 42.03±26 days post-tracheostomy. Meta-analysis showed that 61.2% of patients were weaned from mechanical ventilation [95%CI 52.6%-69.5%], 44.2% of patients were decannulated [95%CI 33.96%-54.67%], and cumulative mortality was found to be 19.23% [95%CI 15.2%-23.6%] across the entire tracheostomy cohort. The cumulative incidence of complications was 14.24% [95%CI 9.6%-19.6%], with bleeding accounting for 52% of all complications. No difference was found in incidence of mortality (RR1.96; p=0.34), decannulation (RR1.35, p=0.27), complications (RR0.75, p=0.09) and time to decannulation (SMD 0.46, p=0.68) between percutaneous and surgical tracheostomy. Moreover, no difference was found in mortality (RR1.57, p=0.43) between early and late tracheostomy, and timing of tracheostomy did not predict time to decannulation. Ten confirmed nosocomial staff infections were reported from 1398 tracheostomies. This study provides an overview of outcomes of tracheostomy in COVID-19 patients, and contributes to our understanding of tracheostomy decisions in this patient cohort.

Head and neck sarcoma: three-year data from a tertiary referral centre.

INTRODUCTION: Sarcomas of the head and neck are neoplasms arising from the embryonic mesenchyme. They are rare and heterogeneous in nature and are associated with significant morbidity and mortality. This study evaluates patients referred to the Oxford Sarcoma Service, a tertiary referral centre. METHODS: Patients discussed over a three-year period were included. Medical records were analysed using the electronic patient record database. Data were acquired on a range of domains, including: demographics, histopathology, treatment modality, recurrence, mortality, survival, etc. RESULTS: Thirty-two eligible patients, 21 male and 11 female, were identified with a mean age of 58 years; 26 out of 32 patients had high-grade sarcomas. The commonest histological subtype was chondrosarcoma (8/32). Twenty-two underwent planned multidisciplinary team surgical resection after biopsy and staging: negative margins were noted in 9, with close and involved margins in 5 and 8, respectively. Local recurrence was noted in 13 and 6 had metastatic disease out of the 32 eligible patients. Mortality was noted in 10 out of 32 patients. Mean survival was 69.5 months. Five-year overall survival was 64%. Surgery demonstrated statistically significant improvement in survival (p=0.0095). There were no significant differences in survival, recurrence or marginal status between methods of adjuvant or neoadjuvant therapy. CONCLUSION: Outcomes of head and neck sarcomas are inferior compared with other types of sarcoma. The nature of the complex surrounding anatomy presents unique challenges in surgical management. This in turn affects rates of local recurrence and prognosis. Therefore, it is critical that they are managed in tertiary, specialist centres with a multidisciplinary approach.

Non-resolving periapical inflammation: a malignant deception.

AIM: To report a case of oral non-Hodgkin's lymphoma with a delayed diagnosis. SUMMARY: Non-Hodgkin's lymphoma of the oral cavity is an uncommon but important condition. Early diagnosis is complicated when the presenting signs and symptoms are similar to those of odontogenic infections. This report describes the case of a 38-year-old female patient who presented to her dentist complaining of pain in her upper jaw. Subsequent dental treatment, including extraction, root canal treatment and apicectomy including biopsy were carried out by the patient's dentist and local dental hospital. Nine months elapsed before a more extensive surgical exploration established a diagnosis of lymphoma.

Paediatrics in Berlin.

The aim of this report is to describe the highlights of the European Respiratory Society annual congress in Berlin, Germany. The best abstracts in asthma and allergy, cystic fibrosis, respiratory infection, paediatric and neonatal intensive care, paediatric investigative techniques (in particular respiratory physiology and bronchoscopy) and respiratory epidemiology are presented and set in the context of the current literature.

The presentation, clinical features, complications, and treatment of congenital dacryocystocele.

