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Context: Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia.Objectives: Assess the natural history of clinical and laboratory findings in 24 patients with JMC and characterize the disease-causing mutant receptors in vitro.Patients and Methods: The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons. Laboratory records were analyzed individually and in aggregate.Results: Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 +/- 1.37 mg/dL) and tended to normalize in adults (10.0 +/- 1.03 mg/dL). Mean phosphate levels were at the lower end of the age-specific normal ranges. Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 +/- 0.40; adults, 0.28 +/- 0.19). Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation. Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease. The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells. The inverse agonist [L-11,dW(12),W-23,Y-36] PTHrP(7-36) reduced basal cAMP signaling for each PTHR1 mutant.Conclusions: Except for T410R, the other PTHR1 mutations were associated with indistinguishable mineral ion abnormalities and cause similarly severe growth impairment. Hypercalciuria persisted into adulthood. An inverse agonist ligand effectively reduced in vitro PTH-independent cAMP formation at all five PTHR1 mutants, suggesting a potential path toward therapy.

This study determined spatio-temporal invasion dynamics of Phytophthora cinnamomi, examined differences between disease centres and inferred mechanisms of invasion. Patch disease extension was measured from aerial photographs of three Banksia woodland areas infested with P. cinnamomi. Disease extension was also determined from the fronts of six disease centres in Banksia woodland biomes and a disease front in Eucalyptus marginata forest. A localised, salient, disjunct pattern of spatial variation in upslope disease extension that occurred in all disease centres between years was probably due to growth of P. cinnamomi in major lateral roots and infection of plants by root to root contact. The square root of the area invaded was significantly related to year after first assessment (R 2 = 0.59–0.97). Linear rates of disease extension from baselines with years after first assessment ranged from 0.1 ± 0.07 and 1.46 ± 0.39 m/year. Differences in P. cinnamomi isolation frequency, community structure and measured variables in different soils did not indicate reasons for the variation in rate of invasion between Banksia woodland disease centres. Management options to limit invasion will depend on whether disease extension is the result of unrestricted movement of infectious propagules in overland and subsurface flows, or relatively restricted growth through roots and root to root contact. The hierarchy of factors affecting the invasive success of P. cinnamomi is discussed.

Objective. Polyarteritis nodosa (PAN) is a rare disease of childhood. The aims of this study were to describe the clinical features, treatment, and outcome of systemic childhood PAN and to identify predictors of relapse. Methods. A single-center retrospective medical records review of children with PAN fulfilling the European League Against Rheumatism (EULAR)/Paediatric Rheumatology European Society (PRES)/Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria who were seen over a 32-year period was performed. Data on demographic and clinical features, treatments, relapses (recurrence of clinical signs/symptoms or occurrence of new symptoms after initial remission requiring escalation or resumption of immunosuppressive therapy), and deaths were recorded. A disease activity score was retrospectively assigned using the Paediatric Vasculitis Activity Score (PVAS) instrument. Cox regression analysis was used to identify significant predictors of relapse. Results. Sixty-nine children with PAN were identified; 55% were male, and their median age was 8.5 years (range 0.9–15.8 years). Their clinical features at presentation were fever (87%), myalgia (83%), skin (88%), renal (19%), severe gastrointestinal (GI) (10%), and neurologic (10%) involvement. The PVAS at presentation was 9 of 63 (range 4–24). Histopathologic analysis of the skin showed necrotizing vasculitis in biopsy samples from 40 of 50 children. Results of selective visceral arteriography suggested the presence of PAN in 96% of patients. Treatment included cyclophosphamide and corticosteroids (83%), plasma exchange (9%), and biologic agents (after 2002; 13%). The relapse rate was 35%, and the mortality rate was 4%. Severe GI involvement was associated with increased risk of relapse (P 0.031), while longer time to induce remission (P 0.022) and increased cumulative dose of cyclophosphamide (P 0.005) were associated with lower relapse risk. Conclusion. Childhood PAN is a severe inflammatory disease of insidious onset and variable clinical presentation. Relapses occurred more frequently in those with severe GI involvement. A higher cumulative dose of cyclophosphamide was associated with a lower risk of relapse.

