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Objective.To compare access to biologic therapies for children with juvenile idiopathic arthritis (JIA) across Canada, and to identify differences in provincial regulations and criteria for access.Methods.Between June and August 2010, we compiled the provincial guidelines for reimbursement of biologic drugs for children with JIA and conducted a multicenter Canada-wide survey of pediatric rheumatologists to determine their experience with accessing biologic therapies for their patients.Results.There were significant difficulties accessing biologic treatments other than etanercept and abatacept for children. There were large discrepancies in the access criteria and coverage of biologic agents across provinces, notably with age restrictions for younger children.Conclusion.Canadian children with JIA may not receive optimal internationally recognized “standard” care because pediatric coverage for biologic drugs through provincial formularies is limited and inconsistent across the country. There is urgent need for public policy to improve access to biologic therapies for these children to ensure optimal short-term and longterm health outcomes.

Two human malignant melanoma cell lines, differing in their patterns of HLA-DR antigen expression, were examined for changes in antigen expression following theophylline treatment. In one line, the basal HLA-DR antigen content of which remained constant during culture, theophylline decreased HLA-DR expression, accompanied by morphological changes indicating increased differentiation. In the second line, the surface HLA-DR antigen expression decreased with time during culture and showed no decrease in antigen expression or morphological changes when cultured in the presence of theophylline.

The large majority of classified primary immune deficiency (PID) diseases present in childhood. Yet, most patients with PID are adults, with a large proportion experiencing onset of symptoms beyond their childhood years. Most of these are diagnosed predominantly with antibody defects, but cellular and other disorders are increasingly being identified in older patients as well. Moreover, advances in clinical immunology are allowing pediatric patients, even those with severe disease, to reach adulthood. Because of differences in the physiology and pathophysiology of children and adults, the presentation, diagnosis, and management of a complex chronic disease could differ significantly between these patient populations and therefore require modifications in approach.

Objective Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. Methods Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. Results In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1β, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor β, in a mutation-positive patient compared with normal controls. Conclusion Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in ∼50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.

Intra-articular injection of long-acting insoluble corticosteroids produces rapid resolution of active arthritis in nearly all injected joints. Almost all of our information on the use of intra-articular corticosteroids in children comes from observational or retrospective analyses or, by inference, from studies in adult patients with arthritis. The duration of response has been found to vary according to the subtype of arthritis, the dose of injected steroids, the accuracy of injection, the duration of disease prior to injection, and possibly the age of the patient. Although the duration of follow-up in most studies has been short, intra-articular steroid therapy seems to be remarkably free of clinically important detrimental effects. Side effects are relatively uncommon and include subcutaneous atrophy and radiologically detectable structural changes or calcification. There is transient suppression of endogenous cortisol production, which may not be clinically important. Although intra-articular steroid therapy is most effective in pauciarticular juvenile rheumatoid arthritis, there are still no solid data to indicate whether it should be used earlier in the course of the disease instead of or along with systemic anti-inflammatory therapy. It has been suggested that repeated injection of the same joint decreases the likelihood of a favorable response. There are still many unanswered questions about how steroids exert their beneficial effects. Newer imaging techniques promise to provide insight into the mechanism of action and possibly to a more informed basis for the use of intra-articular steroids.

Objective To examine the temporal and dose-related effects of glucocorticoids (GCs) on body mass index (BMI) in children with rheumatic diseases. Methods Children initiating GCs for a rheumatic disease (n = 130) were assessed every 3 months for 18 months. BMI, weight, and height Z score trajectories were described according to GC starting dosage in prednisone equivalents: high (≥1.0 mg/kg/day), low (

Corticosteroid related changes in body mass index in children and adolescents with rheumatic diseases Natalie Shiff, Rollin Brant, David A Cabral, Jaime Guzman, Peter B Dent, Janet E Ellsworth, Kristin M Houghton, Adam Huber, Roman Jurencak, Bianca A Lang, Maggie Larche, Claire MA LeBlanc, Paivi M Miettunen, Kiem G Oen, Johannes Roth, Claire Saint-Cyr, Rosie Scuccimarri, Leanne M Ward, Canadian STOPP Consortium

