Common and well-documented HLA alleles over all of Europe and within European sub-regions: A catalogue from the European Federation for Immunogenetics.

BACKGROUND: A catalogue of common and well-documented (CWD) human leukocyte antigen (HLA), previously established by the American Society for Histocompatibility and Immunogenetics (ASHI), is widely used as indicator for typing ambiguities to be resolved in tissue transplantation or for checking the universality of any HLA allele in the world. However, European population samples, which are characterized by a substantial level of genetic variation, are underrepresented in the ASHI catalogue. Therefore, the Population Genetics Working Group of the European Federation for Immunogenetics (EFI) has facilitated data collection for an European CWD catalogue. MATERIALS AND METHODS: To this end, 2nd-field HLA-A, -B, -C,- DRB1,- DQA1,- DQB1 and -DPB1 data of 77 to 121 European population samples (21 571-3 966 984 individuals) from 3 large databases, HLA-net/Gene[VA], allelefrequencies.net and DKMS, were analysed. RESULTS: The total number of CWD alleles is similar in the EFI (N = 1048) and ASHI (N = 1031) catalogues, but the former counts less common (N = 236 vs 377) and more well-documented (N = 812 vs 654) alleles than the latter, possibly reflecting differences in sample numbers and sizes. Interestingly, approximately half of the CWD alleles reported by EFI were not reported by ASHI and vice-versa, underlining the distinct features of the two catalogues. Also, although 78 common alleles are widely distributed across Europe, some alleles are only common within specific sub-regions, showing regional variability. CONCLUSION: Although the definition of CWD alleles itself is affected by different parameters, calling for current updates of the list, the EFI CWD catalogue provides new insights into European population genetics and will be a very useful tool for tissue-typing laboratories in and beyond Europe.

Risk factors for nonpurulent leg cellulitis: a systematic review and meta-analysis.

Nonpurulent cellulitis is an acute bacterial infection of the dermal and subdermal tissues that is not associated with purulent drainage, discharge or abscess. The objectives of this systematic review and meta-analysis were to identify and appraise all controlled observational studies that have examined risk factors for the development of nonpurulent cellulitis of the leg (NPLC). A systematic literature search of electronic databases and grey literature sources was performed in July 2015. The Newcastle-Ottawa Scale (NOS) was used to assess methodological quality of included studies. Of 3059 potentially eligible studies retrieved and screened, six case-control studies were included. An increased risk of developing NPLC was associated with previous cellulitis [odds ratio (OR) 40·3, 95% confidence interval (CI) 22·6-72·0], wound (OR 19·1, 95% CI 9·1-40·0), current leg ulcers (OR 13·7, 95% CI 7·9-23·6), lymphoedema/chronic leg oedema (OR 6·8, 95% CI 3·5-13·3), excoriating skin diseases (OR 4·4, 95% CI 2·7-7·1), tinea pedis (OR 3·2, 95% CI 1·9-5·3) and body mass index > 30 kg m-2 (OR 2·4, 95% CI 1·4-4·0). Diabetes, smoking and alcohol consumption were not associated with NPLC. Although diabetics may have been underrepresented in the included studies, local risk factors appear to play a more significant role in the development of NPLC than do systemic risk factors. Clinicians should consider the treatment of modifiable risk factors including leg oedema, wounds, ulcers, areas of skin breakdown and toe-web intertrigo while administering antibiotic treatment for NPLC.

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.

Identification of patients with low-risk pulmonary embolism suitable for outpatient treatment using the pulmonary embolism severity index (PESI).