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Resumen: La hipertensión en niños y adolescentes ha ido ganando terreno en la medicina cardiovascular, gracias a los avances producidos en distintas áreas de la investigación fisiopatológica y clínica. Estas guías nacen del consenso al que han llegado los especialistas en la detección y control de la hipertensión en niños y adolescentes. Por otra parte, dichas guías son un compendio de los datos científicos y la extensa experiencia clínica con la que se cuenta, y constituyen la información clínica más completa que los médicos, enfermeras y familiares deberían tener en cuenta a la hora de tomar decisiones. Estas guías, que hacen hincapié en la importancia de la hipertensión en niños y adolescentes, así como en el papel que desempeña en la actual epidemia de enfermedades cardiovasculares, deberían constituir un estímulo para que los gobiernos desarrollaran un esfuerzo global para una detección precoz y un tratamiento adecuado de la hipertensión arterial en niños y adolescentes. J Hypertens 27:1719-1742 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. Abstract: Hypertension in children and adolescents has been gaining ground in cardiovascular medicine, mainly due to the advances made in several areas of pathophysiological and clinical research. These guidelines arose from the consensus reached by specialists in the detection and control of hypertension in children and adolescents. Furthermore, these guidelines are a compendium of scientific data and the extensive clinical experience it contains represents the most complete information that doctors, nurses and families should take into account when making decisions. These guidelines, which stress the importance of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, should act as a stimulus for governments to develop a global effort for the early detection and suitable treatment of high pressure in children and adolescents. J Hypertens 27:1719-1742 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Summary Superantigens (SAgs) are potent stimulators of T cells bearing specific Vβ T cell receptors (TCR) and may play a role in the pathogenesis of Kawasaki syndrome (KS), although despite 15 years of intense study this area remains controversial. Because SAgs can cause Vβ restricted T cell activation in the absence of Vβ skewing the aims of this study were to describe a flow cytometric protocol to study both CD4 and CD8 Vβ repertoires, and CD69 expression across the CD4 and CD8 Vβ repertoire in children with KS. Sixteen children with KS were studied. There was no significant increase in overall peripheral blood CD4 or CD8 T cell activation as determined by CD69 expression. However, Vβ restricted CD4 and/or CD8 activation was observed in eight of 11 (72%) of the KS patients, a finding not observed in healthy controls. Thirteen of 16 (81%) of the KS patients had evidence of either Vβ skewing (particularly CD4 Vβ2 and Vβ5·1) and/or Vβ restricted activation. Three patients had Vβ restricted activation in the absence of skewing. We suggest that these preliminary observations highlight the many layers of complexity when considering T cell activation in KS, which could explain some of the conflicting studies regarding peripheral blood T cell activation and Vβ skewing. It is likely that in order to move forward with this debate a combination of detailed microbiological, immunological and molecular techniques applied to individual patients will be required ultimately to prove or refute the SAg hypothesis of KS.

Objectives: Indeterminate intestinal inflammation may result from a variety of inflammatory conditions in addition to ulcerative colitis and Crohn disease. The primary systemic vasculitides may present with intestinal inflammation and an indeterminate colitis. We set out to describe a series of children with primary systemic vasculitis who initially presented with clinical features suggestive of inflammatory bowel disease (IBD) to establish criteria that might help discriminate between IBD and primary systemic vasculitis. Methods: Ten children (6 boys, median age at presentation 8.9 years, range 0.9-14.5 years) satisfied inclusion criteria. Results: All had abdominal pain, weight loss, diarrhea (6 of 10 bloody) and laboratory evidence of a severe acute phase response. Extraintestinal clinical features included vasculitic rash, renal impairment, myalgia, testicular pain and polyarthritis. Endoscopy showed vascular changes or other macroscopic findings suggestive of vasculitis in 5 of 10 patients. Gut histology revealed indeterminate chronic inflammatory mucosal changes and one patient with small artery fibrinoid necrosis in the submucosal vessels. Extraintestinal biopsy was performed in 6 patients and had a higher yield for the demonstration of vasculitis than intestinal biopsy. The results of selective visceral angiography was suggestive of vasculitis in all patients, but was normal in 7 cases of treatment-unresponsive classic IBD. Treatment comprised corticosteroid and azathioprine in all patients. Cyclophosphamide was given to 7 of 10 patients. Conclusions: Extraintestinal manifestations and inflammatory responses that may be disproportionate to the degree of intestinal inflammation provide clues to the presence of an underlying primary systemic vasculitis, and these data suggest that selective visceral angiography plays a key role in the diagnosis of vasculitis in this context. It is important to identify and treat any vasculitic component because failure to do so may result in consequential morbidity or mortality.

Objective. Microparticles are released from endothelial cells in response to a variety of injurious stimuli and recently have been shown to be increased in a number of diseases associated with endothelial dysfunction. This study examined endothelial microparticle (EMP) and platelet microparticle (PMP) profiles in children with systemic vasculitis to test the hypothesis that EMPs may provide a noninvasive means of examining endothelial activation or injury. Methods. The study cohort comprised 39 children with systemic vasculitis at various stages of disease activity, 24 control children with febrile disease, and a control group of 43 healthy subjects. Plasma was ultra-centrifuged at 17,000g for 60 minutes, and the microparticle pellets were examined using flow cytometry. Results. Plasma from patients with active systemic vasculitis contained significantly higher numbers of E-selectin-positive EMPs compared with that from patients in remission, healthy controls, or febrile disease controls (P = 0.000 for each). A similar result was obtained for the numbers of EMPs expressing the marker CD105. There was also a significant increase in PMPs expressing CD42a in the active vasculitis group as compared with the other groups, but this difference was not significant for PMPs expressing P-selectin. The EMP counts correlated with the Birmingham Vasculitis Activity Score and the acute-phase reactant levels in the patients with systemic vasculitis, but there was a poor correlation overall between EMP counts and the acute-phase reactant levels in the febrile disease controls. Conclusion. EMPs may provide a window to the activated endothelium and could provide important pathophysiologic insights into the vascular injury associated with vasculitis of the young.