PurposeTo determine the incidence and presenting features of congenital dacryocystocele in the United Kingdom. To report on those cases complicated by dacryocystitis, respiratory compromise, and the treatment undertaken.MethodsA prospective observational study of cases of congenital dacryocystocele presenting in the United Kingdom between September 2014 and October 2015. Infants <3 months of age presenting with a cystic swelling in the medial canthal area were included. Cases were identified via the British Ophthalmology Surveillance Unit (BOSU) reporting system.ResultsA total of 49 cases were reported during the study period. This gives an incidence of 1 in 18 597 live births. There was a 71% response rate to the questionnaire. The average age at presentation was 16.94 days. Dacryocystoceles were unilateral in 91% of cases. Dacryocystitis was a complicating factor in 49% of patients and 17% had respiratory distress. Uncomplicated dacryocystocele responded well to conservative measures in 86%. Surgical intervention was required in 23% of patients. Those cases complicated by dacryocystitis (29%) and nasal obstruction (17%) were more likely to require surgical intervention compared to those with dacryocystocele alone (14%). Digital massage appears to reduce the likelihood of requiring surgical intervention. The mean time to resolution was 19 days.ConclusionsCongenital dacryocystocele is a rare presentation in the United Kingdom. Dacryocystitis and respiratory compromise commonly complicate a dacryocystocele. The use of digital massage as an early intervention is advocated and conservative measures may be sufficient in cases of uncomplicated dacryocystocele.

Molecular characterization of Xenopus laevis DP proteins.

It is widely believed that in mammalian cells the cellular transcription factor (DRTF1/E2F integrates cell-cycle events with the transcription apparatus by interacting with important regulators of the cell cycle, such as the retinoblastoma gene product (pRb) and related proteins, cyclins, and cyclin-dependent kinases. Here, we have defined DRTF1/E2F in Xenopus laevis that, like its mammalian counterpart, specifically binds to the E2F site, is regulated during development, and interacts with pRb and related proteins. We have isolated cDNAs that encode the functional homologue of mammalian DP-1, X1 DP-1, together with a close relative, X1 DP-2. X1 DP-1, which is highly conserved with murine DP-1, is a major DNA binding component of X1 DRTF1/E2F. Both DP-1 and DP-2 synergistically interact with members of the E2F family of proteins, E2F-1, E2F-2, and E2F-3, to generate DNA binding complexes that specifically recognize the E2F site and functionally interact with E2F-1 in E2F site-dependent transcriptional activation of cellular genes. DP-1 and DP-2 encode maternally stored transcripts that are expressed during early development. In the adult however, the expression of DP-1 and DP-2 is tissue restricted. This study therefore defines a new family of transcription factors, the DP proteins, members of which can interact combinatorially with E2F proteins to generate an array of DNA binding complexes that integrate cell-cycle progression with the transcription apparatus through the E2F binding site. The tissue-specific expression of DP family members suggests that the combination of DP/E2F heterodimers that constitute DRTF1/E2F is influenced by the phenotype of the cell.

ABO incompatible renal transplantation following lung transplantation.

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

A Kv1.5 to Kv1.3 switch in endogenous hippocampal microglia and a role in proliferation.

The proliferation of microglia is a normal process in CNS development and in the defense against pathological insults, although, paradoxically, it contributes to several brain diseases. We have examined the types of voltage-activated K(+) currents (Kv) and their roles in microglial proliferation. Microglia were tissue-printed directly from the hippocampal region using brain slices from 5- to 14-d-old rats. Immediately after tissue prints were prepared, unipolar and bipolar microglia expressed a large Kv current, and the cells were not proliferating. Surprisingly, this current was biophysically and pharmacologically distinct from Kv1.3, which has been found in dissociated, cultured microglia, but it was very similar to Kv1.5. After several days in culture the microglia became highly proliferative, and although the Kv prevalence and current density decreased, many cells exhibited a prominent Kv that was indistinguishable from Kv1.3. The Kv1.5-like current was present in nonproliferating cells, whereas proliferating cells expressed the Kv1.3-like current. Immunocytochemical staining showed a dramatic shift in expression and localization of Kv1.3 and Kv1.5 proteins in microglia: Kv1.5 moving away from the surface and Kv1.3 moving to the surface as the cells were cultured. K(+) channel blockers inhibited proliferation, and the pharmacology of this inhibition correlated with the type of Kv current expressed. Our study, which introduces a method for the physiological examination of microglia from identified brain regions, demonstrates the differential expression of two functional Kv subunits and shows that a functional delayed rectifier current is necessary for microglia proliferation.