BACKGROUND: There is increasing evidence that outpatient treatment of patients with low-risk stable pulmonary embolism (PE) is safe, effective and potentially reduces costs. It is not clear how many patients presenting to an Irish Emergency Department (ED) are potentially suitable for outpatient management. AIMS: To identify how many patients presenting to our ED over a 1-year period who were diagnosed with acute PE are potentially suitable for outpatient treatment. METHODS: A retrospective observational study was conducted over a 1-year period. Clinical notes for patients who had a positive computed tomographic pulmonary angiogram (CTPA) within 24 h of presentation to the ED were examined to risk stratify the patients according to the pulmonary embolism severity index (PESI). RESULTS: Forty-seven patients who presented to our ED were diagnosed with a PE. Clinical notes were missing for 3 cases, and 44 cases were analysed further. The mean age was 64.3 (±16.8 SD) years and 24 (54.5 %, 95 % CI 40-68.3 %) were males. Six patients (13.6 %, 95 % CI 6.4-26.7 %) had a background of cancer. Fifteen cases (34.1 %, 95 % CI 21.9-48.7 %) were deemed to be low risk as they were categorised as PESI risk class I or II. Our study found that 61/420 (14.5 %, 95 % CI 11.5-18.2) of CTPAs done were positive for PE. CONCLUSION: This study suggests that a significant percentage of patients diagnosed with acute PE are low risk as per PESI and therefore potentially suitable for outpatient management.

Must we review printed lab reports without checking them? A prospective analysis of emergency department practice.

This study investigated if results of haematology and biochemistry laboratory tests, carried out at the point of care in our Emergency Department, are checked by the clinician who ordered the test, mitigating the requirement to check printed reports later. Five hundred and nineteen (519) laboratory reports were examined for significant abnormal results and documentation in clinical notes. Thirty percent (30%, n = 158) of these met the inclusion criteria for 'significantly abnormal' laboratory results. Of the 158 significantly abnormal results, 34.8% (n = 55) were not documented in the ED clinical case notes. No patient was discharged inappropriately. Our study suggests it is safe to stop routinely rechecking printed biochemistry and haematology laboratory reports in our department.

Paediatric femoral hernia--the diagnostic challenge.

INTRODUCTION: Femoral herniae are uncommon in childhood and pre-operative misdiagnosis is common. This can result in increased complications or inappropriate inguinal exploration. The aim of this retrospective study was to assess a tertiary centre's experience with paediatric femoral hernia over a 12 year period. METHODS: Children who underwent femoral hernia repair at a single centre were identified from a prospectively maintained database. Casenotes were reviewed for demographic data and details of presentation, operation and recurrence. RESULTS: Sixteen children with a median age of 7 (range 3-16) years were identified. One patient developed bilateral femoral herniae. All children were referred with a groin lump but in only one instance did the referring clinician establish the diagnosis of femoral hernia. Emergency repair was required in 2 patients (12%). Eleven femoral herniae were diagnosed following clinical assessment ultrasound. The remainder were identified intra-operatively following negative inguinal exploration. Intra-operatively the femoral canal was closed with sutures (n = 16) or mesh plug (n = 1). Only one patient had a laparoscopic repair. Two other patients underwent laparoscopy to confirm bowel viability (n = 1) and for inguinal canal assessment with subsequent open femoral hernia repair (n = 1). All patients were reviewed in surgical clinic and no morbidity or hernia recurrences were reported. CONCLUSION: Femoral herniae are a diagnostic challenge and a high index of clinical suspicion is necessary. Ultrasonography or laparoscopy may be appropriate in equivocal cases. The long-term results of paediatric femoral hernia surgery are excellent.

Are we following the guiding SIGN when managing paediatric head injury?

BACKGROUND AND AIMS: The Scottish Intercollegiate Guidelines Network (SIGN) has published guidelines for the management of children with head injuries. The management of children with head injuries admitted to our local unit under the Paediatric Surgeons has been audited to determine whether or not current practice follows SIGN recommendations. METHODS: Data were collected retrospectively from the case records of patients admitted between January and December 2007. The SIGN guideline 'Early Management of Patients with a Head Injury' (Guideline 46) was published in 2000 and updated in 2009 (Guideline 110). Head injury admission practices were audited against both guidelines. RESULTS: The case records of 200 patients were analysed. According to SIGN Guideline 46 (2000), 146 Computed Tomography (CT) scans were indicated but only 24 were performed (16%). The updated Guideline 110 (2009) suggests a CT scan was indicated in 24 patients and should have been considered in a further 87. However, only 12 (50%) and 18 (21%) patients were imaged in these respective groups. Both guidelines indicated neurosurgical review in 13 patients but sought in only 4 (31%). 50 patients were deemed to have suffered a significant head injury warranting follow-up, but this was arranged in only 14 (28%). CONCLUSIONS: Our study has identified that management of paediatric head injuries in our unit is reliant on clinical acumen rather than the SIGN guidelines when making decisions regarding the need for imaging, neurosurgical review and follow-up. We suggest further investigation is required to determine whether greater awareness and closer adherence with the guidelines would alter clinical outcomes.