Objective. To study the clinical spectrum of Behcet's disease (BD) in childhood, and to report our experience of using thalidomide. Method. Ten children, diagnosed with BD, were studied retrospectively. Results. The median (range) age at first presentation was 4 (1.2-12.0) yr, at diagnosis was 11 (3-15) yr and the follow-up period was 4.1 (0.6-6.3) yr. Oral ulcers were present in all patients (100%), genital ulcers were present in six (60%), peri-anal ulcers were present in three (30%), skin manifestations were present in nine (90%), intracranial hypertension was present in two (20%), mild gastrointestinal symptoms were present in five (50%), joint symptoms were present in six (60%), ocular lesions were present in five (50%), but only one child had anterior and posterior uveitis. Therapeutically, a range of drugs was used, including colchicine, that resulted in good responses in five children. Thalidomide (1 mgukguweek to 1 mgukguday) was used in five children who were unresponsive to other immunosuppressive agents. It resulted in complete remission in three children and less frequent milder oral ulcers in two. Neuropathy developed in two children and in one it was irreversible. Conclusion. BD in children is similar to the disease in adults. Thalidomide provided a useful therapeutic option for severe oral and genital ulceration which was unresponsive to other therapies. Awareness of the danger of axonal neuropathy and teratogenesis at all times during thalidomide therapy is crucial. A low dose is probably as effective as higher doses.

Cytotoxic drugs prevent cell division or cause cell death.1 They act predominantly on rapidly dividing cells such as T lymphocytes, and are therefore immunosuppressive and anti-inflammatory.1 When cytotoxic drugs were initially used in the treatment of cancer, it became apparent that they had profound effects on the immune system. This “unwanted” side effect has subsequently been exploited for the treatment of non-malignant disease where autoimmune mechanisms are considered important in the pathogenesis.2 More recently drugs such as cyclosporine, which act more specifically on the immune system via the inhibition of T lymphocyte function, are being used for the treatment of disease with immunologically mediated mechanisms. Generally speaking cytotoxic drugs (CDs) have anticancer activity as well as immunosuppressive properties, whereas immunosuppressive drugs (ISDs) show a more specific immunosuppressive effect, although this distinction is partly arbitrary. For the purposes of this review we have adopted the classification described in the British National Formulary defining cyclosporine as an ISD; cyclophosphamide, vincristine, chlorambucil, and methotrexate as CDs; and azathioprine (and its active metabolite 6-mercaptopurine) and mycophenolate mofetil as “cytotoxic immunosuppressants”. This review concentrates on the use of ISDs and CDs in the management of vasculitis and rheumatological disease, idiopathic nephrotic syndrome, and inflammatory bowel disease. For the majority of the disorders discussed treatment with ISDs and CDs will usually be initiated by clinicians with experience of the condition. Reference to efficacy and safety of ISDs and CDs in children will be made. Specifically, the use of ISDs and CDs in organ transplantation will not be addressed. CDs act primarily on rapidly dividing cells such as malignant cells, or those of the immune system, particularly T lymphocytes.1 Thus CDs have both anti-inflammatory and immunosuppressive effects. Azathioprine (and its metabolite 6-mercaptopurine) and mycophenolate mofetil inhibit biosynthesis of purines and act during the …

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense muta...

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension.

The prevalence of antineutrophil cytoplasmic antibodies (ANCA) was studied in 12 children with Wegener's granulomatosis. The serum samples were taken in the active phase of disease and were screened for ANCA by indirect immunofluorescence with normal neutrophils and enzyme linked immunosorbent assay (ELISA) using crude neutrophil extract, proteinase 3, myeloperoxidase, cathepsin G, lactoferrin, and elastase as antigens. Of these 12 patients, 10 were positive for ANCA in the active phase of their illness, and they showed a predominantly cytoplasmic ANCA staining pattern on indirect immunofluorescence. There were high titres of ANCA directed against crude neutrophil extract, proteinase 3, myeloperoxidase, and cathepsin G. IgM isotypes occurred as commonly as IgG isotypes. Therefore, screening for ANCA is usually but not invariably positive in children with Wegener's granulomatosis. Specific diagnosis still relies on clinical and pathological features, and the value of ANCA in the diagnosis of paediatric Wegener's granulomatosis requires further study.

Renal scarring associated with vesico-ureteric reflux (VUR), most commonly detected in young children, is associated with a significant risk of developing hypertension in later life. Hypertension in reflux nephropathy contributes significantly to morbidity including deterioration of renal function. The mechanism of onset of hypertension is not clear although abnormalities of the renin-angiotensin system and sodium/potassium ATPase activity have been described in some cases. It is becoming clear that radiologically detectable renal scars or small kidneys may histologically indicate a variety of diagnoses. Prediction of the risk of developing hypertension in individual cases is difficult and therefore regular follow-up remains the only current means of recognising these subjects. Although prevention of renal scar development in children with VUR may offer some benefit in reducing the incidence of hypertension, there is no uniform action that can definitely achieve this, particularly in the very young, before any urinary infection occurs. Primary VUR seems to be a disorder with mendelian dominant inheritance and location of the gene may offer some hope of early identification within certain families. Timely introduction of preventative measures may then be possible even though reservations exist about their effectiveness.

Vasculitis can and does occur in childhood. Apart from the relatively common vasculitides (Henoch–Schönlein purpura, Kawasaki disease and in world wide terms Takayasu disease) there are a number of important but comparatively rare disorders affecting children. These include macroscopic and microscopic polyarteritis, cutaneous polyarteritis, Wegener's granulomatosis, Churg–Strauss syndrome, primary angiitis of the central nervous system, hypersensitivity angiitis, hypocomplimentaemic urticarial vasculitis, vasculitis associated with various connective tissue disorders and vasculitis associated with conditions such as Behçets syndrome, familial Mediterranean fever and Cogan's syndrome. Distinguishing these conditions from other disorders is often difficult and requires clinical acumen and appropriate investigative procedures. With modern therapeutic agents, it is possible to implement appropriate therapy but in spite of this, there remains a not inconsequential morbidity and mortality.

