Trimellitic anhydride-induced airway syndromes: Clinical and immunologic studies

This report describes a spectrum of respiratory symptoms in workers exposed to trimellitic anhydride (TMA), a biologically reactive chemical used in the plastics industry. Fourteen workers who had worked on a unit which synthesized TMA were evaluated by clinical and immunologic methods. Respiratory syndromes induced by TMA inhalation included asthma and rhinitis of the immediate type, late onset asthma with systemic symptoms, and airway irritation. TMA was shown to couple rapidly to human serum albumin, forming an immunoreactive hapten-protein complex. The workers' immunologic reactivity to this complex could be quantitated and correlated with the three respiratory syndromes. The asthma-rhinitis syndrome was mediated by IgE antibody specific for the TMA hapten. The syndrome of late onset asthma with systemic symptoms was accompanied by elevated levels of TMA-specific IgG antibody. Rheumatoid factor in high titer was found in one worker with IgE-mediated asthma and in two workers with asthma of late onset. Lymphocyte reactivity of TMA-HSA was demonstrated in three workers representative of the three clinical syndromes. Leukocyte histamine release was demonstrated to TMA-HSA in one worker with high levels of IgE antibody specific for TMA-HSA who had severe symptoms of acute rhinitis and asthma.     

The genetic basis of Turner syndrome aortopathy

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene‐based burden test, SKAT‐O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z‐scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome‐wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13‐fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.     

ApoE genotype accounts for the vast majority of AD risk and AD pathology

In this review, evidence is provided that apolipoprotein E (apoE) genotype accounts for the majority of Alzheimer's disease (AD) risk and pathology. The three major human isoforms, apoE2, apoE3, and apoE4, are encoded by different alleles (2, 3, 4) and regulate lipid metabolism and redistribution. ApoE isoforms differ in their effects on AD risk and pathology. Clinical and epidemiological data have indicated that the 4 allele may account for 50% of AD in the United States. Further, the rarity of AD among carriers of the 2 allele suggests that allelic variations in the gene encoding this protein may account for over 95% of AD cases. ApoE4 disrupts memory function in rodents. Further studies have indicated that fragments of apoE may contribute to both plaque and tangle formation. Thus, the epidemiologic and basic science evidence suggest that apoE genotype accounts for the vast majority of AD risk and pathology.     

Initial evaluation of a continuous speech recognition program for radiology

The aims of this work were to measure the accuracy of one continuous speech recognition product and dependence on the speaker's gender and status as a native or nonnative English speaker, and evaluate the product's potential for routine use in transcribing radiology reports. IBM MedSpeak/Radiology software, version 1.1 was evaluated by 6 speakers. Two were nonnative English speakers, and 3 were men. Each speaker dictated a set of 12 reports. The reports included neurologic and body imaging examinations performed with 6 different modalities. The dictated and original report texts were compared, and error rates for overall, significant, and subtle significant errors were computed. Error rate dependence on modality, native English speaker status, and gender were evaluated by performing ttests. The overall error rate was 10.3 +/- 3.3%. No difference in accuracy between men and women was found; however, significant differences were seen for overall and significant errors when comparing native and nonnative English speakers (P = .009 and P = .008, respectively). The speech recognition software is approximately 90% accurate, and while practical implementation issues (rather than accuracy) currently limit routine use of this product throughout a radiology practice, application in niche areas such as the emergency room currently is being pursued. This methodology provides a convenient way to compare the initial accuracy of different speech recognition products, and changes in accuracy over time, in a detailed and sensitive manner.     

Evaluation of anhydride oligomers within polymer microsphere blends and their impact on bioadhesion and drug delivery in vitro

The effect of the addition of small molecular weight anhydride oligomers to polymer microspheres was evaluated and increased bioadhesion of the composite was demonstrated. Blends of low molecular weight anhydride oligomers with thermoplastic poly(fumaric-co-sebacic anhydride) [p(FASA)] and polycaprolactone were examined. The effects of anhydride oligomers on polymer microsphere degradation, crystallinity, and surface morphology were also explored. The results demonstrated that fumaric anhydride oligomer remained within polymer microspheres for several hours after exposure to phosphate buffer, formed a homogenous crystalline blend, increased bioadhesion as measured on rat intestine, and enhanced drug delivery in vitro as measured by the everted sac technique.