Objective. To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk. Methods. Children with rheumatic diseases initiating GC were enrolled in a prospective observational study. Annual spine radiographs were evaluated using the Genant semiquantitative method. Spine areal bone mineral density (aBMD) was measured every 6 months. Clinical features, including cumulative GC dose, back pain, disease and physical activity, calcium and vitamin D intake, and spine aBMD Z scores, were analyzed for association with IVF. Results. Seven (6%) of 118 children (95% confidence interval 2.9-11.7%) had IVF. Their diagnoses were: juvenile dermatomyositis (n = 2), systemic lupus erythematosus (n = 3), systemic vasculitis (n = 1), and mixed connective tissue disease (n = 1). One child was omitted from the analyses after 4 months because of osteoporosis treatment for symptomatic IVF. Children with IVF received on average 50% more GC than those without (P = 0.030), had a greater increase in body mass index (BMI) at 6 months (P = 0.010), and had greater decrements in spine aBMD Z scores in the first 6 months (P = 0.048). Four (67%) of 6 children with IVF and data to 12 months had spine aBMD Z scores less than-2.0 at 12 months compared to 16% of children without IVF (P = 0.011). Conclusion. The incidence of VF 12 months following GC initiation was 6%; most children were asymptomatic. Children with IVF received more GC, had greater increases in BMI, and had greater declines in spine aBMD Z scores in the first 6 months. © 2012, American College of Rheumatology.

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.

Background/Purpose: To determine the incidence of vertebral fracture (VF) in the three years following glucocorticoid (GC) initiation, and the effect of GC on the risk of incident VF in children with rheumatic disorders (RD). Methods: Children with RD were enrolled within 30 days of GC initiation and followed for 3 years, with VF assessed at baseline and then annually using the Genant method on lateral spine radiographs. An incident VF was defined as a new fracture in a previously normal vertebral body or worsening of an existing VF. The annual and the 3 year cumulative incidences were calculated as the number of new cases divided by the number of subjects who completed VF assessment at the specified time periods. Six different time-dependent GC exposure measures were constructed: cumulative dose, average daily dose, duration on GC therapy, dose intensity (cumulative dose divided by duration on GC therapy) over 3 years, recent average daily dose and duration on GC therapy over the preceding 12 months. Extended Cox's models were used with alternative time-dependent variables, adjusting for factors at baseline including age, gender, body mass index, vitamin D and calcium supplementation, disease activity, bone mineral density, physical activity, and presence of prevalent VF. Results: 136 enrolled children (mean ± SD age 9.9 ± 4.4 years, 65% girls) held the following diagnoses: 22% juvenile dermatomyositis (JDM), 21% non-systemic juvenile idiopathic arthritis (JIA), 19% systemic lupus erythematosus (SLE), 18% systemic JIA, 12% systemic vasculitis, and 9% other RD. 9 children had VF at baseline (3 JDM, 2 systemic JIA, 2 SLE, 1 systemic vasculitis, 1 localized scleroderma), with an estimated prevalence of 6.6% (95% confidence interval (CI) 2.4–10.8%). 18 incident VF were identified in 15 children during the 3 years following GC initiation (6 JDM, 4 SLE, 2 systemic vasculitis, 2 systemic JIA, and 1 non-systemic JIA). The 3-year cumulative VF incidence was 13.0%, at a rate of 4.9 per 100 person-years. Of the 18 incident VF events, 7 occurred during the first year at an annual incidence of 6.0% (95% CI 1.7–10.3%); 6 VF occurred during the second year (annual incidence 5.6%; 95% CI 1.2–9.9%); 5 VF occurred during the third year (annual incidence 4.3%; 95% CI 1.0–8.1%). 64% of patients had mild incident VF as the worst grade, 36% had moderate fractures, and none had severe fractures. Of those with incident fractures, 21% had no complaints of back pain in the preceding 12 months. Multivariable models showed that every 100 mg/kg increase in cumulative GC dose was associated with a 30% increased incident VF risk (hazard ratio (HR) = 1.3, 95% CI 1.1, 1.6). Every 0.5mg/kg increase in average daily dose over the 3 year period was associated with a 4.2 fold increased VF risk (HR = 4.2, 95% CI 2.3, 7.7), and every 0.5 mg/kg increase in daily dose during the preceding 12 months was associated with a 2.7 fold increased incident VF risk (HR =2.7, 95% CI 1.3, 5.2). Conclusion: We have shown that 13.0% of children with RD sustained VF within three years followingGC initiation, of which 36% had moderate fractures. Cumulative dose, average daily GC dose, and recent average daily GC dose were associated with a significantly increased VF risk. Funded by CIHR FRN 64285

