Causes of Isolated Aortic Insufficiency in an Urban Population in the 1990s: A Review of 56 Surgical Pathology Cases

Until recently, the cause of isolated aortic insufficiency (AI) was usually thought to be inflammatory or rheumatic in most cases. However, at our institution we have noted a high prevalence of myxomatous degeneration (MD) in aortic valves removed for AI. In this study we report anatomic observations on valves from 56 consecutive patients with isolated AI undergoing aortic valve replacement surgery. Fifty-six consecutive aortic valves removed at our institution from 1994 to 1996 for isolated AI and/or aortic aneurysm were reviewed. Anatomic features were compared with clinical history and echocardiographic data. The anatomic results were also compared to 22 age-matched control aortic valves obtained at autopsy. In 13/56 cases (23%), a specific valvular cause of AI was determined (infectious endocarditis, seven cases; chronic rheumatic disease, four cases; congenital bicuspid valve, two cases). Of the remaining (idiopathic) 43 cases, 18 (42%) had severe isolated MD defined as >50% expansion of the spongiosa and disruption of the fibrosa by the deposition of acid mucopolysaccharides in the absence of severe calcification, fibrosis, or other pathologic findings. Only 1/22 aortic valves from the autopsy controls had severe MD. Eighteen of the 56 patients also had a clinical history of aortic dilatation/aneurysm of which 12 were confirmed to be dilated by echocardiographic criteria. Of these 12, five (42%) had MD of the aortic valve only, three (25%) had both MD and cystic medial degeneration (CMD) of the aorta, two (17%) had CMD of the aorta only, and two (17%) had no specific diagnosis. Isolated MD of the aortic valve is the most common cause of isolated AI in our patient population. Furthermore, in a subset of non-Marfan’s patients with both AI and dilatation of the aortic root/aortic aneurysm the incidence of MD is even higher (67%). These results suggest that there is overlap between MD and CMD in non-Marfan’s patients and that both entities may be part of a spectrum of a generalized connective tissue disorder.     

PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy.

Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the laminin alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy.     

Association between atrial fibrillation and central sleep apnea

BACKGROUND: We previously described an association between atrial fibrillation and central sleep apnea in a group of patients with congestive heart failure. We hypothesized that the prevalence of atrial fibrillation might also be increased in patients with central sleep apnea in the absence of other cardiac disease. METHODS AND RESULTS: We compared the prevalence of atrial fibrillation in a series of 60 consecutive patients with idiopathic central sleep apnea (apnea-hypopnea index > 10 events per hour, > 50% central events) with that in 60 patients with obstructive sleep apnea (apnea-hypopnea index > 10, > 50% obstructive events) and 60 patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. Subjects with a history of congestive heart failure, coronary artery disease, or stroke were excluded from the study. The prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was found to be significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively, P < .001). However, hypertension was most common and oxygen desaturation most extreme among patients with obstructive sleep apnea. CONCLUSIONS: We conclude that there is a markedly increased prevalence of atrial fibrillation among patients with idiopathic central sleep apnea in the absence of congestive heart failure. Moreover, the high prevalence of atrial fibrillation among patients with idiopathic central sleep apnea is not explainable by the presence of hypertension or nocturnal oxygen desaturation, since both of these were more strongly associated with obstructive sleep apnea.     

Nerve growth factor and substance P regulation in nasal sensory neurons after toluene diisocyanate exposure

Toluene diisocyanate (TDI) exposure produces rhinitis and nasal irritation, and increases the synthesis and release of substance P (SP) from airway sensory nerves. The mechanism leading to enhanced SP production following irritant inhalation remains unclear, but may involve actions of nerve growth factor (NGF). NGF binds trkA receptors located on sensory nerve terminals. Activation of trkA receptors initiates kinase-signaling cascades, which ultimately may increase SP. However, the effects of inhaled irritants on NGF release are not known. In this study, NGF levels in nasal lavages were examined following instillation of 10% TDI into both nasal cavities. NGF was significantly increased 2, 6, 12, and 24 h after TDI exposure compared with controls. The increase in NGF preceded the neuronal and mucosal increases in SP. Pretreatment with K252a, a nonselective tyrosine-kinase inhibitor, prevented the increase in SP-immunoreactivity in TG neurons and epithelial nerve fibers and the inflammatory response to TDI exposure. Because NGF binds to trkA tyrosine-kinase receptors, the NGF released during TDI exposure may mediate SP upregulation in airway sensory neurons, innervating the nasal cavity.     