Systemic vasculitis is a rare condition and diagnosis is often difficult. Any organ system can be affected and patients can present with an insidiously progressive illness, a remitting/relapsing pattern, or acute multisystem failure. The early institution of aggressive and potentially toxic immunosuppression may be necessary to minimise permanent organ damage, and, despite the difficulties, rapid and unambiguous diagnosis is sometimes of great importance. The development of assays for antineutrophil cytoplasm antibodies (ANCAs) over the past decade has provided clinicians with a laboratory test for vasculitis. Classification of the vasculitides is confusing and has been the subject of a recent international consensus conference.1The conditions most associated with the presence of ANCAs are small vessel necrotising vasculitides such as Wegener’s granulomatosis, microscopic polyangiitis (microscopic polyarteritis), and pauci-immune crescentic glomerulonephritis. ANCAs were first described in 1982 in eight Australians with segmental necrotising glomerulonephritis,2 and the association with vasculitis was soon recognised.3 In 1985 van der Woude et al reported that ANCAs were specific for Wegener’s granulomatosis, and that the titre was associated with the degree of disease activity.4 In 1988 ANCAs were first described in children, in three cases of necrotising glomerulonephritis.5 Subsequently ANCAs have been reported, in both adults and children, in numerous conditions characterised by vasculitis and inflammation.6 Recent work has also suggested that they may be pathogenic in vasculitis. ### INDIRECT IMMUNOFLUORESCENCE (IIF) IIF detects the binding of antibodies to antigens in the cytoplasm of whole ethanol fixed neutrophils. It is subjective, semiquantitative, and requires experience to interpret. However, it is a rapid and standard technique and is widely available.7 Two major staining patterns can be distinguished: granular cytoplasmic staining with central accentuation, known as C-ANCA, and perinuclear staining, known as P-ANCA. A C-ANCA pattern usually corresponds to antibodies against proteinase 3,8 and P-ANCA staining …

Craniometaphyseal and craniodiaphyseal dysplasia are rare genetic disorders of bone due to modelling errors of long bones and skull bones. These syndromes present with multiple ENT symptomatology from an early age. The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis. We review the clinical, radiological, computed tomography (CT) scan, otological, audiological and histopathological findings in two cases with craniodiaphyseal, and two cases with craniometaphyseal dysplasia, and report our experiences of medical and surgical treatment to date.In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up. Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion. Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived. Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases. The underlying defect, causing net bone formation in these phenotypically similar syndromes, appears to be different when based on the differing biochemical responses to calcitriol and bone biopsy findings. Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia.Early recognition is crucial in these conditions as therapy directed at the underlying bony defect has the best chance of success if initiated in infancy (Cole et al., 1988; Fanconi et al., 1988; Key et al., 1988).

SUMMARY Fifty-nine children with acute Kawasaki disease (KD), a childhood vasculitis, were compared with 35 children with fever due to infection and 48 healthy children. Levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1)in the healthy children were double those found in adults. All three soluble cell adhesion molecules and von Willebrand factor (vWF) were higher in the children with KD than in the healthy children, but only sE-selectin, a marker for activated endothelial cells, and sICAM-1 were higher than in the febrile children. The high levels of vWF in KD appear to reflect the prominent acute-phase reaction. This information can help us to understand further the complex interactions between cytokines. circulating inflammatory cells and the vascular endothelium, and may lead to new therapeutic avenues in KD and other inflammatory diseases and vasculitides.

SUMMARY To confirm the presence of antiendothelial cell antibodies (AECA) and study the clinical value of their measurement in Kawasaki disease (KD), sera from patients with KD were assessed for binding to human umbilieal vein endothelial cells (HUVEC) using a cellular based ELISA, and for complement-mediated cytotoxicity using 111 In-labelled HUVEC. In the ELISA assay, IgM AECA were detected in 16/22 sera, whereas IgG AECA were only present in one out of 19 sera. There was a significant difference in IgM AECA titres when comparing patients with controls. Eight out of 16 sera showed cytotoxicity against HUVEC, and this was significantly enhanced when HUVEC were pretreated with tumour necrosis factor (TNF). IgM AECA titres measured by ELISA were positively correlated with their cytotoxicity. The findings suggest that IgM class AECA in sera from patients with KD are detectable by ELISA method, and that some of these antibodies. 50% in this study, can mediate complement-dependent cytotoxicity against endothelial cells.

Hypertension in children and adolescents has been gaining ground in cardiovascular medicine, mainly due to the advances made in several areas of pathophysiological and clinical research. These guidelines arose from the consensus reached by specialists in the detection and control of hypertension in children and adolescents. Furthermore, these guidelines are a compendium of scientific data and the extensive clinical experience it contains represents the most complete information that doctors, nurses and families should take into account when making decisions. These guidelines, which stress the importance of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, should act as a stimulus for governments to develop a global effort for the early detection and suitable treatment of high pressure in children and adolescents. J Hypertens 27:1719-1742 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.2010 Asociaci?n Espa?ola de Pediatr?a. Published by Elsevier Espana. All rights reserved.