The Last Glacial Maximum.

We used 5704 14C, 10Be, and 3He ages that span the interval from 10,000 to 50,000 years ago (10 to 50 ka) to constrain the timing of the Last Glacial Maximum (LGM) in terms of global ice-sheet and mountain-glacier extent. Growth of the ice sheets to their maximum positions occurred between 33.0 and 26.5 ka in response to climate forcing from decreases in northern summer insolation, tropical Pacific sea surface temperatures, and atmospheric CO2. Nearly all ice sheets were at their LGM positions from 26.5 ka to 19 to 20 ka, corresponding to minima in these forcings. The onset of Northern Hemisphere deglaciation 19 to 20 ka was induced by an increase in northern summer insolation, providing the source for an abrupt rise in sea level. The onset of deglaciation of the West Antarctic Ice Sheet occurred between 14 and 15 ka, consistent with evidence that this was the primary source for an abrupt rise in sea level approximately 14.5 ka.

Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery.

BACKGROUND: Sedation of critically ill children requiring artificial ventilation remains a therapeutic challenge due to large individual variation in drug effects and a paucity of knowledge of pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of remifentanil in children requiring ventilation after cardiac surgery. METHODS: Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 microg kg(-1) h(-1) and a remifentanil infusion that was commenced at 0.8 microg kg(-1) min(-1) for a minimum of 60 min and subsequently decreased by 0.1 microg kg(-1) min(-1)every 20 min until the patient awoke. Arterial blood concentrations of remifentanil and midazolam were measured using high-performance liquid chromatography. Mixed-effects population models were fitted to the remifentanil concentration-time data. RESULTS: Satisfactory sedation was achieved in all patients as assessed by Comfort score during the initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn from the study due to hypotension. Remifentanil pharmacokinetics were best described using a two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance was 68.3 ml kg(-1) min(-1), intercompartmental clearance was 80 ml kg(-1) min(-1), the central compartment volume was 91.7 ml kg(-1), and the peripheral compartment volume was 141 ml kg(-1). CONCLUSIONS: A combination of remifentanil and midazolam provided satisfactory sedation for these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood concentrations.

Spatial restriction of spontaneous activity towards the rostral primary initiating zone during development of the embryonic mouse hindbrain.

In the developing embryonic mouse hindbrain, we have previously shown that synchronized spontaneous activity is driven by midline serotonergic neurons at E11.5. This is mediated, at least in part, by the 5-HT2A receptor, which is expressed laterally in the hindbrain. Activity at E11.5 is widespread within the hindbrain tissue, propagating from the midline to more lateral regions. Using rapid acquisition of [Ca2+]i events along the midline, we now show that the rostral midline, primarily in the region of former rhombomere r2, is the primary initiating zone for this activity. We propose that at E11.5, the combined events along the rostral-caudal axis in combination with events propagating along the medial-lateral axis could assign positional information to developing neurons within the hindbrain. With further development, to E13.5, both the lateral and caudal dimensions of spontaneous activity retract to the rostral midline, occupying an area only 14% of that exhibited at E11.5. We also show that increased levels of [K+]o (to 8 mM) at E13.5 are able to increase the spread of spontaneous activity laterally and rostro-caudally. This suggests that spontaneous activity in the hindbrain depends in a dynamic way on the dominant initiating zone of the rostral midline, and that this relationship changes over development.

Primary role of the serotonergic midline system in synchronized spontaneous activity during development of the embryonic mouse hindbrain.

