Allergic fetal priming leads to developmental,behavioral and neurobiological changes in mice

The state of the mother''s immune system during pregnancy has an important role in fetal development and disruptions in the balance of this system are associated with a range of neurologic, neuropsychiatric and neurodevelopmental disorders. Epidemiological and clinical reports reveal various clues that suggest a possible association between developmental neuropsychiatric disorders and family history of immune system dysfunction. Over the past three decades, analogous increases have been reported in both the incidence of neurodevelopmental disorders and immune-related disorders, particularly allergy and asthma, raising the question of whether allergic asthma and characteristics of various neurodevelopmental disorders share common causal links. We used a mouse model of maternal allergic asthma to test this novel hypothesis that early fetal priming with an allergenic exposure during gestation produces behavioral deficits in offspring. Mothers were primed with an exposure to ovalbumin (OVA) before pregnancy, then exposed to either aerosolized OVA or vehicle during gestation. Both male and female mice born to mothers exposed to aerosolized OVA during gestation exhibited altered developmental trajectories in weight and length, decreased sociability and increased marble-burying behavior. Moreover, offspring of OVA-exposed mothers were observed to have increased serotonin transporter protein levels in the cortex. These data demonstrate that behavioral and neurobiological effects can be elicited following early fetal priming with maternal allergic asthma and provide support that maternal allergic asthma may, in some cases, be a contributing factor to neurodevelopmental disorders.     

Prospective clinical evaluation of an improved fluorescence polarization assay for predicting fetal lung maturity

We performed a prospective clinical evaluation of our newly developed fluorescence polarization procedure to predict fetal lung maturity (Clin Chem 1986;32:248-54). Net fluorescence polarization was measured at 34 degrees C after a 6.5-min incubation of amniotic fluid with fluorophore. For the 26 cases of neonatal respiratory distress syndrome encountered in 196 deliveries, the net polarization exceeded 0.287 for 22 (85%) of these, and exceeded 0.260 for all 26. The specificity of the polarization assay equaled or exceeded the specificity of the lecithin/sphingomyelin ratio for all sensitivities greater than 70%. Neither assay was a good predictor of the clinical severity of respiratory distress. For a separate group of 21 amniotic fluid specimens clinically contaminated with blood or meconium, the discriminatory power of the polarization assay was decreased, but six of seven respiratory-distress cases still had polarization values greater than 0.260. We conclude that this fluorescence polarization assay is a better overall predictor of fetal lung maturity than is the lecithin/sphingomyelin ratio, and that polarization values less than 0.260 are associated with little risk of respiratory distress.     

A single-dose study of the pharmacodynamic effects of chlormethiazole, temazepam and placebo in elderly parkinsonian patients.

Nine elderly parkinsonian volunteers took single doses of 384 mg of chlormethiazole, 10 mg of temazepam and placebo capsules in a double-blind three-way cross-over study on separate visits at least one week apart. In the 6 hours following the dose, the level of drowsiness, performance on a series of psychomotor tests, effects on parkinsonian symptoms and signs, and standing and lying blood pressure were recorded. Chlormethiazole produced drowsiness on all tests and impaired psychomotor performance, as compared with placebo, without affecting parkinsonian symptoms and signs, or postural blood pressure. Temazepam was consistently less potent than chlormethiazole on tests of drowsiness and psychomotor performance. Both treatments were well tolerated. It is suggested that chlormethiazole is safe to use as a hypnotic at this dosage in this group of patients with Parkinson's disease, while temazepam did not appear to be effective as a hypnotic at this dosage.     

A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Using 16O35Cl to correct for chloride interference improves accuracy of urine arsenic determinations by inductively coupled plasma mass spectrometry.

We have observed inaccurate urine arsenic values with the method of isobaric fractionation, which was designed to correct for the 40Ar35Cl interference with 75As quantitation by inductively coupled plasma mass spectrometry. Isobaric fractionation, which is based on ion intensities at m/z 77 and 82, consistently underestimates the 40Ar35Cl interference and overestimates urine arsenic. We present an improved method for identifying the argon-chloride interference. We observed that signal intensities for the species 16O35Cl and 40Ar35Cl are proportional (I75 = 0.0295 x I51 - 14.7, r2 = 0.998; where Ix is the normalized ion intensity at m/z X) in water and urine, over a broad range of chloride concentrations (0-800 mmol/L). The proportionality constant is remarkably stable within a run (mean and SD, 0.0295 +/- 0.0023, based on 10 replicates of five chloride calibrators, 0, 100, 200, 400, and 800 mmol/L). Increased sensitivity (50-fold) for detecting the 40Ar35Cl interference provides improved accuracy for urine arsenic quantitation as demonstrated by a split-sample comparison with graphite-furnace atomic absorption spectrophotometry.     

Security in the clinical laboratory. Guidelines for managing the information resource

The principal product produced by the clinical laboratory is information. This is true whether or not an automated system is used to organize and retrieve this information. It follows that great care must be exercised in ensuring that the stored data are accurate in the sense that they truly and always represent those data that were meant to be recorded. Various forces may act to compromise this information including (1) accidents, such as fire, floods, or earthquakes; (2) human error; and (3) deliberate acts, such as sabotage or theft of information. An organized plan for systematically managing the "information resource" has become critical. To safeguard against the potential catastrophic loss of information, a formal information resource management policy must be adopted within the clinical laboratory and directed by a specific individual, under the guidance of the director of pathology.     

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.