OBJECTIVES: To describe the biologic treatment regimens and report the efficacy and safety of biologic therapies in a multicentre series of children with primary systemic vasculitis (PSV). METHODS: This was a retrospective descriptive case series of children with PSV treated with biologic therapy between February 2002 and November 2007. Primary retrospective outcome assessment measures were: daily corticosteroid dose; Birmingham Vasculitis Activity Score (BVAS); and adverse events (including infection rate). RESULTS: Twenty-five patients median age 8.8 (range 2.4-16) years; 11 male with active PSV (n = 6 with anti-neutrophil cytoplasmic antibody associated vasculitides, n = 11 with polyarteritis nodosa, n = 7 with unclassified vasculitis and n = 1 with Behcet's disease) were treated with biologic agents including infliximab (n = 7), rituximab (n = 6), etanercept (n = 4), adalimumab (n = 1) or multiple biologics sequentially (n = 7). Overall, there was a significant reduction in BVAS from a median of 8.5 (range 5-32) at start of therapy to 4 (range 0-19) at median 32 months follow-up (P = 0.003) accompanied by significant reduction in median daily prednisolone requirement from 1 (range 0.2-2) to 0.25 (range 0-1) mg/kg/day, P = 0.000. For those receiving multiple biologic agents sequentially, a similar clinical improvement was observed with corticosteroid sparing. Infections occurred in 24%, the most severe in those receiving infliximab. CONCLUSION: Our data provide retrospective evidence of efficacy of these agents, and highlight the associated infectious complications. Further multicentre standardization of treatment protocols and data collection to inform clinical trials of biologic therapy in systemic vasculitis of the young is required

Four children (two boys and two girls) with hypoparathyroidism, renal insufficiency, and developmental delay are described. They were the products of consanguineous marriages in three related Asian families presenting over a six year period. All the children died within the first 15 months of life despite treatment. Postmortem examination on one child showed absent parathyroid glands. We believe these children represent a previously undescribed syndrome that appears to be inherited in an autosomal recessive manner.

We report 101 episodes of Kawasaki disease in 100 patients seen over a 12 year period. A total of 35 patients had cardiac involvement ranging from pericardial effusion to coronary artery aneurysms with ischaemic complications, which resulted in death in one patient. Laboratory investigations showed leucocytosis, thrombocytosis, and a raised erythrocyte sedimentation rate to be common features and the first two variables were significantly associated with cardiac involvement. Treatment regimens changed over the study period. Aspirin was used in most patients often in conjunction with dipyridamole and from 1986 intravenous immunoglobulin was given routinely to those patients seen early in the illness. Additional therapeutic measures in individual patients included prostacyclin, heparin, streptokinase, and plasma exchange/exchange transfusion. Attention is drawn to the uncertainity of the long term cardiovascular consequences in the light of adults reported with premature atherosclerotic lesions of similar appearance to those seen in Kawasaki disease.

Renal tubular function was assessed in seven patients with methylmalonic acidaemia not responsive to vitamin B12. Five patients failed to concentrate their urine normally and in these patients the glomerular filtration rate was also reduced. Fractional excretion of sodium was increased in four patients, fractional excretion of potassium in one patient and in three there was a decreased tubular reabsorption of phosphate. Although possibly representing primary tubular damage these findings were thought to be consistent with adaptive changes secondary to the reduced glomerular filtration rate. Two patients had evidence of a defect of urinary acidification and several had a degree of hyporeninaemic hypoaldosteronism suggesting type 4 renal tubular acidosis. In one patient with a mild variant no renal disease was detected. Decreased renal function and tubular abnormalities were common in patients with methylmalonic acidaemia. It is likely that they are linked and essentially secondary to the tubulo-interstitial nephritis that is histologically demonstrable on renal biopsy. The failure of urinary concentrating ability and the disturbed urine acidification will contribute to the metabolic derangement during episodes of decompensation.

Ninety-one patients with Kawasaki disease were examined by cross sectional echocardiography between 1980 and 1988. In the 75 patients evaluated during the acute phase of the illness (the first month), the first echocardiographic examination was carried out at a mean time of 16 days (range 5-30) and coronary arterial lesions were seen in 21 (28%). Two patients with medium sized aneurysms had myocardial infarctions, and one died. Coronary arterial lesions persisted in 17 (23%) patients, most often in younger children. The remaining 16 patients were examined from one month to four years after their acute illnesses, and this group did not have coronary arterial abnormalities. Seven patients with coronary artery lesions have reached school age and require regular echocardiographic examination and exercise electrocardiography. Selective coronary arteriography may be indicated in some patients to identify coronary artery stenosis, which the Japanese experience has shown may progress for several years after the acute illness.

To investigate the influence of a family history of essential hypertension on abnormalities of red cell membrane sodium transport, 28 hypertensive children and their families were studied. In 15 families one or both parents had either essential hypertension or a strong family history. In 13 families neither parent had essential hypertension or a positive family history. There were significant differences between the children with a positive family history of essential hypertension compared with those without. Values are expressed as mean (SD): intracellular sodium concentration (mmol/l cells) 8.19 (2.18) compared with 6.41 (0.98); sodium efflux rate constant 0.4873 (0.1379) compared with 0.5831 (0.1104); and numbers of sodium-potassium ATPase pump sites (BMax) (nmol/l cells) 7.96 (1.71) compared with 9.56 (1.7). Significant differences were also found when the index hypertensive children were excluded and the normotensive siblings with and without hypertensive family histories were compared. These data suggest that abnormal red cell membrane sodium transport has a familial component, and although it is not caused by the hypertension it may be the earliest pathophysiological step in its development, perhaps allowing the identification of children at risk of essential hypertension.

