Who are the PDCO?

In January 2007, the Paediatric Regulation entered into force and established the Paediatric Committee (PDCO) within the European Medicines Agency. The goal of the PDCO is to improve the health of the children of Europe by increasing high-quality research for medicinal products and promoting the development and authorization of such medicines at the EU level. A major function of the PDCO is to formulate and authorize Paediatric Investigation Plans and Paediatric Use Marketing Authorisations. The EU's Seventh Framework Programme for Research has facilitated the establishment of consortia whose ultimate goal is to answer important clinical questions involving medicines commonly used "off-label", in children. The benefits of these consortia include enhanced collaboration amongst paediatricians, scientists and small to medium enterprises whose ultimate goal is to obtain an authorization for a new indication or formulation for use in the paediatric population. It will be interesting in a number of years time to measure the success of this very important European initiative.

Psychiatric consultation of patients with hyperemesis gravidarum.

The request for a psychiatric examination of patients with hyperemesis gravidarum (HG) is a unique challenge for the psychiatric consultant. Unfortunately, there are little data in the psychosomatic medicine literature to guide diagnostic evaluations and treatment of patients with HG. In this article, we summarize the existing literature and propose a practical approach to such patients based on the literature and our clinical experience.

PC2 and 7B2 null mice demonstrate that PC2 is essential for normal pro-CCK processing.

Analysis of CCK content in extracts of whole forebrain from PC2 and 7B2 null mouse brain showed a significant decrease relative to wild-type brains. More detailed analysis revealed that CCK 8 amide levels in cerebral cortex and forebrain regions were more decreased than in hypothalamus. CCK 8 content in PC2 null mouse intestines was identical to control. Null mutant brains contained less CCK 8 than wild type and no other forms were seen when analyzed by gel filtration chromatography. No brain area examined was completely devoid of CCK, suggesting that other enzymes can partially compensate for the loss of PC2. This is the first demonstration that any endoprotease is important for CCK processing but also suggest the presence of a redundant system to ensure production of active CCK in the brain.

Elevated levels of TNF in the joints of adjuvant arthritic rats.

The primary purpose of this study was to determine whether local levels of tumor necrosis factor (TNF) were elevated in chronically inflamed joints in rats with adjuvant-induced arthritis (AA). We also wished to develop methodology for the quantitative measurement of joint TNF, and to examine the effects of known anti-inflammatory agents on joint TNF levels. TNF levels were measured in joints from AA rats taken during the systemic phase (day 20) of arthritic disease. Using the L929 bioassay, joint extracts from AA rats had significantly greater TNF levels (1054 +/- 147 pg/g tissue) than joint extracts from normal rats (110 +/- 42 pg/g tissue). Administration of ibuprofen failed to significantly inhibit TNF levels in the joint at a time point when paw swelling was significantly reduced. The immunomodulating agents, methotrexate, cyclosporin A (CSA) and HWA486 profoundly inhibited both joint TNF levels and paw swelling. The specificity of this assay for TNF was supported by studies with a polyclonal rabbit anti-mouse TNF antibody which neutralized 78-87% of the TNF activity in the joint extracts. Our studies demonstrate a quantitative increase in local TNF expression in adjuvant arthritis and support a role for TNF in chronic inflammation.

Effects of maternal iodine supplementation during pregnancy.

Reduced maternal thyroid hormone concentrations during pregnancy can adversely affect fetal neurological development. In the context of national iodine supplementation programmes, concern has been expressed over the theoretical possibility that iodine supplementation during pregnancy might adversely affect fetal development as a result of maternal thyroid inhibition from the Wolff-Chaikoff effect. In a double blind controlled trial in five villages in Papua New Guinea, several measures of motor and cognitive function showed no significant differences at either age 11 or 15 years between those children whose mothers had received supplementary iodine during pregnancy and the control children whose mothers had received the placebo.

Differential effects of anti-arthritic agents on subnormal plasma iron levels in adjuvant arthritic rats.

Nonsteroidal anti-inflammatory drugs (NSAID's) and other antirheumatic compounds such as disease modifying antirheumatic drugs (DMARD's), immunosuppressives and glucocorticoids were tested to determine if daily medication for two weeks could elevate subnormal levels of plasma iron in adjuvant-arthritic (AA) rats. Aspirin, indomethacin, ibuprofen and phenylbutazone were chosen as representative carboxylic acids and pyrazole NSAID's. Although NSAID's at all doses significantly reduced noninjected paw swelling, no NSAID significantly enhanced subnormal plasma iron levels in AA rats. In contrast, the standard DMARD's auranofin and gold sodium thiomalate, as well as the glucocorticoid, dexamethasone and the immunosuppressives, methotrexate and cyclosporin-A all significantly restored plasma iron levels 28 to 100 percent. Plasma iron depression, a parameter of the acute phase response probably under regulation by pro-inflammatory cytokines, is not reversed by NSAID treatment. This appears to be a useful method for distinguishing NSAID's from other anti-arthritic compounds.

The effect of danazol in the MRL/lpr mouse model of autoimmune disease.