In the developing embryonic mouse hindbrain, we have shown that previously widespread synchronized spontaneous activity at E11.5 retracts to the initiating zone of the rostral hindbrain by E13.5, and ceases completely by E14.5. We now confirm that at E11.5 and E13.5, the primary driver of spontaneous activity is serotonergic input, while other transmitters (GABA, glutamate, NE, and ATP) have only modulatory roles. Using immunocytochemistry, we also show that at E13.5, 5-HT-positive neurons in the midline extend over a larger rostro-caudal distance than at E11.5, and that in the presumptive initiating zone, cell bodies occupy a band that extends 200 microm laterally on each side of the midline, with extensive axonal processes. The 5-HT2A receptor retains expression in lateral tissue over this developmental time. We find that in addition to being sensitive to 5-HT receptor antagonists, spontaneous activity is also abolished by blockers of gap junctions, and is increased in frequency and lateral spread by application of ammonium, presumably via increased intracellular pH augmenting gap junction conductance. Thus, 5-HT neurons of the midline remain the primary drivers of spontaneous activity at several stages of development in the hindbrain, relying in part on gap junctional communication during initiation of activity.

Testicular torsion: a complication of laparoscopic orchidopexy.

A 19-month-old boy presented with an impalpable right testis. At second-stage Fowler-Stephens laparoscopic orchidopexy, the testicle was found to be torted, a complication that has not been described previously. The procedure, known complications, possible reasons for torsion and possible techniques to avoid torsion occurring are reviewed.

Rapid rise of sea level 19,000 years ago and its global implications.

Evidence from the Irish Sea basin supports the existence of an abrupt rise in sea level (meltwater pulse) at 19,000 years before the present (B.P.). Climate records indicate a large reduction in the strength of North Atlantic Deep Water formation and attendant cooling of the North Atlantic at this time, indicating a source of the meltwater pulse from one or more Northern Hemisphere ice sheets. Warming of the tropical Atlantic and Pacific oceans and the Southern Hemisphere also began at 19,000 years B.P. These responses identify mechanisms responsible for the propagation of deglacial climate signals to the Southern Hemisphere and tropics while maintaining a cold climate in the Northern Hemisphere.

The value of transcranial Doppler in predicting cerebral ischaemia during carotid endarterectomy.

OBJECTIVES: transcranial Doppler (TCD) measurement of middle cerebral artery velocity (MCAV) is an indirect method of assessing cerebral blood flow and therefore predicting patients at risk of stroke during carotid endarterectomy (CEA), and may be used to determine the need for shunting. This study evaluates the accuracy of three accepted TCD criteria in predicting the need for a shunt. DESIGN: prospective study. METHODS: one hundred and twenty consecutive CEA were performed under loco/regional anaesthesia. Patients monitored by TCD and Awake neurological examination were included. Shunts were inserted if there was neurological deterioration. Awake patient monitoring was compared with the three TCD criteria. RESULTS: inadequate TCD recordings were obtained in 16 operations (13%). In the remainder (104 cases), 12 developed symptoms of cerebral ischaemia and required a shunt (12%). Comparisons with the three accepted criteria were as follows: (1) m MCAV <30 cm/s had a sensitivity, specificity, PPV and NPV of 92%, 49%, 19%, and 98%, respectively; (2) clamp/pre-clamp ratio <0.6 had a sensitivity, specificity, PPV and NPV of 92%, 75%, 33% and 99%, respectively; (3) greater than 50% reduction in m MCAV had a sensitivity, specificity, PPV and NPV valves of 83%, 77%, 32% and 97%, respectively. CONCLUSIONS: TCD flow velocities are not a reliable method for detecting cerebral ischaemia and therefore determining the need for a shunt in CEA.

Myeloperoxidase activity as a lung injury marker in the lamb model of congenital diaphragmatic hernia.

