ADAM12-cleaved ephrin-A1 contributes to lung metastasis.

Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-ß1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis.

Thirst perception and arginine vasopressin production in a kindred with an activating mutation of the type 2 vasopressin receptor: the pathophysiology of nephrogenic syndrome of inappropriate antidiuresis.

BACKGROUND: Activating mutations of the vasopressin receptor gene on the X chromosome cause the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). We describe a male child who presented with persistent hyponatraemia and whose mother was also found to be hyponatraemic. She had learnt to avoid excess fluid consumption because of associated malaise. Both individuals had a subnormal ability to excrete a water load with mother also demonstrating a heightened sense of thirst at low serum osmolalities. RESULTS: Mother and child were found to have the previously characterised activating mutation (p.Arg137Cys) of the arginine vasopressin receptor type 2 gene (AVPR2), but had measurable levels of AVP when hyponatraemic. CONCLUSIONS: We conclude that female carriers of activating mutations of the vasopressin receptor are susceptible to hyponatraemia and therefore need to be provided with advice regarding fluid intake. An altered thirst perception may increase susceptibility to hyponatraemia. We confirm that the presence of measurable amounts of AVP in patients with hyponatraemia does not exclude the diagnosis of NSIAD.

Do systemic symptoms predict the risk of kidney scarring after urinary tract infection?

BACKGROUND AND AIMS: In the NICE guideline on childhood urinary tract infection (UTI), it is assumed that the presence or severity of systemic symptoms, especially fever, predicts for renal scarring, and different management is recommended accordingly. We aimed to test this hypothesis by retrospective case note analysis. DESIGN AND SUBJECTS: Notes of children aged under 5 years referred with a first UTI who were assessed for scarring were reviewed. MAIN OUTCOME CRITERIA: Ability to predict for single or multiple scarring from age, sex, fever, vomiting or anorexia or malaise, or need for hospitalisation, within the age bands used by NICE. RESULTS: There were 51 (65% girls) scarred and 140 (69% girls) unscarred children. Fever, systemic symptoms and hospitalisation were all commoner among younger children (<6 months vs 6 months-3 years vs >3 years; fever 0.67 vs 0.38 vs 0.38; systemic symptoms 0.78 vs 0.62 vs 0.43; hospitalisation 0.67 vs 0.29 vs 0.19; p<0.001 for all). Having vomiting, anorexia or malaise at presentation correlated weakly with single or multiple renal scarring (R(2) = 0.03; p = 0.02), but sex, age, fever or hospitalisation did not (p>0.5 for all). Sensitivity and specificity data, and plots of proportionate reduction of uncertainty showed that none of these variables was useful for predicting any scarring in children aged <3 years and that they were only weakly predictive in older children. CONCLUSIONS: Clinical signs at presentation in childhood UTI cannot be used to predict for mild or multiple scarring, and should not be used to guide management. NICE's recommendation to do so is not justified.

Will changing maintenance intravenous fluid from 0.18% to 0.45% saline do more harm than good?

The recommended change in maintenance intravenous fluid in children from 0.18% to 0.45% saline might cause more children to develop hypernatraemia than it would prevent children from developing hyponatraemia, and thus could do more harm than good. There is no simple formula that will guarantee to prevent either hyponatraemia or hypernatraemia in all children, and it is impossible to decide on a safe fluid regimen merely by knowing the plasma sodium concentration and estimating the degree of dehydration, as is often done. Changing which fluid is used for routine maintenance therapy will not compensate for using a too-simple approach to fluid replacement. Instead, it is necessary to base the fluid regimen on an assessment of the child's physiology. A vital part of that assessment includes measuring the urinary volume, sodium and creatinine, and using them to calculate the fractional excretion of water and sodium. This enables fluid replacement to be decided using a logical approach in which plasma sodium measurements are just used for fine-tuning. Also, 0.18% saline provides a more physiological standard replacement than 0.45% saline, equivalent to normal oral intakes, and should remain the basic maintenance fluid.