The purpose of the study was to determine if danazol was efficacious in the treatment of lupus MRL/MpJ (lpr) mice, as measured by longevity, proteinuria and serum amyloid protein (SAP) levels. Danazol, administered at an oral dose of 100 mg/kg, significantly prolonged survival of female MRL/MpJ (lpr) mice but had no effect on the mortality of their male counterparts. Medication with danazol began 40 days after birth of the mice and resulted in a significant decrease in proteinuria in female but not male lupus mice. The concentration of SAP, an acute phase reactant, was significantly decreased in danazol-treated female lupus mice at 80, 100, 120, 140 and 160 days of age when compared to vehicle-treated control mice. SAP levels in male lupus mice treated with danazol were significantly lower than normal control levels only at the 120 and 160 day time points. Measurements of mortality, proteinuria and SAP concentration indicate that danazol at 100 mg/kg is orally active in the treatment of MRL/MpJ (lpr) female, but not male mice.

Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs.

Interleukin-1 (IL-1) activity and the acute phase response, as measured by plasma CRP and iron, were used to determine if the standard disease modifying antirheumatic drugs (DMARDs), gold, chloroquine and D-penicillamine had a common profile of activity in the adjuvant arthritic (AA) rat. All drugs were tested at a dose which significantly reduced noninjected paw swelling in AA rats. Inhibition of paw edema ranged from 37% for D-penicillamine (100 mg/kg) to 69% for auranofin (10 mg/kg). Two week medication of AA rats with gold sodium thiomalate (GST, 10 mg/kg, i.m.) or auranofin (10 mg/kg, p.o.) resulted in a significant decrease in splenic IL-1 activity, as measured in the standard lymphocyte activating factor (LAF) assay. The acute phase response, often associated with elevated IL-1 activity, was also significantly reduced following treatment of AA rats with 10 mg/kg of GST or auranofin (oral gold). Inhibition of the acute phase response by gold was determined by a significant reduction of plasma CRP levels (56-71% reduction) and enhancement of plasma iron levels (27-52% enhancement). In contrast to the effect of GST and auranofin on IL-1, CRP and iron, treatment with chloroquine (20, 30 and 35 mg/kg) and D-penicillamine (55 and 100 mg/kg) failed to reduce the acute phase response (as measured by plasma CRP and iron) or alter LAF activity from AA rat spleen cell supernatants. Based on its ability to reduce LAF activity in spleen cell supernatants and reduce the acute phase response, it is possible that the activity of gold in the AA rat may in part be due to its ability to inhibit IL-1 production in vivo. The inability of chloroquine and D-penicillamine to alter LAF activity and the acute phase response in AA rats does not preclude their possession of an immunoregulatory mechanism of action, but it does indicate that their mechanism of action in the AA rat probably differs from that of GST and auranofin.

Modulation of the acute phase response and in vitro measurement of interleukin-1 activity following administration of dexamethasone to adjuvant-arthritic rats.

Adjuvant-arthritic (AA) rats were medicated with dexamethasone to determine if this glucocorticoid suppressed the activity of interleukin-1 (IL-1) or the acute phase response. Dexamethasone (0.1 mg/kg, p.o.) administered daily for two weeks to AA rats, significantly (p less than or equal to 0.01) decreased high splenic IL-1 production (60% inhibition). Dexamethasone at a 0.5 mg/kg dose reduced AA rat splenic IL-1 production below normal (100% inhibition). In addition, dexamethasone significantly inhibited the AA rat acute phase response as measured by reduction of plasma C-reactive protein levels and enhancement of plasma albumin and iron levels. Following medication with 0.02, 0.1 or 0.5 mg/kg dexamethasone, high plasma C-reactive protein levels decreased by 33, 77 and 95% respectively, compared to untreated AA controls. Under the same dosing regimen of 0.02, 0.1 or 0.5 mg/kg dexamethasone, plasma albumin levels increased by 44, 128 and 239% respectively, while plasma iron levels rose by 19, 64 and 98% respectively, compared to AA controls. At the 0.02, 0.1 and 0.5 mg/kg doses dexamethasone also significantly reduced injected and noninjected paw swelling in AA rats. In view of the ability of dexamethasone to decrease IL-1 production and the acute phase response often associated with it, it is possible that part of the anti-inflammatory activity of dexamethasone may stem from inhibition of IL-1 formation in vivo.

Examination of interleukin-1 activity, the acute phase response, and leukocyte subpopulations in rats with adjuvant-induced arthritis.