We describe two children with multiple abnormalities, neither of whom fits neatly into a classical diagnostic category, but who show overlapping features of Ellis-van Creveld syndrome, Jeune syndrome, and renal-hepatic-pancreatic dysplasia. It seems possible that these three entities form part of a disease spectrum rather than being distinct conditions.

Since 1960 we have diagnosed phaeochromocytoma (paraganglioma) in 10 children. The cases include a 15 year old girl who over a three year period presented with multiple paragangliomata and an associated malignant carotid body tumour. All children were hypertensive, eight of 10 presenting with severe headaches. Diagnosis was based on finding a raised urinary vanillylmandelic acid excretion and plasma noradrenaline concentration. In addition six of eight children were hypercalcaemic with raised plasma calcitonin concentrations; plasma parathyroid hormone concentrations were high in two of seven and four out of eight children had raised plasma renin activities on presentation. No child, however, was found to have a multiple endocrine neoplasia syndrome. Despite the introduction of newer techniques for the detection of catecholamine producing tumours we found that selective arteriography and venous catecholamine sampling were superior for tumour localisation compared with ultrasound scanning, computed tomography, and metaiodo-benzyl-guanidine (MIBG) scanning.

We describe six infants, from consanguineous marriages, with a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea. In addition two of the infants were found to have abnormal platelet morphology — the grey platelet syndrome. No evidence of a recognised metabolic disorder was found in any of the six infants, nor did they appear to be typical of any previously described syndromes. Their progress was poor: they required high fluid and bicarbonate intakes and all died by the age of 6 months of dehydration, acidosis and sepsis.

Recent developments in relation to Henoch-Schönlein purpura (HSP) include: a) a proposed new classification of childhood vasculitides including new classification criteria for HSP; b) the identification of various, potentially important, genetic polymorphisms in HSP that may be relevant in terms of predisposition to or protection from complications; c) evidence that prophylactic steroid at the onset of disease does not protect against renal or gastrointestinal complications but does seem to have beneficial effects in treating them.

Objectives. The British Isles Lupus Assessment Group (BILAG) index is a standardized systemic lupus erythematosus (SLE) disease activity assessment. The main aim of this study was to correlate the BILAG index with laboratory measures of disease activity in childhood-onset SLE with and without biopsy-proven lupus nephritis. Method. Prospective observational comparison study of the BILAG index in 21 SLE patients under 18 yr of age over a 12-month period in a tertiary referral paediatric outpatient clinic. Results. Eleven patients with lupus non-nephritis and 10 patients with lupus nephritis were reviewed. The lupus nephritis patients had significantly (P

To investigate the potential for endothelial cells to operate as superantigen-presenting cells for T cells and the potential for such an interaction to cause endothelial cell activation and injury.Class II major histocompatibility complex (MHC)-positive human umbilical vein endothelial cells (HUVECs) were cocultured for 4 hours with purified T cells and the superantigens staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin 1 (TSST-1). After staining with fluorescence-conjugated monoclonal antibodies, flow cytometric analysis was performed on the HUVECs and T cells to examine V(beta)-restricted T cell adherence to the endothelial cell monolayer, V(beta)-restricted T cell activation (CD69 up-regulation), surface expression of endothelial cell activation markers, and generation of endothelial microparticles (EMPs).Coculture of purified T cells with class II MHC-positive HUVECs and either TSST-1 or SEB resulted in V(beta)-restricted CD69 up-regulation by CD4 and CD8 cells (V(beta)2 activation for TSST-1; V(beta)3, V(beta)5.1, and V(beta)12 activation for SEB). Additionally, there was CD4 and CD8 T cell V(beta)-restricted adherence to the HUVEC monolayer at 4 hours. Expression of intercellular adhesion molecule 1, E-selectin, and vascular cell adhesion molecule 1 was up-regulated on the class II MHC-positive HUVECs following exposure to superantigen in the presence of T cells, and there was increased EMP release from activated HUVECs, which occurred earlier and was of greater magnitude than that observed in response to tumor necrosis factor alpha.Class II MHC-positive endothelial cells operate as competent superantigen-presenting cells for CD4 and CD8 lymphocytes in vitro. Dual signaling between endothelial cells and T cells results in V(beta)-restricted activation and adherence to endothelial monolayers and endothelial cell activation and release of EMPs expressing inducible cell adhesion molecules. It is proposed that this mechanism could account in part for the vascular injury associated with superantigen-mediated diseases including Kawasaki disease.