Using saline solutions for ACE washouts.

We had found that twice-normal saline (2NS) antegrade continence enema (ACE) lavages were better than with normal saline (NS) but caused unpleasant symptoms. We therefore undertook a double-blind crossover study comparing water, NS and 2NS in four children. NS produced no disturbances, but water caused a transient fall in plasma osmolality of 7.3 mosmol/kg at 20 min, and falls in urine sodium and osmolality. With 2NS, the plasma sodium rose by 2.5 mmol/l, the plasma proteins rose by 2.3 g/l and the lavage fluid sodium fell, suggesting that about 10 ml/kg of plasma water had moved into the colonic lumen, and two subjects became thirsty. Five other children did home testing. Their home-produced saline was too concentrated and varied widely, and they found that 30 ml/kg of NS produced the same washout result as 20 ml/kg of 2NS. Carefully made-up NS should be used for lavage, increasing volumes if necessary.

Effect of heparin-bonded central venous catheters on the incidence of catheter-related thrombosis and infection in children and adults.

The use of central venous catheters, while advantageous, is associated with a range of complications including thrombosis and infection. These complications can pose significant physical and financial costs to the patient and health care system. A critical appraisal of the two randomized controlled trials examining this topic in critically ill patients has shown that heparin-bonded central venous catheters significantly reduced the incidence of catheter-related thrombosis and infection in children and adults. These findings suggest that heparin-bonded central venous catheters should be considered for routine use in critically ill patients.

Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly.

The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic (MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated than that of the unaffected twin (P < .0001), which was significantly more methylated than those of the controls (P = .02). We have confirmed that this CpG island does function as a promoter in vitro and that its activity is inversely proportional to the extent of methylation. This finding raises the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. This case may be paradigmatic for some cases of MZ discordance.

Does antenatal pelvic dilation predict renal scarring?

Moderate antenatal renal pelvic dilation (5-15 mm) may suggest vesicoureteric reflux, but it is not known to predict renal scarring. Dimercaptosuccinic acid scans on such children aged over 4 years showed a scarring rate (0/133 boys, 1/56 girls) similar to our local population. Investigation and treatment of moderate dilation may not be required.

End stage renal disease due to bilateral renal malakoplakia.

Malakoplakia typically affects the bladders of immunocompromised adults who have defective intracellular killing of Escherichia coli. Renal malakoplakia is rare in children and generally has a good outcome. In the case presented, however, it caused end stage renal failure in a 5 year old girl. The management dilemmas surrounding renal transplantation are highlighted.

Outcome of reaching end stage renal failure in children under 2 years of age.

AIMS: To determine the outcome of children who reach end stage renal failure before the age of 2 years. METHODS: Using a retrospective questionnaire, 10 years' data were collected from the paediatric nephrology units in Britain and Ireland (1988 to 1997, follow up 1.3-11.5 years). RESULTS: A total of 192 children were identified; 0.31/million/year. Most had congenital or inherited conditions, and there were more boys. Latterly, half were diagnosed antenatally. Ninety per cent were dialysed initially, most using home peritoneal cyclers, some by haemodialysis through central lines. Five per cent recovered sufficient function to come off dialysis. Most required tube feeding (often gastrostomy) and erythropoietin; some needed growth hormone. A total of 56% received a transplant (2% without prior dialysis) at (medians) 2.6 years and 12.3 kg. The 2 and 10 year survival of first kidneys was 78%. Growth improved following transplantation. Fourteen per cent died because treatment was not started or was withdrawn. Most had particularly complex renal conditions, or additional major non-renal diagnoses. Typically, decisions not to treat were made mutually between clinicians and families. When treatment was continued, 71% survived, and few had serious non-renal conditions. Most attended normal schools, and by 6 years of age, less than 10% still required dialysis. Infants starting treatment under and over 1 month of age fared equally well. CONCLUSIONS: By school age, most infants treated for end stage renal failure will have a functioning transplant, reasonable growth, and will attend a normal class, regardless of the age at which they commence treatment. Treatment is seldom sustained in children who have serious additional medical conditions. It is reasonable to treat infants with uncomplicated renal failure.