Disk displacement frequently causes dysfunction of the temporomandibular joint (TMJ). Magnetic resonance imaging (MRI) of the TMJ is 95% accurate in the assessment of disk position and form. Various restorative procedures are used for treatment of disk displacement. However, several authors have noted a lack of correlation between MRI findings of disk displacement and the extent of pain and dysfunction of the TMJ. The purpose of this study was to evaluate whether MRI findings of various degrees of disk displacement could be correlated with the presence of clinical signs and symptoms in patients with a clinical disorder of the TMJ.One hundred and forty-four TMJs (in 72 patients) were imaged. Displacement of the posterior band in relation to the condyle was quantified as mild or significant.Disk displacement was found in 45 (54%) of the 84 symptomatic joints and 13 (22%) of the 60 asymptomatic joints. Among the 84 symptomatic joints, 31 (37%) had disk displacement with reduction and 14 (17%) had disk displacement without reduction. In the latter group, 11 (79%) of the 14 joints had significant displacement of the posterior band (8 or 9 o'clock) and 21% had mild displacement of the posterior band (10 o'clock). Of the 60 clinically asymptomatic joints, 47 (78%) had no signs of disk displacement on MRI, whereas 13 (22%) had disk displacement with reduction. None of the asymptomatic joints had disk displacement without reduction. The difference in occurrence of disk displacement between symptomatic and asymptomatic joints was statistically significant (54% vs. 22%; p0.001). However, the difference in occurrence of disk displacement with reduction of the disk on mouth opening was not statistically significant (37% vs. 22%; p = 0.06).Disk displacement on MRI correlated well with clinical symptoms in cases of significant disk displacement and in cases of disk displacement without reduction. When disk displacement with reduction was mild, there was no statistically significant difference between symptomatic and asymptomatic joints, which suggests that other causes should be considered.

OBJECTIVE. Acute lymphocytic leukemia (ALL) often presents with musculoskeletal concerns such as pain or swelling, even before appearance of blasts in the peripheral blood. Such presentation may lead to misdiagnosis of a child with juvenile rheumatoid arthritis (JRA). This study was designed to identify the predictive factors for leukemia using basic clinical and laboratory information. METHODS. A retrospective chart review was performed using a simple questionnaire to compare the clinical and laboratory findings present during the initial visit to a pediatric rheumatology clinic for 277 children who were ultimately diagnosed with either JRA (n = 206) or ALL (n = 71). Sensitivity and specificity analysis of a variety of parameters, both singly and in combination, was performed to identify predictive value for ALL. RESULTS. The majority (75%) of children with ALL did not have blasts in the peripheral blood at the time of evaluation by pediatric rheumatologists. In children presenting with unexplained musculoskeletal complaints, the 3 most important factors that predicted a diagnosis of ALL were low white blood cell count ( CONCLUSIONS. When a child develops new-onset bone-joint complaints, the presence of subtle complete blood count changes combined with nighttime pain should lead to consideration of leukemia as the underlying cause.

OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.

Introduction Idiopathic retroperitoneal fibrosis (RPF) was first described as a clinical entity in 1948 (1). Most patients with RPF are 30–60 years old, and very few pediatric cases have been reported. Although in most cases the RPF is idiopathic, it may also be secondary to underlying infection, malignancy, drugs, radiation, trauma, or surgery. In most patients, fibrosis is confined to the retroperitoneal region of the lower lumbar spine; however 15% have fibrosis in other organs (2). Spondylarthritis, which may also be complicated by extraarticular fibrosis, has been reported in patients with RPF. We present a case of a 7-year-old boy who originally presented with RPF and was later diagnosed as having spondylarthritis, and discuss the relevance of this association.