Summary Superantigens (SAgs) are potent stimulators of T cells bearing specific Vβ T cell receptors (TCR) and may play a role in the aetiopathogenesis of systemic vasculitis, although this remains contentious. To investigate the possible aetiological role of SAgs, this study examined peripheral blood T cell Vβ repertoires in children with systemic vasculitis. FACS analysis of 17 different peripheral blood T cell Vβ families was performed in 20 healthy control children, 27 disease control children with nonvasculitic inflammatory disease, 25 children with primary systemic vasculitis, six patients with Kawasaki disease (KD) and six patients with Henoch–Schönlein purpura (HSP). There was a significantly increased variance of CD4 Vβ12 and Vβ17, and CD8 Vβ1 in the primary systemic vasculitis group compared to control and disease controls. Moreover, 80% of the primary systemic vasculitis children had one or more CD4 Vβ expansions or deletions, compared with 30% of controls (P

The prevalence and antigen specificity of anti-neutrophil cytoplasmic antibodies (ANCA) in sera from 23 children with active systemic lupus erythematosus (SLE) were studied utilizing indirect immunofluorescence and IgG and IgM ELISA using crude neutrophil extract and purified proteinase 3, myeloperoxidase, lactoferrin, cathepsin G and elastase. ANCA were present in 69% of SLE children and consisted of IgM and IgG antibodies of variable specificities, but did not correlate with organ involvement or disease activity. It remains unclear whether they have pathogenic significance or are epiphenomena in the category of polyclonal B-cell activation. However, their presence is entirely compatible with SLE even though they have hitherto been commonly associated with other systemic vasculitides.

Erythromelalgia is an unusual syndrome of painful vasodilatation. Aetiopathology is probably different in children and adults. Presentation can be severe and associated with hypertension. Dramatic benefit from infused nitroprusside suggests the disorder could represent a dysfunctional endothelium.

This article proposes a clinical guideline for the diagnosis and treatment of Kawasaki disease in the UK based on the best available evidence to date, and highlights areas of practice where evidence is anecdotal or based on retrospective data. Future research as proposed by the London Kawasaki Disease Research Group is outlined, and clinicians are invited to prospectively enroll their suspected cases into this collaborative research project.

Background: Polyarteritis nodosa is a necrotising vasculitis of the medium sized and small muscular arteries. The inflammatory and subsequent reparative processes may alter the arterial mechanical properties. The effect of vasculitic damage on arterial distensibility has never been explored however. Aim: To determine the normal values and the effect of childhood vasculitis on arterial distensibility in children and teenagers. Methods: Distensibility of the brachioradial arterial segment was studied using pulse wave velocity (PWV ∝1/√distensibility), in 13 children with polyarteritis nodosa at a median age of 11.8 (range 4.9-16) years. As a control group, 155 healthy schoolchildren (6-18 years, 81 boys) were studied. PWV was assessed using a photoplethysmographic technique; blood pressure was measured by an automatic sphygmomanometer (Dinamap). Data from patients were expressed as z scores adjusted for age and compared to a population mean of 0 by a single sample t test. Determinants of PWV in normal children were assessed by univariate and multivariate linear regression analyses. Results: Age, height, weight, and systolic blood pressure correlated individually with the brachioradial PWV. Multivariate analysis identified age as the only independent determinant. Ten of the patients were in clinical remission, while three had evidence of disease activity at the time of study. The PWV in the patient group as a whole was significantly greater than those in healthy children (mean z score +0.99). Raised C reactive protein concentration (>2 mg/dl) in the three patients with active disease was associated with a higher PWV when compared to those in remission (z score +2.78 v +0.45). The diastolic blood pressure of the patients was higher than those of the controls (z score + 1.04) while the systolic pressure was similar (z score -0.36). Conclusions: PWV in the brachioradial arterial segment increases gradually during childhood independent of body weight, height, mass, and blood pressure. Increased PWV, and hence decreased distensibility, in this peripheral arterial segment occurs in polyarteritis nodosa and is amplified during acute inflammatory exacerbation., published_or_final_version

Two infants with a florid erythematous rash and generalised oedema, hypoalbuminaemia, and anaemia were found to have cystic fibrosis. This rare presentation is associated with false negative sweat tests, delays in diagnosis, and a considerable mortality. It is proposed that this presentation represents a manifestation of kwashiorkor secondary to malabsorption. The recognition that these infants have kwashiorkor provides some insight into the pathogenesis and management of their illness.

This article reviews the spectrum of vasculitic illness affecting children. Apart from the relatively common vasculitides (Henoch-Schonlein purpura, Kawasaki disease, and in worldwide terms Takayasu disease) there are a number of important but comparatively rare disorders affecting children. As in adults, there is a considerable degree of overlap between the various vasculitic syndromes in childhood. With modern therapeutic agents, the prognosis for many of the childhood vasculitides has improved; however, in spite of this, there remains a not inconsequential morbidity and mortality. It is anticipated that as our knowledge of the immunopathogenesis of this group of disorders expands, classification and treatment of vasculitis in both children and adults will improve.

