Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma.

OBJECTIVE: To evaluate the long-term effects of the anti-IgE antibody omalizumab in children with asthma. METHODS: This was a 28-week, double-blind, randomized, placebo-controlled trial with a 24-week open-label extension. In the core trial 225 children (ages 6 to 12 years) with moderate-to-severe allergic asthma requiring inhaled beclomethasone dipropionate (BDP) received omalizumab every 2 or 4 weeks, and 109 received placebo. BDP dosage was stable for weeks 1 to 16, then reduced during weeks 17 to 24 using strict safety criteria. The lowest dose for optimal asthma control was maintained for 4 more weeks. During the 24-week extension, all patients (n = 309) received open-label omalizumab in addition to other asthma medications. One-year safety data were analyzed. RESULTS: The incidence of adverse events in patients treated with omalizumab for 52 weeks was similar to those treated for 28 weeks in the core trial, which was generally comparable with placebo. In the 52-week omalizumab group, upper respiratory tract infection and headache were the most frequently reported adverse events (47.1% and 42.7%, respectively). Eleven patients (4.9%) reported urticaria, which resolved spontaneously or with antihistamine, except for 1 patient who was discontinued because of severe urticaria. No anaphylactic reactions or adverse events suggestive of serum sickness or immune complex formation occurred. No anti-omalizumab antibodies were detected in any of the children. There is no evidence that new or more serious adverse events occur with long-term omalizumab treatment. CONCLUSIONS: Long-term treatment with omalizumab is safe and well tolerated in children with allergic asthma.     

Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods

Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM-DNA adducts were assayed by high pressure liquid chromatography-electrospray tandem mass spectrometry (HPLC-ES-MS/MS), TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), and (32)P-postlabeling with either thin layer ((32)P-P-TLC) or liquid chromatography ((32)P-P-HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-alpha-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-N(2)-TAM) adduct in replicate rat livers varied by 3.5-fold when quantified using 'in house' TAM-DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM-DNA values were quantified using both 'in house' approaches as well as a newly synthesized [N-methyl-(3)H]TAM-DNA standard that was shared among all the participating groups. In the second study, the total TAM-DNA adduct values varied by 2-fold, while values for the dG-N(2)-TAM varied by 2.5-fold. Ratios of dG-N(2)-TAM:(E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-N(2)-N-desmethyl-TAM) in the second study were approximately 1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM-DNA adduct measurements among the diverse methods employed.     

Segregation of a supernumerary del(15) marker chromosome in sperm

Supernumerary marker chromosomes (SMC) can be associated with both normal and abnormal phenotypes. In addition, SMC are found at higher frequency in males with infertility. We identified a SMC, characterized as a del(15)(q11.2) chromosome, in a phenotypically normal male. Using fluorescence in situ hybridization (FISH), we examined the segregation of the del(15) chromosome in sperm from this patient. Only 6.23% of sperm nuclei showed disomy using a chromosome 15 alpha-satellite FISH probe, instead of the expected 50%. In addition, FISH analysis showed no increase for non-disjunction of chromosome 18, excluding an interchromosomal effect for this chromosome. The significant decrease in sperm bearing the del(15) may be due to tissue-specific mosaicism or a result of some form of selection against the del(15) during spermatogenesis. This finding provides a basis for the observation that SMC(15) are less likely to be inherited from a paternal carrier.     

20q13.2 Amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast

The 20q13 region harboring recently described putative oncogenes is frequently amplified in invasive ductal carcinoma (IDC). The aim of this study was to examine the 20q13 copy number in intraduct hyperplasia (IH), atypical duct hyperplasia (ADH), and ductal carcinoma in situ (DCIS) adjacent to IDC. In 5 patients, comparative genomic hybridization (CGH) after laser microdissection revealed 20q13 amplification in four of five cases of IH, in all of three cases of IH with atypia, all five of DCIS, and all five of IDC. Fluorescence in situ hybridization (FISH) confirmed the amplification at 20q13.2 in IH in the two specimens analyzed. The amplification rate, however, was higher in DCIS and IDC. In phenotypically normal ductal epithelium normal values were found for 20q13 copy number by FISH (n=2) and CGH (n=5). Although the number of cases presented here is small, our results suggest that mutations in the 20q13.2 region in IH may be associated with accelerated proliferation and hyperplasia of the ductal epithelium. Progression to DCIS and ICD is accompanied by a further increase in the 20q13.2 copy number. Received: 17 March 1999 / Accepted: 22 June 1999     

Thalamic and cortical projections to middle suprasylvian cortex of cats: constancy and variation

 We investigated the constancy and variability in the numbers of thalamic and cortical neurons projecting to cat middle suprasylvian (MS) visual cortex. Retrograde pathway tracers were injected at a single anatomically and physiologically defined locus in MS cortex. Counts of labeled neurons showed that the visual thalamic projections to MS cortex consistently arose from a fixed set of nuclei in relatively constant proportions. In contrast, counts of cortical neurons revealed that transcortical inputs to MS cortex were much more variable. This differential variability may be linked to the developmental program, which affords greater influence of experiential factors on cortical pathway development than on thalamocortical pathway development. These results have implications for the development of models of cerebral connectivity that include measures of pathway variability. Received: 29 March 1996 / Accepted: 3 September 1996     

Infant feeding and overweight in two Oxfordshire towns

In a study of feeding and growth in the first year of life in two Oxfordshire market towns, the frequency of overweight babies was the same for the 'intervention' town (where a research health visitor gave intensive advice to mothers on feeding) as for the control town. Eighteen per cent of bottle-fed infants and three per cent of those breast fed were overweight at one year. It seems that an increase in the number of health visitors does not affect the frequency of overweight infants, but it may be that a greater emphasis on breast feeding might reduce the frequency.