Background/Purpose: Little is known about the long-term morbidity and mortality of childhood-onset SLE (cSLE) after transition to adult care; however, linking clinical data to administrative databases enables study of previously unknown outcomes. Our objectives were to describe long-term outcomes in young adults with cSLE, including: i) cardiovascular outcomes; ii) renal outcomes; iii) joint replacement surgery due to avascular necrosis; iv) malignancies; and v) pregnancies and births. Methods: A retrospective chart review of all cSLE patients (

Objective To increase the current knowledge of the outcome of juvenile systemic sclerosis (jSSc), which is currently limited. Methods In order to investigate the patient outcome and prognostic factors, starting October 1994, we distributed questionnaires to 324 paediatric rheumatology centres. Results Until 15 May 1998 responses from 46 centres were received, 34 of which returned completed questionnaires on a total of 135 patients. One hundred and twenty-two of the 135 patients were Caucasian, 100 were female. The mean age at disease onset was 8.8 yr (S.D. +/- 3.3 yr). The mean disease duration at the last follow-up was 5 yr(S.D. +/- 3.3 yr). At the last follow-up the disease was still active and required medication in 82 patients, 36 had inactive disease on medication, and 16 were in remission. Ninety per cent of the living patients were fully active in daily life at the last follow-up. Eight of the 135 patients had died. These patients had a median age at onset of the disease of 10.5 yr (range 6.7-15.8 yr). The median disease duration until death was 2 yr (range 1-8 yr). The causes of death were heart failure (five), renal failure (one), sepsis (one) and in one case the cause was not defined. The 1 yr survival rate was 99%, the 2 yr was 97% and the 4 yr was 95%. Conclusions At a mean follow-up of 5 yr, the current results show a favourable outcome in most patients with childhood onset jSSc and a significantly better survival than in the adult SSc patients.

To the Editor: Chronic nonbacterial osteomyelitis (CNO) is a sterile osteitis of unknown etiology. The diagnosis is based on characteristic clinical, laboratory, and imaging features1. Currently, CNO is considered an autoinflammatory disorder. However, the association of CNO with inflammatory bowel diseases2, psoriasis3, and vasculitis suggests that both innate and adaptive immunity may contribute to pathogenesis. A 3-year-old girl presented with proximal muscle weakness, Gottron papules, and periorbital heliotrope rash. Erythrocyte sedimentation rate (ESR) was 30 mm/h (normal 0–12 mm/h); creatine kinase, aspartate aminotransferase, and lactate dehydrogenase were normal. Antinuclear autoantibody (ANA) titers were 1:320; antibodies against Jo-1, ribonuclear proteins, Smith, Ro, La, Scl-70, and double-stranded DNA were not detected. Muscle biopsy result was consistent with dermatomyositis. She was started on oral corticosteroids 1.5 mg/kg/day and methotrexate 0.5 mg/kg weekly. After 9 months, muscle strength normalized and treatment was discontinued. Family history revealed that her brother and maternal grandmother had psoriasis and a paternal uncle was diagnosed with Crohn disease (Figure 1). Figure 1. The family history of a child with chronic recurrent nonbacterial osteomyelitis and previous … Address correspondence to Dr. R.M. Laxer, Division of Rheumatology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail: ronald.laxer{at}sickkids.ca

OBJECTIVE: This study was undertaken to investigate the recent finding of a seasonal difference in the onset of systemic-onset juvenile rheumatoid arthritis (SoJRA). We hypothesized that a seasonal onset pattern might implicate an infectious agent as a cause of SoJRA. METHODS: The date of onset was collected from the records of all patients with SoJRA from 1980 to 1992 at presentation to pediatric rheumatology clinics across Canada. The onset pattern of SoJRA was then compared with incidence data on viral infections obtained for the same period. RESULTS: Across Canada the onset of SoJRA was constant across the seasons. However, in the Prairie region there was a statistically significant seasonal pattern, with peaks in autumn and early spring. We could find no evidence that viral incidence correlated with disease incidence either throughout Canada or in the Prairie region. CONCLUSIONS: If a seasonal infectious agent causes SoJRA, then it is likely only one of several causes and may act only in certain regions. Future studies should be carried out in those areas where SoJRA does have a seasonal onset pattern. (J P EDIATR 1996:129:513-8)

Incident vertebral fractures 12 months following glucocorticoid initiation in children with rheumatic disorders Bianca A Lang, Celia Rodd, Timothy Ramsay, David A Cabral, Peter B Dent, Janet E Ellsworth, Kristin M Houghton, Adam Huber, Roman Jurencak, Maggie Larche, Claire MA LeBlanc, Brian Lentle, MaryAnn Matzinger, Paivi M Miettunen, Kiem Oen, Johannes Roth, Claire Saint-Cyr, Rosie Scuccimarri, Nazih Shenouda, Leanne M Ward, Canadian STOPP Consortium

The monoclonal antibody 140.240, which reacts with a melanoma-associated oncofetal antigen, identifies an epitope present on an 87 kd molecule present on the surface of melanoma cells. This molecule is a single-chain monomer, which by tunicamycin treatment and two-dimensional tryptic mapping has been shown to arise from a 77 kd polypeptide precursor (p77). This precursor is rapidly glycosylated to an 83 kd intermediate (gp83) which in turn is rapidly further glycosylated into the mature 87 kd glycopolypeptide (gp87). Neuraminidase treatment of the glycopeptides indicates that only gp87 contains accessible sialic acid moieties.