PURPOSE: The antioxidant system is the primary intracellular defense system of the lung against oxygen toxicity (neutrophil sequestration). The CDH lamb model antioxidant system is deficient. It is hypothesized that pulmonary neutrophil sequestration may play a part in the acute lung injury of CDH patients. Myeloperoxidase (MPO) is a major constituent of neutrophil cytoplasmic granules and its activity therefore is a direct measure of neutrophil presence and an indirect indicator of lung injury. METHODS: Eight lambs had left-sided diaphragmatic hernias surgically created at 80 days' gestation and were delivered by cesarean section at 140 to 145 days. Eight littermate lambs served as controls. Lambs were either killed before ventilation or were ventilated conventionally for 4 hours with 100% O(2) and then killed. The lungs were dissected en bloc and snap frozen. The samples were homogenized, sonicated, freeze-thawed, and separated by density centrifugation. Supernatants were analyzed for myeloperoxidase (MPO) activity by spectrophotometry with o-dianisidine dihydrochloride and hydrogen peroxide at 460 nm. The MPO activity was normalized to the protein content of the supernatant and expressed as units of MPO activity per milligram of protein. RESULTS: There was significantly more MPO activity in the CDH-ventilated lungs than controls similarly ventilated (3,203 +/- 665 versus 1,220 +/- 194, P =.001). There was no difference in MPO activity between the CDH and control lungs (318 +/- 57 v 348 +/- 61; P =.5). There was no difference between right and left lungs in any group. CONCLUSION: Ventilation and hyperoxia leads to neutrophil accumulation in lung tissue, which is most pronounced in the CDH lung tissue. This is a further clue to the pathophysiology of iatrogenic lung injury in CDH. The myeloperoxidase assay may now be used to evaluate antenatal or postnatal antioxidant therapies for iatrogenic lung injury in CDH.

Upregulation of keratinocyte growth factor in the tracheal ligation lamb model of congenital diaphragmatic hernia.

PURPOSE: Congenital diaphragmatic hernia (CDH) carries a high mortality rate of 60% because of associated anomalies, pulmonary hypoplasia, pulmonary hypertension, and type II cell dysfunction. Prenatal tracheal ligation has been shown to improve lung growth in experimental models. This could be caused by a direct effect of increased endothoracic pressure in utero, secondary to the induction of specific growth factors, or both. Keratinocyte growth factor (KGF) is involved in normal lung organogenesis and is a potent mitogen of alveolar type II cells. The authors have therefore investigated the protein and mRNA levels of keratinocyte growth factor in the lung tissue of control, CDH, and CDH tracheal ligation lambs. METHODS: Eight lambs had left-sided diaphragmatic hernias surgically created at 80 days' gestation. Tracheal ligation was performed at 110 days in 4 lambs, and they were delivered by cesarean section at 140 to 145 days. Twin littermates served as controls. The lungs were dissected en bloc and snap frozen. KGF protein levels were determined by ELISA. Total RNA was isolated, and a RNase protection assay was performed using an ovine cDNA probe for KGF, and a human cDNA probe for GAPDH (house keeping control). Densitometric analysis was used to quantify the relative amounts of mRNA in each sample. RESULTS: There was a significant decrease in the KGF protein levels of the CDH samples (110 v 73.2 pg/mg protein, P =.02). This decrease was mirrored by a significant fall in the level of mRNA expression for KGF (0.694 v 0.235, P = .02). Tracheal ligation normalized the KGF protein levels (96.1 pg/mg protein). This elevation of KGF protein was accompanied by an upregulation of KGF gene expression to control levels (0.56). CONCLUSIONS: Tracheal ligation clearly is accompanied by an upregulation of keratinocyte growth factor protein and gene expression. It is not yet clear whether keratinocyte growth factor is solely responsible for the growth observed in these tracheal ligation preparations. Further growth factor blocking experiments are required.

Bioavailability of n-3 polyunsaturated fatty acids (PUFA) in foods enriched with microencapsulated fish oil.

OBJECTIVE: Incorporation of fish oil into food products provides a means of increasing n-3 fatty acid intake, particularly in populations where fish consumption remains low. The aim of the present study was to evaluate the bioavailability of n-3 PUFA in microencapsulated fish-oil-enriched foods compared with an equal amount of n-3 PUFAs contained in fish oil capsules. METHODS: Twenty-five healthy female volunteers were randomly assigned to one of two groups for the 4-week intervention: one group received 0.9 g of n-3 PUFA/day as fish oil capsule (capsule group), while the second group (food group) received an equal amount of n-3 PUFA/day from enriched foods. Baseline and post-intervention samples were analysed for platelet fatty acid composition. RESULTS: There was no significant difference in the change in platelet arachidonic acid (AA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) between the two groups following the intervention. CONCLUSIONS: The results indicate that n-3 PUFA from microencapsulated fish-oil-enriched foods are as bioavailable as n-3 PUFA in a capsule. Fortification of foods with microencapsulated fish oil, therefore, offers an effective way of increasing n-3 PUFA intakes and status in line with current dietary recommendations.