Despite the publication of several expert committee guidelines for the measurement of blood pressure (BP) and the diagnosis of hypertension in children and adolescents, it was our perception and clinical experience that there still appeared to be a general lack of standardisation of BP measurement techniques and little consensus on the criteria for diagnosing hypertension. To investigate this further, we have conducted a postal survey of consultant-grade paediatricians who were members of the British Paediatric Association (BPA). A total of 1500 questionnaires were sent out and 708 analysable replies were received (47.1%). This showed that 68.6% of paediatricians routinely measured BP, at least on one occasion, in children or adolescents attending their outpatient clinics, 17.7% started at or soon after birth, 12.3% started at the age of 1 year, 20.0% at 3 years, 12.0% from 7 years of age and 3.5% from the age of 13. Only 60.5% reported that they had a choice of four or more different cuff sizes in their clinic. Forty-one percent of respondents reported that the BP was always or sometimes measured by nurses. Fifty-one percent of respondents measured diastolic BP at the phase of muffling of sound (Korotkoff phase IV), 31.9% used the disappearance of sound (phase V) whilst 15.9% claimed that they measured both end-points. The criteria for diagnosing a child as being hypertensive varied greatly; 17.9% reported that they responded to the systolic BP alone, 13.5% to the diastolic BP alone, 65.9% relied on both pressures, and 2.7% responded to either the systolic or diastolic pressure if it was raised. Furthermore, 12.9% diagnosed hypertension if the BP exceeded the 90th percentile in relation to age and 41.8% used the 95th percentile. However 45.3% of respondents employed a higher dividing line. In hospitalised children, leg blood pressures were measured routinely by 30.3%, although a further 44.0% would do so if aortic coarctation or other vascular diseases were suspected. Despite considerable variation in clinical practice, techniques and criteria, only 11.4% of clinicians would manage the patients themselves, with the remainder referring the child on to the appropriate specialist. The survey suggests a general lack of standardisation of BP measurement techniques and little consensus on the criteria for diagnosing hypertension amongst paediatricians. Simplified, shortened and updated guidelines on hypertension in paediatric practice and research are needed.

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen's metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense mutation was found that changes isoleucine 458 in the receptor's seventh membrane-spanning region to arginine (I458R). In COS-7 cells expressing the human PTH/PTHrP receptor with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than that in cells expressing the wild-type receptor despite impaired surface expression of the mutant receptor. Furthermore, the I458R mutant showed higher responsiveness to PTH than the wild-type receptor in its ability to activate both downstream effectors, adenylyl cyclase and phospholipase C. Like the H223R and the T410P mutants, the I458R mutant had no detectable effect on basal inositol phosphate accumulation. Overall, the patient with the I458R mutation exhibited clinical and biochemical abnormalities similar to those in patients with the previously identified H223R and T410P mutations.

Reflux nephropathy i. e. renal scarring associated with vesico-ureteric reflux and urinary tract infection is primarily a diagnosis based on renal imaging. It is well known to be associated with hypertension and renal failure. This has led to regular long-term follow-up of patients, clinically and radiologically. We report the findings of renal imaging in a cohort of 37 patients with reflux nephropathy 15 or more years after successful surgical correction of vesico-ureteric reflux. The degree of renal scarring had been assessed and recorded at the beginning of the study utilizing a score on the original X-ray films. The scar scores of the current intravenous urography (IVU) imaging underestimate the degree of scarring in 35% of cases when compared with the previously recorded scar scores of the original IVU images suggesting a reduction in the renal scar score in some cases over the years. In the current review, concomitant renal images obtained by IVU and 99mTc dimercapto succinic acid (DMSA) scanning were in agreement for scar scoring in only 50% of cases. The original scar score by IVU or the current scar score by either technique does not correlate with blood pressure, urine albumin excretion or glomerular filtration rate (GFR). We conclude that serial long-term two-dimensional renal imaging in children with damaged kidneys who no longer have vesico-ureteric reflux, does not provide additional information that will alter clinical management. However, the changes in renal volume and echogenicity were not assessed in this study.

A child presented with ischaemic episodes of his left leg from the age of 2 months. He was found to have raised anticardiolipin antibodies so was started on low dose aspirin. At a three year follow up he was asymptomatic with a normal anticardiolipin antibody level while taking aspirin daily, probably for life.

Hypertension is a complication of reflux nephropathy commonly occurring during adolescence and young adult life. We studied cellular sodium transport in an adolescent cohort with this condition as abnormal sodium transport is a feature of human hypertension. Thirty males and 52 females with reflux nephropathy, (median age 20.3 years) had erythrocyte ouabain sensitive sodium-potassium ATPase (Na/K ATPase) pump site number (Bmax) and red cell sodium concentration (RBC Na+) measured in 1988. Six years later, 55 of those had red cell sodium-lithium counter transport (LCT) measured. On both occasions, their renal function and blood pressure (BP) were determined. Bmax in the study group (median 10.3 nmol/l) was significantly less than that of controls (median 11.45 nmol/l). Nine patients who were diagnosed as having hypertension during the 6 year study period appeared to have a lower Bmax compared with that of normotensives in the group. RBC Na+ and LCT of the study group were not significantly different from that of controls. The Na/K ATPase activity is diminished, and sodium-lithium counter transport is unchanged in reflux nephropathy. Further study is needed to ascertain the link between these observations and the onset of high BP.

SUMMARY sE-selectin, sICAM-1, sVCAM-1 and von Willebrand factor (vWF) were assayed in 238 samples in a longitudinal study of 81 normal children from 9.5 to 15.5 years old. Multilevel modelling was used to quantify changes with age. sE-selectin, sICAM-1 and sVCAM-1 all fell significantly over the age range (by 17%, 16%, and 10%, respectively). In contrast, levels of vWF were not age-dependent. Our findings highlight the need for age-matched controls when studying cell surface adhesion molecules in disease groups, and may imply developmental changes in expression of these molecules and their shedding from the cell surface.