Neonatal onset multisystem inflammatory disease is a rare disorder first described by Lorber in 1973. An additional 29 cases have been recorded. Two patients are described here, one with a 17 year follow-up. The typical features are a rash, fever, adenopathy, hepatosplenomegaly, and a severe, deforming arthropathy predominantly affecting large joints. The most striking feature is the onset in the neonatal period. Other associated features include inflammation, chronic meningitis, anemia, and persistent leukocytosis. Most, if not all, patients develop bizarre epiphyseal radiographic findings that are virtually pathognomonic. This disease is distinct from Still disease.

Studies of lymphocyte blastogenesis were carried out on two children with demonstrated unusual susceptibility to recurrent herpes infections and on twenty volunteers suffering from recurrent cold sores. Depressed responses were observed in the two children as well as their parents and in five individuals with a high frequency of clinical disease (greater than six attacks per year). There was a significantly greater blastogenic response during convalescence from cold sores as compared to the response during the acute attack. The blastogenic response was not antibody dependent although the response of cells cultured in sera from seronegative nonresponders and seropositive low responders was significantly less than in allogeneic serum from seropositive high responders. Depressed in vitro responses to suboptimal concentrations of phytohemagglutinin of lymphocytes from individuals with impaired HSV responses suggest that the latter may be due to a generalized reduction in lymphocyte responsiveness which could represent a macrophage-dependent defect. This defect is probably the result rather than the cause of herpes simplex virus recurrence.

Sera from 40 patients with malignant melanoma entered into a randomized controlled trial of nonspecific and specific active immunotherapy were studied for the presence of melanoma-specific IgG antibody. Reactivity was revealed by mixed hemadsorption assay against a panel of 10 cultured melanoma cell lines. Prior to therapy 3 of 40 patients had antibody to one or more melanoma lines which in all cases was eliminated by absorption with platelets or colon carcinoma cells. After 6 months of therapy patients in the group not receiving tumor vaccine had no absorption-resistant antimelanoma reactivity. However all 10 patients receiving allogeneic tumor vaccine had high titered melanoma reactivity which in 8 patients was not removed by platelet or carcinoma absorption. Three patients reacted only against melanoma targets while of the remaining 5 patients, 4 reacted against cultured brain tumor cells supporting previous suggestions of a possible antigenic cross-reactivity among tumors of neuroectodermal origin. Clinical outcome was not correlated with the presence of antibody to melanoma target cells. Persistance of antibody was dependent on continued vaccine administration suggesting that rather than being an index of resistance, the presence of antibody may be a marker for the presence of tumor. Sera from alloimmunized melanoma patients identify a heterogeneous complex of melanoma-associated surface antigens. More information about the serological and immunological properties of these antigens is required to determine if these responses are clinically relevant.

41.5% of 200 newborn infants had levels of carcinoembryonic antigen (CEA) in excess of 2.5 ng/ml in their cord plasma. There was no direct correlation with the maternal CEA level although the frequency of elevated CEA was significantly greater among infants born to mothers with CEA levels greater than 2.5 ng/ml. There was no preponderance of high CEA levels among infants with low birth weights and there was no influence of maternal smoking on a cord CEA level. There was a tendency toward an increased incidence of cancer in families with infants who had elevated CEA levels and a reverse trend was noted with respect to diabetes; however, these associations were not statistically significant. We were unable to define clearly the factors accounting for the persistent elevation of this oncofetal antigen at birth; however, the possible association with susceptibility to the development of neoplasia merits further study.