Xenopus eHAND: a marker for the developing cardiovascular system of the embryo that is regulated by bone morphogenetic proteins.

The bHLH protein eHAND is a sensitive marker for cardiovascular precursors in the Xenopus embryo. The earliest site of expression is a broad domain within the lateral plate mesoderm of the tailbud embryo. This domain comprises precursors that contribute to the posterior cardinal veins in later stages. Surprisingly, expression is profoundly asymmetric at this stage and is random with respect to embryo side. XeHAND is also expressed in an anterior domain that encompasses the prospective heart region. Within the myocardium and pericardium, transcripts are also asymmetrically distributed, but in these tissues they are localised in a left-sided manner. Later in development XeHAND transcripts are largely restricted to the ventral aorta, aortic arches and venous inflow tract (sinus venosus) which flank the heart itself, but no expression is detected in neural crest derivatives at any stage. This demonstrates that patterns of XeHAND expression differ markedly amongst vertebrates and that in Xenopus, XeHAND expression identifies all of the earliest formed elements of the cardiovascular system. In animal cap explants, expression of XeHAND (but not other markers of cardiogenic differentiation) is strongly induced by ectopic expression of the TGFbeta family members, BMP-2 and BMP-4, but this can be blocked by coexpression of a dominant negative BMP receptor. This suggests that XeHAND expression in the embryo is regulated by the ventralising signals of bone morphogenetic proteins. High levels of expression are also detected in explants treated with high doses of activin A which induces cardiac muscle differentiation. No such effect is seen with lower doses of activin, indicating that a second pathway may regulate the XeHAND gene during cardiogenesis.

DAN is a secreted glycoprotein related to Xenopus cerberus.

We report that DAN, a potential cell cycle regulator and tumour suppressor, is a secreted glycoprotein related to Xenopus cerberus. DAN, cerberus, its mouse relative Cer-1/cer-l/Cerberus-like/Cerr1, and the recently described factor DRM/Gremlin, appear to be members of the cystine knot superfamily, which includes TGFbetas and BMPs. Like cerberus and mCer-1, DAN-induced cement glands as well as markers of anterior neural tissue and endoderm in Xenopus animal cap assays, features of BMP signalling blockade. During mouse embryogenesis, Dan was expressed from E8.5 in cranial mesenchyme and somites, then later in limb and facial mesenchyme. The pattern in somites was highly dynamic, with transcripts initially localized to the caudal half of the nascent epithelial somite, then, after maturation, to sclerotomal cells adjacent to the neural tube. Dan was also expressed in the developing myotome. The expression domains include sites in which BMP inhibition is known to be important for development. Thus, DAN appears to be a secreted factor belonging to the cystine knot superfamily, and one of a growing number of antagonists acting to modulate BMP signalling during development.

A multicentre audit of GDPs knowledge of orthodontic retention.

OBJECTIVE: To determine GDP knowledge and willingness to supervise orthodontic retention and provide replacements retainers. DESIGN: An audit sampling GDPs from six centres within England (Bradford, Cambridge, Burton-Upon-Trent, Croyden, Norwich and Plymouth). A gold standard of 100% of GDPs should be aware of commonly used retainers and be able to provide replacements was selected. METHOD: Overall, 1,053 postal questionnaires were sent to local GDPs. The questions covered knowledge and provision of various retainers, practitioner background and education. GDP satisfaction with the information provided by the orthodontist at discharge was also explored. RESULTS: Five hundred and two questionnaires were received (response rate of 48%). The majority of GDPs (64%) were trained in the UK. Awareness of vacuum-formed, Hawley and fixed retainers was generally high. A significantly smaller number of GDPs were willing to prescribe, fit or review the retainers. The most common reasons for reluctance in provision were insufficient knowledge, financial and time constraints. Over two thirds (72%) of GDPs would like further training on retention. CONCLUSION: This audit highlights a need for increased training at undergraduate and postgraduate levels to update practitioners about contemporary retention practice. Better communication is required from orthodontists to GDPs to ensure that on discharge the dentist is aware of the retainer type and retention regime.

