Use of multivariate statistical methods to identify immunochemical cross‐reactants

Quantitative competition immunoassays with appropriate combinations of antibodies give consistent dose‐response patterns which may be used to identify and estimate amounts of cross‐reacting compounds. Previously reported methods of analyzing cross‐reaction patterns include multiple regression, principal components analysis and minimum estimates of variance (MEV). Four other techniques which are preferable in theory have been surveyed: discriminant analysis (DA), maximum likelihood estimates (MLE), classification and regression trees (CART), and computational neural networks (NN). MLE and simple back‐propagation neural networks can estimate the concentration, as well as the identity, of individual compounds. These four methods worked well with unfitted, unscaled data from monoclonal assays of triazines, phenylureas and avermectins. Immunoassays must be properly designed to provide adequate data for pattern recognition. Cross‐reactivity pattern analysis will make multi‐analyte, multi‐antibody immunoassays feasible for many applications in toxicology and hazard assessment.     

Congenital abnormalities in newborn lambs after infection of pregnant sheep with Akabane virus.

Akabane virus (a Bunyavirus) has been associated with epizootics of congenital deformities in cattle, sheep, and goats. Experimental studies using mouse-adapted virus inoculated intravenously into pregnant sheep gave an inapparent infection. Neutralizing antibodies were detected on day 5, and peaks in the titer were seen at days 10 and 48. Ewes infected at day 30 to 36 of pregnancy produced five (31% incidence) deformed lambs. Sera from four of these possessed neutralizing antibodies to Akabane virus before ingesting colostrum. Two lambs had arthrogryposis, hydranencephaly, kyphosis, scoliosis, and brachygnathia; one had micrencephaly; and the other two had porencephaly. The two lambs with arthrogryposis and hydranencephaly also had extensive lesions in other tissues. In the spinal cord there was a marked decrease in the number of ventral horn neurones and a depletion of myelin. Skeletal muscles showed marked atrophy. The medulla of the thymus possessed large Hassall's corpuscles and a reduced number of thymocytes in the cortex. It would appear that the pathogenic effects of Akabane virus are related to the gestational age (30 to 36 days) at which the fetus is infected. Akabane virus can now be included in the growing list of teratogenic viruses and provides an interesting system for studying such congenital diseases.     

Effects of enclomiphene and zuclomiphene on basal and gonadotrophin-stimulated progesterone secretion by isolated subpopulations of small and large ovine luteal cells

We examined the effects of enclomiphene and zuclomiphene, aloneand in combination with oestradiol, on basal and gonadotrophin-stimulatedprogesterone secretion by isolated subpopulations of both large(granulosa-lutein) and small (theca-lutein) ovine luteal cells.Isolated large and small luteal cells derived from intact, enucleatedovine corpora lutea were incubated for 48–120 h with orwithout 22R-hydroxycholesterol or pregnenolone (2.5 µM)and a range of enclomiphene, zuclomiphene, and/or oestradiolconcentrations (3–100 µM), both with and withoutovine Iuteinizing hormone (100 ng/ml). Spent media were assayedin duplicate for progesterone content by radioimmunoassay. Enclomiphene,zuclomiphene, and oestradiol exhibited equivalent dose-dependentinhibitory effects on basal and gonadotrophin-stimulated smalland large ovine luteal cell progesterone secretion under allsubstrate conditions. Both cell types became more sensitiveto clomiphene inhibition with increasing time in culture. Incombined treatments, the effects of oestradiol and either enclomipheneor zuclomiphene became additive in longer-term cultures andwere never antagonistic In this model system, (i) clomiphene,like oestradiol, appears to inhibit 3-hydroxysteroid dehy-drogenaseactivity, (ii) both stereoisomers act as oestrogen agonists,(iii) neither demonstrates any anti-oestrogenic properties,and (iv) both large and small luteal cells become more sensitiveto clomiphene inhibition with increasing duration of exposure.     

Pharmacokinetics of vindesine bolus and infusion

Summary The pharmacokinetics of vindesine were investigated during treatment of 15 patients with progressive malignancies refractory to conventional treatment. Patients were administered one of three IV dose schedules: 3.0 mg/m² bolus injection, 1.2 mg/m²/day infusion for 5 days, or 2.0 mg/m²/day infusion for 2 days. Concentrations of the drug in the serum and urine were determined by radioimmunoassay. Serum concentrations were highest (5×10^-7 M) in patients receiving a bolus injection, but fell to nondetectable levels by 48 h in four of five patients (terminal t_1/2 15.0±9.4 h). Compared with bolus injection, 1.2-to 1.4-fold greater areas under the blood concentration curve were observed during infusions of 2.0 mg/m² and 1.2 mg/m². Whereas steady-state concentrations (1×10^-8 M) were maintained throughout the infusion of 1.2 mg/m²/day progressively increasing serum levels were observed during the infusion of 2.0 mg/m²/day. Serum concentrations fell rapidly following discontinuation of the 2.0-mg/m² infusion, but were somewhat more sustained in the 1.2-mg/m² infusion group. The average urinary excretion was similar for each dose-schedule (8%–11% of the total dose). The pharmacokinetics of vindesine are influenced by variations in dose schedule.     