The presence of immune complexes and carcinoembryonic antigen (CEA) was investigated in 50 patients with bronchogenic carcinoma at the time of and/or following diagnostic or definitive surgery. Immune complexes were measured by the C1q binding test and CEA by the Z gel method and elevations defined as values in excess of 2 S.D. above the normal mean, greater than or equal to 9.2% for C1q binding activity (C1q-BA) and greater than or equal to 5.0 ng/ml for CEA. The overall incidence of elevated values was 30.7% for C1q-BA and 34.2% for CEA. There was a greater incidence of elevated values of C1q-BA among patients with clinically evident disease. The differences with respect to CEA elevation were not significant due to the fact that 6 of 9 samples with elevated CEA values obtained from patients with no evident disease were in fact associated with the presence of clinically undetectable disease in these patients. Elevation of C1q-BA and CEA beyond the immediate postoperative period was predictive of a significantly shorter median survival time. The most significant differences in survival time were seen between patients with normal values for C1q-BA and CEA and those with elevations of one or both parameters, 6.0 vs. 19.5 months (p less than 0.001). Elevation of either parameter during the immediate pre- and postoperative period was not predictive of a poor survival. In terms of clinical application, it appears that CEA estimation had the best predictive value but that the addition of C1q-BA measurement may provide additional prognostic information, particularly in patients who do not have elevated CEA values.

The mixed hemadsorption assay is a sensitive method for the detection of antibodies to cell surface antigens as well as to soluble antigens. Miniaturization of this assay through the use of microplates with 12 μl rather than 400 μl wells allows a 5-fold reduction in volume of test serum and equivalent reduction in target antigen and other reagents used in the indicator system. Using 5 different antigen systems, melanoma-associated antigens, carcinoembryonic antigen, HLA antigen, β-2 microglobulin and fetal calf serum, a 4–8-fold increase in sensitivity is realized. The geometry of the 12 μl wells results in no significant detachment of target cells which may account for the improved sensitivity and quality of the titration curves.

In order to assess the mechanisms of host resistance to Newcastle disease virus (NDV), the susceptibility of young adult normal, T cell deficient and agammaglobulinemic chickens to an avirulent live vaccine (Bl) and a mesogenic strain of NDV was studied. All animals, regardless of immunological status resisted the vaccine strain. Most normal birds resisted mesogenic NDV, HOWEVER T cell deficient birds were much more susceptible and agammaglobulinemic chickens were extremely susceptible. There was no difference in the kinetics and levels of hemmagglutination-inhibition activity of plasma between normal, control-irradiated and T cell deficient birds nor between dying and surviving birds. Agammaglobulinemic chickens could be partially protected against an otherwise lethal challenge following immunization with avirulent NDV, low doses of mesogenic NDV inoculated intranasally or im injection of beta-propriolactone inactivated NDV mixed in complete Freund's adjuvant. The possible mechanisms for this protection together with the relative roles of humoral, cell mediated and non-specific immunity are discussed.

140.240, an IgG2a mouse monoclonal antibody raised against a cultured human melanoma cell line, was highly specific for melanoma cells as determined by direct and absorption analyses in a mixed hemadsorption assay. Supernatants of doubly cloned hybridomas producing antibody 140.240 reacted with all cultured and fresh melanomas tested but failed to react with a variety of carcinomas, sarcomas, lymphomas, leukemias and other tumors of neuroectodermal origin. This antibody did not react with B-lymphoid cell lines, ruling out HLA-DR specificity. Non-reactivity of antibody 140.240 with peripheral blood lymphocytes obtained from the donor of the immunizing melanoma line excluded the possibility of detecting histocompatibility antigens. Nevus cells were also non-reactive. However, antibody 140.240 did identify an antigenic determinant on tissue homogenates prepared from fetuses of 10-14 weeks' gestation. The antigen involved was shed by cultured melanoma lines and, by immunoprecipitation analysis of radiolabelled lysates, had a molecular weight of approximately 87kdal. Thus, the structure identified by monoclonal antibody 140.240 is a melanoma-specific oncofetal antigen.

Cultured human malignant melanoma cells, when added to normal human lymphocytes stimulated to proliferate by mitogen or antigen, were found to inhibit the uptake of 3H-thymidine (3

Raynaud's phenomenon is a rare condition in the pediatric age group. Because of this, there is little information on the outcome of these patients. We have followed three patients in our clinic for extended period of time, and all remain well clinically despite the presence of im munologic abnormalities in two. This suggests that, while careful follow up is necessary, the presence of Raynaud's phenomenon and immunologic abnormalities in the pediatric age group are not necessarily of bad prognostic significance.