Tissue printed cells from teleost electrosensory and cerebellar structures.

A modification of the tissue printing technique was used to acutely isolate and culture cells from the electrosensory lateral line lobe (ELL), corpus cerebelli (CCb), and eminentia granularis pars posterior (EGp) of the adult weakly electric fish, Apteronotus leptorhynchus. Cells were isolated without the use of proteolytic enzymes and tissue printed as a monolayer onto glass coverslips through centrifugation in the presence of a medium designed to preserve cell structure. Tissue printed cells were reliably distributed in an organotypic fashion that allowed for the identification of anatomical boundaries between the ELL and cerebellar regions, distinct sensory maps in the ELL, and specific cell laminae. Many cells were isolated with an excellent preservation of soma-dendritic structure, permitting direct identification of all electrosensory cell classes according to morphological or immunocytochemical criteria. Several classes of glial cells were isolated, including small diameter microglia and the complex arborizations of oligodendrocytes. A plexus of fine processes were often isolated in conjunction with cell somata and dendrites, potentially preserving synaptic contacts in vitro. In particular, immunolabel for gamma-aminobutyric acid (GABA) revealed a previously unrecognized network of GABAergic axonal processes in the CCb and EGp granule cell body and molecular layers. Tissue printed cells were readily maintained with an organotypic distribution of glial and neuronal elements for up to 27 days in culture. This procedure will allow for the isolation of electrosensory cells from adult central nervous system for electrophysiological analyses of membrane properties or synaptic interactions between identified cells.

Dietary and other characteristics relevant for coronary heart disease in men of Indian, West Indian and European descent in London.

The origins of the high standardized mortality ratio (SMR) for coronary heart disease (CHD) among Indians in Britain, and the low SMR for West Indian immigrants, have been explored by a community survey in London. Serum lipoproteins, plasma glucose, haemostatic factors and other putative risk characteristics were measured in 75 Indian, 64 European and 24 West Indian men aged 45-54 years. These represented 81% of men registered with a general practice and resident within a defined area. In 51 men, diet was assessed by 5-day weighed inventory. Plasma phospholipid fatty acids (PFA) were measured in 18 Indians and 19 Europeans with dietary records. The relatively high HDL and HDL2-cholesterol concentrations, low LDL-cholesterol concentration, reduced fat intake, increased ratio of dietary polyunsaturated/saturated fat, relatively frequent use of alcohol, and lack of obesity in West Indians accorded with their low SMR from CHD. By contrast, only the relatively low HDL and HDL2-cholesterol concentrations, infrequency of alcohol consumption, and lower proportion of PFA as n-3 fatty acids of marine origin afforded explanations for the high SMR of Indians. Hyperglycaemia appeared similarly prevalent in Indians and West Indians, but less common in Europeans. Of the haemostatic factors, West Indians had a relatively low VIIc (not statistically significant), while Indians had an increased platelet count and reduced platelet volume. Improved understanding of these ethnic differences in CHD mortality may depend upon elucidation of the contrasts in HDL-cholesterol concentration.

Convergence of PKC-dependent kinase signal cascades on NMDA receptors.

Synaptic plasticity, or long-term potentiation (LTP), of excitatory synapses in the hippocampus contributes to learning and the establishment of spatial memories. In the CA1 region, induction of LTP enhances the function of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) because of the Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of this subtype of glutamate receptor. Entry of Ca2+, via N-methyl-D-aspartate receptors (NMDARs), during strong synaptic stimulation provides the stimulus to trigger phosphorylation of AMPARs. However, this induction also requires activation of a protein kinase C (PKC)-dependent tyrosine kinase signal cascade and a concomitant upregulation of NMDARs. This review focuses upon NMDARs as potential targets of PKC and/or of the PKC-dependent tyrosine kinase cascade. PKC, acting via the CAKbeta/Src tyrosine kinase cascade, enhances NMDAR activation and may increase the number of receptors expressed in synapses. In contrast, direct phosphorylation of NMDARs by PKC increases the sensitivity of NMDA channel inactivation to intracellular Ca2+. In CAI neurons, PKC provides a point of convergence of control of NMDARs and synaptic plasticity for a wide variety of G-protein coupled and growth factor receptors.