Rats with adjuvant-induced arthritis (AA) were used to determine whether chronic systemic paw inflammation was accompanied by appearance of the acute phase response, an increase in splenic interleukin-1 (IL-1) production, and a reduction of nonhelper T cells in the spleen and peripheral blood. Two weeks after injection of adjuvant, the rats developed significant (P less than or equal to 0.01) swelling of the noninjected paw indicative of systemic inflammation. The rats with AA also exhibited signs of the acute phase response, as measured by a significant increase in plasma C-reactive protein (138% above normal) and a significant decrease in plasma albumin (47% below normal), zinc (30% below normal), and iron (58% below normal). IL-1 production from spleen cells of rats with AA was increased 115% compared with normals. Results from immunofluorescence studies with W3/25 and OX8 antibodies to distinguish rat T-helper-inducer (TH) spleen cells from suppressor-cytotoxic (nonhelper T) spleen cells indicated no significant difference between the percentage of OX8+ cells in spleens of arthritic rats compared with OX8+ cells in spleens of normal rats. The W3/25+-to-OX8+ ratio of 1.6 +/- 0.2 for normal rat spleen cells (33% to 21%) was not significantly different from the arthritic rat ratio of 1.9 +/- 0.1 (36% to 19%). When the phenotypes of peripheral blood mononuclear cells were analyzed, the normal animals possessed a greater percentage of W3/25+(TH) cells than did rats with AA. Normal blood mononuclear cell samples were composed of 51% +/- 3% W3/25+ cells and 22% +/- 2% OX8+ cells, and the samples from rats with AA contained 43% +/- 4% W3/25+ cells and 24% +/- 3% OX8+ cells. Thus, the helper-to-nonhelper ratio was higher for normal rats (2.3 +/- 0.1) than for arthritic rats (1.8 +/- 0.2). The data indicated that the appearance of the acute phase response and the abnormally high rate of splenic IL-1 production in the rats with AA did not stem from a subnormal percentage of OX8+ nonhelper T cells in the spleen or peripheral blood.

Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate.

The purpose of the paper was to determine whether two clinically active antirheumatic compounds, cyclosporin-A (CS-A) and methotrexate (MTX) were efficacious in the treatment of adjuvant arthritis (AA) in rats, as measured by reduction of paw inflammation, lymphocyte activating factor (LAF) activity and the acute phase response. Parameters of the acute phase response consisted of plasma fibronectin (Fn), C-reactive protein (CRP), albumin and iron. Rats injected with Freund's complete adjuvant on day 1, developed systemic arthritis, which was quantitated by measuring non-injected paw swelling on day 17. When compared to normal animals, AA rats had significantly (P less than or equal to 0.01) increased: (1) splenic LAF activity (100% increase), (2) plasma Fn (58%), and (3) CRP (122%), as well as abnormally reduced levels of: (1) plasma albumin (53% reduction), and (2) iron (54%). Orally dosing AA rats from days 3 to 17 with the immunoregulatory drugs, CS-A (3 and 5 mg/kg) or MTX (0.5 and 1 mg/kg), significantly (P less than or equal to 0.01) reduced paw inflammation (100% reduction), increased final body wt 40-50 g over arthritic controls and decreased LAF activity from splenic leukocytes. The acute phase response, often associated with a high degree of LAF activity, was significantly (P less than or equal to 0.01) decreased by dosing with CS-A (3 and 5 mg/kg) and MTX (0.5 and 1 mg/kg). The inhibition of the acute phase response was measured by reduction of high plasma Fn levels (42-79% decrease) and CRP levels (57-100% decrease) as well as elevation of subnormal levels of plasma albumin (57-101% increase) and iron (40-114% increase). Dosing with the nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (50 and 100 mg/kg) or phenylbutazone (10 and 30 mg/kg), significantly inhibited paw inflammation (29-85%), but did not decrease the high rate of splenic LAF activity, nor did aspirin (55, 100 and 200 mg/kg) or phenylbutazone (1, 10 and 30 mg/kg) alter the acute phase response in AA rats, as measured by levels of plasma Fn, CRP, albumin and iron. Since CS-A and MTX have been reported to be effective in the treatment of RA, their activity in the LAF, Fn, CRP, albumin and iron assays of the AA rat suggests that these immunological and serological parameters may be useful in identifying potential antirheumatic drugs and distinguishing them from standard NSAIDs.

A controlled trial of iodinated oil for the prevention of endemic cretinism: a long-term follow-up.

A double blind controlled trial designed to examine the effectiveness of intramuscular iodinated oil as a prophylactic for the nervous type of endemic cretinism was begun in 1966 in the highlands of Papua New Guinea. Infants born into the trial between 1966 and 1972 were followed up until 1982. The results showed that if the iodine supplement was given before conception the nervous form of endemic cretinism was prevented. Also a striking difference in the 15-year cumulative survival rate in favour of the test (iodinated oil) group was observed. Measures of motor and intellectual function revealed that children born to mothers given an iodine supplement performed significantly better. This observation shows that iodine deficiency leads to sub-clinical as well as clinical deficits. It also justifies the use of the term iodine deficiency disorder to cover the polymorphic nature of the abnormalities attributable to iodine deficiency.

Fetal iodine deficiency and motor performance during childhood.

Motor performance of children born to mothers living in an iodine-deficient region was assessed. The mothers were participants in a controlled trial of intramuscular iodised oil in the prevention of endemic cretinism carried out in the Western Highlands of Papua New Guinea. Mothers received either iodised oil or placebo saline. Children born to mothers given iodine were significantly faster and more accurate in tests of manual function than children from control mothers. The findings indicate that iodine deficiency may lead to a spectrum of subclinical deficits which place the children at a developmental disadvantage.