Polycythaemia and hypertension caused by renal artery stenosis.

A girl with failure to thrive and a haemoglobin of 140 g/l at 1.3 years died from a brain haemorrhage 2.5 years later. Renal artery stenosis had caused severe, chronic hypertension and increased erythropoietin secretion (haemoglobin 182 g/l). Blood pressure should be measured in all unwell children, including those failing to thrive.

Selective renal embolisation for renovascular hypertension?

An 11 year old girl developed hypertensive encephalopathy and renal failure from reflux nephropathy. Resection of her shrunken left kidney did not control her hypertension. Two selective arterial embolisations of the scarred right lower pole produced only transient benefit, but a heminephrectomy gave good control. Embolisation may delay definitive treatment.

Medical emergencies in general practice in south-east Queensland: prevalence and practice preparedness.

OBJECTIVE: To determine the type and frequency of emergencies in general practice, and the extent to which general practices are equipped to appropriately respond to emergencies. DESIGN: Random-sample, cross-sectional questionnaire survey of general practitioners, October 1999 - March 2000. SETTING: General practices in south-east Queensland. PARTICIPANTS: 512 of 900 eligible GPs in current clinical practice. MAIN OUTCOME MEASURES: The type and frequency of medical emergencies presenting to GPs, and descriptive details of emergency drugs and equipment available in their practices. RESULTS: 512 GPs (response rate, 57%) reported managing a cumulative total of 5640 emergencies over the preceding 12 months. Non-metropolitan GPs saw about 30% more emergencies than their metropolitan counterparts (median, 9 and 7, respectively; P=0.02). The most common emergencies (seen by more than 30% of all GPs) were acute asthma, psychiatric emergencies, convulsions, hypoglycaemia, anaphylaxis, impaired consciousness, shock, poisoning and overdose. Most GPs (77%) stocked 15 or more of the 16 emergency doctor's bag drugs, but a smaller proportion (67%) had all of the basic emergency equipment items considered essential. CONCLUSIONS: A substantial number of patients with potentially life-threatening emergencies present to GPs. Doctor's bag emergency drugs are available in most general practices, but availability of basic emergency equipment is suboptimal.

Characterization of the Epha1 receptor tyrosine kinase: expression in epithelial tissues.

The Eph family of receptor tyrosine kinases plays a crucial role during development and is implicated in oncogenesis. Using a partial cDNA clone of an Eph-related kinase (Esk) we isolated the complete coding region of a gene which we show to be murine EphA1 by both structural and functional criteria. The chromosomal localization is shown to be syntenic to hEphA1 and the genomic organization also shows distinct features found in the hEphA1 gene. Functionally, in keeping with findings for the human homologue, both soluble recombinant and "native" mEphA1 show preferential binding to ephrin A1. However, we also observed significant binding to other A-type ligands as has been observed for other Eph receptors. We analysed the expression of mEphA1 mRNA by in situ hybridization on tissue sections. mEphA1 was expressed in epithelial elements of skin, adult thymus, kidney and adrenal cortex. Taken together with previous Northern blotting data these results suggest that mEphA1 is expressed widely in differentiated epithelial cells.

Haemodialysing infants: theoretical limitations, and single versus double lumen lines.

Haemodialysing small infants is difficult because of vascular access limitations. We show that Poiseuille's law (that flow through a tube varies with its radius4) makes it inevitable that the blood flow that can be achieved in smaller patients will fall disproportionately compared to their need for dialysis. Poiseuille's law also predicts that for single and multiple lumen cannulae of the same outside gauge, blood flow through the single lumen will be several times greater. Measurements confirmed this. It is argued that haemodialysis efficiency will therefore be improved by using a single lumen cannula to alternately withdraw and return blood, compared to sampling and returning continuously through a multiple lumen cannula, despite only withdrawing for half the time.