Safety of levocetirizine treatment in young atopic children: An 18-month study

There are more than 40 H(1)-antihistamines available worldwide. Most of these medications have never been optimally studied in prospective, randomized, double-masked, placebo-controlled trials in children. The aim was to perform a long-term study of levocetirizine safety in young atopic children. In the randomized, double-masked Early Prevention of Asthma in Atopic Children Study, 510 atopic children who were age 12-24 months at entry received either levocetirizine 0.125 mg/kg or placebo twice daily for 18 months. Safety was assessed by: reporting of adverse events, numbers of children discontinuing the study because of adverse events, height and body mass measurements, assessment of developmental milestones, and hematology and biochemistry tests. The population evaluated for safety consisted of 255 children given levocetirizine and 255 children given placebo. The treatment groups were similar demographically, and with regard to number of children with: one or more adverse events (levocetirizine, 96.9%; placebo, 95.7%); serious adverse events (levocetirizine, 12.2%; placebo, 14.5%); medication-attributed adverse events (levocetirizine, 5.1%; placebo, 6.3%); and adverse events that led to permanent discontinuation of study medication (levocetirizine, 2.0%; placebo, 1.2%). The most frequent adverse events related to: upper respiratory tract infections, transient gastroenteritis symptoms, or exacerbations of allergic diseases. There were no significant differences between the treatment groups in height, mass, attainment of developmental milestones, and hematology and biochemistry tests. The long-term safety of levocetirizine has been confirmed in young atopic children.     

Translocation X;10 in a case of congenital acute monocytic leukemia

Unusual cytogenetic findings were noted in the leukemic cells from a patient with congenital acute monocytic leukemia (AMol or M5, according to the FAB classification), whereas, the chromosomes of cultured skin fibroblasts were normal. G-banded karyotypes of leukemic cells showed an X-autosome translocation, 46,X,t(X;10)(Xpter----q13::10q11.2----qter)(10pter---- q11.2::Xq28----q13:: Xq28----qter). Review of reported cases of acute nonlymphocytic leukemia (ANLL) with rearrangements involving chromosomes #10 or X showed a high frequency of abnormalities of the short arm of #10 in myelomonocytic (M4) and monocytic (M5) leukemias, particularly in patients less than 2-yr-of-age. Although previously reported cases of ANLL in infants are predominantly of these types, the translocation observed in this case is unique. Fragile sites known to exist on chromosomes #10 and X are not associated with neoplasia and, except for Xq27-28, were not at the breakpoints of the case presented. The precise location of a human cellular oncogene recently identified on the X chromosome remains unknown.     

Safety of cetirizine in infants 6 to 11 months of age: a randomized,double-blind,placebo-controlled study

BACKGROUND: H(1)-antihistamines are widely used for symptom relief in allergic disorders in infants and children; however, there are few prospective, randomized, double-blind, controlled studies of these medications in young children, and to date, no such studies have been conducted in infants. OBJECTIVE: This prospective, randomized, parallel-group, double-blind, placebo-controlled study was designed to evaluate the safety of the H(1)-antihistamine cetirizine, particularly with regard to central nervous system and cardiac effects, in infants age 6 to 11 months, inclusive. METHODS: Infants who met the entry criteria for age and had a history of treatment with an H(1)-antihistamine for an allergic or other disorder were randomized to receive 0.25 mg/kg cetirizine orally or matching placebo twice daily orally for 1 week. RESULTS: The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg (SD). No differences in all-cause or treatment-related adverse events were observed between the cetirizine- and placebo-treated groups. A trend was observed toward fewer adverse events and sleep-related disturbances in the cetirizine group compared with the placebo group. No prolongation in the linear corrected QT interval was observed in cetirizine-treated infants compared with either baseline values or with values in placebo-treated infants. CONCLUSIONS: We have documented the safety of cetirizine in this short-term investigation, the first randomized, double-blind, placebo-controlled study of any H(1)-antihistamine in infants. Additional prospective, randomized, double-blind, placebo-controlled, long-term studies of cetirizine and other H(1)-antihistamines are needed in this population.     

A chimeric T cell receptor with super-signaling properties

A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR-alphabeta chains result in the activation of distinct signal transduction pathways by the CD3-gammadeltaepsilon/zeta complex? To investigate which part of the TCR-beta chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR-beta chain with the corresponding TCR-gamma chain domains. We show here that hybridoma cells expressing a chimeric TCR-beta chain (betaIII) containing intracellular and transmembrane TCR-gamma amino acids, together with a wild-type TCR-alpha (alphawt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR-alphawt/betawt chains. This super-signaling phenotype of the betaIII chain was observed in two different TCRs. One specific for an alloantigen (I-A(bm12)) and one for an autoantigen (I-A(b)/MOG(35-55)). We found that this chimeric alphawt/betaIII TCR had normal association with CD3-gammadeltaepsilon and zeta chains. To investigate the effect of the chimeric betaIII chain in transgenic T cells, we made MOG(35-55)-specific TCR transgenic mice expressing either the alphawt/betawt or chimeric alphawt/betaIII TCR. Similar to what was observed in hybridoma cells, transgenic alphawt/betaIII T cells showed a super-signaling phenotype upon antigenic stimulation. Further studies may help us understand the effect of increased TCR signaling on autoimmunity and may lead to the identification of signaling molecules that can be targeted to stop the progression of autoimmune disorders such as multiple sclerosis.     

Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia

The present study was designed to assess the effects of dietary leucine supplementation on muscle protein synthesis and whole body protein kinetics in elderly individuals. Twenty healthy male subjects (70 ± 1 years) were studied before and after continuous ingestion of a complete balanced diet supplemented or not with leucine. A primed (3.6 μmol kg⁻¹) constant infusion (0.06 μmol kg⁻¹ min⁻¹) of l -[1-¹³C]phenylalanine was used to determine whole body phenylalanine kinetics as well as fractional synthesis rate (FSR) in the myofibrillar fraction of muscle proteins from vastus lateralis biopsies. Whole body protein kinetics were not affected by leucine supplementation. In contrast, muscle FSR, measured over the 5-h period of feeding, was significantly greater in the volunteers given the leucine-supplemented meals compared with the control group (0.083 ± 0.008 versus 0.053 ± 0.009% h⁻¹, respectively, P < 0.05). This effect was due only to increased leucine availability because only plasma free leucine concentration significantly differed between the control and leucine-supplemented groups. We conclude that leucine supplementation during feeding improves muscle protein synthesis in the elderly independently of an overall increase of other amino acids. Whether increasing leucine intake in old people may limit muscle protein loss during ageing remains to be determined.     

The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the T-independent IgG3, but not IgM, response was impaired in the TACI-IgxBcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.     

Screening methods for thyroid hormone disruptors

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.