Influence of outdoor aeroallergens on hospitalization for asthma in Canada

BACKGROUND: The risk of hospitalization for asthma caused by outdoor aeroallergens is largely unknown. OBJECTIVE: The objective of this study was to determine the association between changes in outdoor aeroallergens and hospitalizations for asthma from the Pacific coast to the Atlantic coast of Canada. METHODS: A daily time series analysis was done to test the association between daily changes in aeroallergens and daily changes in hospitalizations for asthma during a 7-year period between 1993 and 2000 in 10 of the largest cities in Canada. Results were adjusted for long-term trends, day of the week, climate, and air pollution. RESULTS: A daily increase, equivalent to the mean value of each allergen, was associated with the following percentage increase in asthma hospitalizations: 3.3% (95% CI, 2.3 to 4.1) for basidiomycetes, 3.1% (95% CI, 2.8 to 5.7) for ascomycetes, 3.2% (95% CI, 1.6 to 4.8) for deuteromycetes, 3.0% (95% CI, 1.1 to 4.9) for weeds, 2.9% (95% CI, 0.9 to 5.0) for trees, and 2.0% (95% CI, 1.1 to 2.8) for grasses. After accounting for the independent effects of trees and ozone, the combination of the 2 was associated with an additional 0.22% increase in admissions averaged across cities (P <.05). CONCLUSION: These findings provide evidence for the hypothesis that aeroallergens are an important cause of severe asthma morbidity across Canada, and in some situations there might be a modest synergistic adverse effect of ozone and aeroallergens combined.     

Testicular metastasis of primary cecal carcinoid tumor

Testicular carcinoids are rare and the majority are of primary testicular origin. Testicular carcinoids can also be secondary from extra-testicular primary tumors, but the incidence is even less common. The case described here is a patient who initially had an infiltrating cecal carcinoid with hepatic metastasis. Following surgery, he was managed with octreotide and had close monitoring of the levels of serum serotonin and its urinary metabolite. He experienced a fairly indolent clinical course and 5 years after excision of the primary cecal carcinoid, his hepatic lesion has virtually been unchanged. However, he developed a secondary testicular metastasis. He has otherwise remained well, without evidence of metastases elsewhere on imaging studies.     

Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: seven new mutations

We have studied the molecular genetics of 27 Brazilian families with ataxia telangiectasia (AT). Five founder effect haplotypes accounted for 55.5% of the families. AT is an autosomal recessive disorder of childhood onset characterized by progressive cerebellar ataxia, ocular apraxia, telangiectasia, immunodeficiency, radiation sensitivity, chromosomal instability, and predisposition to cancer. The ATM gene spans more than 150 kb on chromosome region 11q23.1 and encodes a product of 3056 amino acids. The ATM protein is a member of the phosphatidylinositol 3-kinase (PI-3K) family of proteins and is involved in cell cycle control and DNA repair pathways. DNA was isolated from lymphoblastoid cell lines and haplotyped using four STR markers (D11S1818, NS22, D11S2179, D11S1819) within and flanking the ATM gene; all allele sizes were standardized in advance. In addition to the STR haplotypes, SNP haplotypes were determined using 10 critical polymorphisms. The entire gene was screened sequentially by protein truncation testing (PTT), single strand conformation polymorphism (SSCP), and then denaturing high performance liquid chromatography (dHPLC) to identify the disease-causing mutations. Of the expected 54 mutations, 50 were identified. All mutations but one, led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Five families (18.5%) carried a deletion of 3450nt (from IVS28 to Ex31), making this one of the two most common Brazilian mutations. Mutations were located throughout the entire gene, with no clustering or hotspots. Standardized STR haplotype analysis greatly enhanced the efficiency of mutation screening.     

Attenuation of intracavitary applicators in 192Ir-HDR brachytherapy

Unlike the penetrating monoenergetic 662 keV gamma rays emitted by 137Cs LDR sources, the spectrum of 192Ir used in HDR brachytherapy contains low-energy components. Since these are selectively absorbed by the high-atomic number materials of which intracavitary applicators are made, the traditional neglect of applicator attenuation can lead to appreciable dose errors. We investigated the attenuation effects of a uterine applicator, and of a set of commonly used vaginal cylinders. The uterine applicator consists of a stainless steel source guide tube with a wall thickness of 0.5 mm and a density of 8.02 g/cm3, whereas the vaginal cylinders consist of the same stainless steel tube plus concentric polysulfone cylinders with a radius of 1 or 2 cm and a density of 1.40 g/cm3. Monte Carlo simulations were performed to compute dose distributions for a bare 192Ir-HDR source, and for the same source located within the applicators. Relative measurements of applicator attenuation using ion-chambers (0.125 cm3) confirmed the Monte Carlo results within 0.5%. We found that the neglect of the applicator attenuation overestimates the dose along the transverse plane by up to 3.5%. At oblique angles, the longer photon path within applicators worsens the error. We defined attenuation-corrected radial dose and anisotropy functions, and applied them to a treatment having multiple dwell positions inside a vaginal cylinder.