The noninvasive diagnosis of pulmonary hemorrhage usually relies upon the presence of hemoptysis or hemosiderin-laden macrophages in the sputum. Respiratory tract secretions, however, may be contaminated with blood during passage through the large airways or upper respiratory tract, and hemosiderin-laden macrophages may be found in the sputum of patients with other diseases such as pulmonary edema. In addition, pulmonary hemorrhage may occur without associated hemoptysis or significant changes in the chest roentgenogram.1 We have used serial measurements of the pulmonary uptake of carbon monoxide combined with M-mode echocardiography to monitor left atrial size in order to document pulmonary hemorrhage in an 11-year-old girl with rheumatoid arthritis.

Supernatants of established cultures of human neoplastic and normal cells have been shown to contain a number of different biological activities, including inhibition of DNA synthesis as measured by thymidine uptake. We have found that supernatants of melanoma cell lines contain an inhibitor of thymidine uptake which is heat labile, ultraviolet sensitive, non-filtrable (0.22 mu) and partially sedimentable at 20,000 x g. The mechanism of action of the inhibitor involves the degradation of 3H-thymidine to a non-utilisable form, which we detect by failure of uptake of 3H-thymidine by cultures of mitogen stimulated lymphocytes to which the inhibitor is added. While microbiological tests have failed to reveal mycoplasma contamination of inhibitor producing cultures, treatment of these cultures with kanamycin suppresses inhibitor production. Qualitative evaluation of DNA synthesis by the inhibitor producing cultures using autoradiography and fluorescent DNA staining has confirmed the presence of mycoplasma. With the widespread use of established cell lines in cancer research, it is imperative that screening for mycoplasma contamination go beyond routine microbiological assays. Detection of 3H-thymidine degradation by cell culture supernatants is an additional simple and sensitive indirect test which could be used for this purpose.

Estimation of CEA levels by the Z-gel method indicates that smokers, patients with limited lung cancer and patients with extensive lung cancer have higher values than nonsmoking controls. The CEA levels within each group are significantly different from one another. Use of CEA estimation for diagnostic purposes is limited because of the considerable overlap between normal controls and patients with cancer, the relatively low incidence of elevated values in patients with limited disease and the high incidence of false negatives (20%) even in patients with extensive disease. Elevated CEA values are associated with a poor prognosis and could be of clinical value as an addition to clinical staging to determine survival particularly for patients with extra-thoracic disease. Persistently high values in patients deemed clinically disease-free postoperatively are indicative of residual disease and a poor prognosis. If and when effective therapy for bronchogenic carcinoma becomes available, monitoring of CEA values may be useful in some patients as an early indication of release. Further studies are required to determine if the extraordinarily poor prognosis associated with marked elevations of CEA may be used as an additional criterion of inoperability in such patients.

We have established conditions for the study of membrane glycoprotein synthesis and turnover in cultured human malignant melanoma cell lines using the labeled precursor [3H]glucosamine. Uptake of label increased parallel with cell growth, reaching a steady state in resting cultures. Fifteen to 30% of incorporated label can be released from the cells by trypsin treatment depending on the conditions of exposure to the enzyme, and about 50% of the incorporated label is spontaneously shed from the cells within 96 hr of incubation. Labeling in exhausted medium gave a 5- to 8-fold increase in uptake which was inhibited by addition of glucose (2 mg per ml) into the culture medium. The percentage of trypsin-releasable material was identical in fresh and exhausted medium; however, the percentage shed was less in cells initially labeled in exhausted medium. These data provide background information for further studies on the antigenic composition of the glycoproteins of cultured melanoma cells.

Early monolayer outgrowths of cells from human cutaneous malignant melanomas mostly derived from metastatic lesions were examined microscopically. Cells resembling the two dendritic types of melanoma previously described in the established lines could readily be recognized. Of 22 specimens, 14 consisted of cells with a triangular dendritic morphology, four had both triangular and elongated dendritic morphology, and one had a cuboidal morphology. The remaining three specimens showed only fibroblastic outgrowths. It is concluded that cells with a triangular dendritic morphology are either the most common type of the secondary cutaneous melanomas, or alternately the most adaptable to the present culture conditions. An association of a more favorable prognosis with the homogeneous triangular dendritic cell type is noted.