Neuroendocrine mechanisms that delay and initiate puberty in higher primates

This paper highlights a series of studies using the male rhesus monkey that has led to a model for the control of the onset of puberty in higher primates. The model proposes that the timing of puberty in these species is governed by the duration of a central brake that, during juvenile development, holds in check the hypothalamic network of gonadotropin-releasing hormone (GnRH) neurons, which, in the adult, drive the pituitary-gonadal axis. The neurobiology of this hypothalamic brake, and the physiological mechanisms that time its application and removal, are incompletely understood. Nevertheless, the pubertal resurgence of pulsatile GnRH release, which terminates the juvenile phase of primate development and triggers the initiation of puberty in man and monkeys, is associated with structural and molecular remodeling of the hypothalamus. A major component of this developmental plasticity appears to involve neuropeptide Y (NPY). NPY inhibits GnRH release, and NPY gene expression in the hypothalamus is elevated during juvenile development when GnRH release is restrained. Since the changes in hypothalamic function and morphology that trigger primate puberty unfold in the absence of gonadal steroid feedback, the possibility is raised that, in addition to activating the pituitary-gonadal axis at this stage of development, they may also contribute directly to the causation of behaviors and affective states that emerge at adolescence.     

Specific cerebellar reductions in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome commonly are found to have morphological brain changes, cognitive impairments, and elevated rates of psychopathology. One of the most commonly and consistently reported brain changes is reduced cerebellar volume. Here, we demonstrate that, in addition to the global cerebellum reductions previously reported, volumetric reductions of the anterior lobule and the vermal region of the neo-cerebellum in the mid-sagittal plane best differentiate children with the deletion from typically developing children. These results suggest that the morphological changes of specific portions of the cerebellum may be an important underlying substrate of cognitive impairments and increased incidence of psychopathology in this group.     

"Could it be asthma?": the impact of a mass media campaign aimed at raising awareness about asthma in Australia

Asthma is a very common chronic illness in Australia; however,unrecognized and undertreated asthma is responsible for muchpreventable morbidity in the community. In 1988, a coalitionof private and public sector agencies was formed to conducta national mass communications program aimed at increasing awarenessabout asthma. This pilot campaign comprised a mailout to allprimary care physicians and a mass media campaign, entitled"Could it be asthma?". The impact of this media-based strategywas assessed using population surveys of 1300 adults beforeand after the campaign. Following the campaign, recall of recentasthma media messages increased from 24 to 49% (P < 0.001)and the proportion who recognized possible asthma symptoms intheir household increased from 3.4 to 5.5% following the campaign.Of those with symptoms, twice as many reported that they visiteda doctor to have their symptoms assessed after the campaign.Knowledge of asthma symptoms was significantly higher followingthe campaign (P < 0.001), after adjustment for age, sex andthe presence of asthma in the respondents family. The campaignappeared to have some success in raising awareness about asthma,and has been followed by the development of a National AsthmaCampaign in Australia focusing on reducing asthma morbidityand improving its management.     

Genotoxic activity of chlorohydroxyfuranones in the microscale micronucleus test on mouse lymphoma cells and the unscheduled DNA synthesis assay in rat hepatocytes

Chlorohydroxyfuranones (CHFs) are mutagenic disinfection by-productsfound in chlorine-treated drinking water. In the current study,the genotoxicity of four CHFs, 3,4-dichloro-5-hydroxy-2(5H)-furanone(MCA), 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone(CMCF) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone(MX), was determined. Two in vitro assays, the microscale micronucleusassay on L5178Y mouse lymphoma cells and the unscheduled DNAsynthesis assay on a hepatocyte primary culture from FisherF344 rats, were carried out. All four CHFs demonstrated genotoxiceffects in both assays. In the two systems used, CMCF was themost genotoxic compound, followed by MCA, MX and MCF, respectively.This work was the first study of the DNA damaging propertiesof all four CHFs in two in vitro genotoxicity tests. These newdata expand the range of genetic damages induced by this groupof compounds. ² To whom correspondence should be addressed. Tel: +33 3 20 8779 14; Fax: +33 3 20 87 73 10; Email: daniel.marzin{at}pasteur-lille.fr     

Osteochondroma and secondary synovial osteochondromatosis

Secondary synovial osteochondromatosis (SOC) is a rare disorder caused by a variety of joint disorders. Two unusual cases of secondary SOC are presented. The first patient is a 43-year-old man with extensive SOC developing within a bursa surrounding an osteochondroma of the pubic bone. The second patient is a 23-year-old man who developed florid and progressive SOC of his hip joint following excision of a femoral neck osteochondroma. SOC recurred despite three excisions over a 15-month period. Imaging was useful in pre-operative diagnosis of bursal SOC in the first patient and in detecting multiple recurrences in the second patient. Both cases illustrate prominent SOC developing secondary to osteochondroma. The different hypotheses regarding bursal and secondary SOC are reviewed. Received: 8 October 1998 Revision requested: 28 October 1998 Revision received: 13 November 1998 Accepted: 16 November 1998     

Balancing the equation: The significance of professional and lay perceptions in the promotion of cervical screening amongst minority ethnic women

Studies of minority ethnic women and cancer screening have, in the past, suffered from many theoretical and methodological weaknesses. In addition, no attempts have been made to study the complexity of the issue involved in the intercultural context, or the possible contribution of women's experiences to low uptake rates. In order to further our understanding of the issues, an alternative approach, participatory action research (PAR), was adopted to identify factors that might have contributed to the persistently low participation of minority ethnic women in the cervical screening programme, and address them collaboratively. This paper presents the key findings of the ‘problem identification' phase of the project. Using mainly the focus-group method, it explores both smear takers' and minority ethnic women's perceptions and experiences of cervical screening. Data suggest that there was a divergence in perceptions held by these groups regarding cervical screening, which contributed to negative experiences for both groups. There is also clear evidence of dysfunctional clinical communication arising from these differing perceptions. Opportunistic screening at post-natal examination adopted by many general practices appeared to have perpetuated the perceptions that the majority of minority ethnic women held about the purpose of the smear test. Compounded by language differences, the majority of women who had undergone smear testing understood neither the purpose of screening programme nor the procedure of the test. This has clear implications for promoting regular uptake, and more importantly for informed consent and choice.