Dissociation Between Changes in Intramyocardial Function and Left Ventricular Volumes in the Eight Weeks After First Anterior Myocardial Infarction

Objectives. We sought to examine the relation between regional changes in intramyocardial function and global left ventricular (LV) remodeling in the first 8 weeks after reperfused first anterior myocardial infarction (MI).

Background. Because of limitations in imaging methods used to date, this relation has not been thoroughly evaluated.

Methods. We studied 26 patients (21 men, 5 women; mean age 51 years) by magnetic resonance imaging (MRI) on day 5 ± 2 (mean ± SD) and week 8 ± 1 after their first anterior MI. All patients had single-vessel left anterior descending coronary artery disease and although they had received reperfusion therapy, all had regional LV dysfunction and an initial ejection fraction (EF) ≤50%. Short-axis magnetic resonance tagging was performed spanning the LV. Percent intramyocardial circumferential shortening (%S) on a topographic basis, LV mass index, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index and LV ejection fraction (LVEF) were measured.

Results. Left ventricular mass index tended to decrease, whereas the LVEDVI increased from 82 ± 24 to 96 ± 27 ml/m² (p = 0.002). Left ventricular end-systolic volume index remained unchanged, whereas LVEF increased from 39 ± 12% to 45 ± 14% (p = 0.002). Apical %S improved from 9 ± 6% to 13 ± 5% (p < 0.0001), as it did in the midanterior (6 ± 6% to 10 ± 7%, p < 0.02) and midseptal regions (8 ± 7% to 12 ± 6%, p < 0.02). Early dysfunction in remote midinferior and basal lateral regions resolved by 8 weeks. By multivariate analysis, the only significant predictor of an increase in LVEDVI over the study period was peak creatine kinase (p = 0.04).

Conclusions. In the first 8 weeks after a large, reperfused anterior MI, %S improved in the apex, midanterior and midseptal regions and normalized in remote noninfarct-related regions, but LV end-diastolic volumes also increased. This increased LVEDVI correlated with infarct size by peak creatine kinase and was not related to changes in global and regional LV function.     

Classical Noonan syndrome is not associated with deletions of 22q11

Deletions of 22qll cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22qll deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22qll deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22qll deletion. A 2-month-old infant with several findings suggestive of NS did have a 22qll deletion, suggesting that a small number of 22qll deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. © 1995 Wiley-Liss, Inc.     

LcrV plague vaccine with altered immunomodulatory properties

Yersinia pestis, the causative agent of plague, secretes LcrV (low-calcium-response V or V antigen) during infection. LcrV triggers the release of interleukin 10 (IL-10) by host immune cells and suppresses proinflammatory cytokines such as tumor necrosis factor alpha and gamma interferon as well as innate defense mechanisms required to combat the pathogenesis of plague. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of LcrV as a human vaccine. Here we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271 to 300 (rV10) elicited immune responses that protected mice against a lethal challenge with Y. pestis. Compared to full-length LcrV, rV10 displayed a reduced ability to release IL-10 from mouse and human macrophages. Furthermore, the lipopolysaccharide-stimulated release of proinflammatory cytokines by human or mouse macrophages was inhibited by full-length LcrV but not by the rV10 variant. Thus, it appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.     

Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation

Motility of unicellular organisms occurred early in evolution with the emergence of cilia and flagella. In vertebrates, motile cilia are required for numerous functions such as clearance of the airways and determination of left-right body asymmetry. Ependymal cells lining the brain ventricles also carry motile cilia, but their biological function has remained obscure. Here, we show that ependymal cilia generate a laminar flow of cerebrospinal fluid through the cerebral aqueduct, which we term as 'ependymal flow'. The axonemal dynein heavy chain gene Mdnah5 is specifically expressed in ependymal cells, and is essential for ultrastructural and functional integrity of ependymal cilia. In Mdnah5-mutant mice, lack of ependymal flow causes closure of the aqueduct and subsequent formation of triventricular hydrocephalus during early postnatal brain development. The higher incidence of aqueduct stenosis and hydrocephalus formation in patients with ciliary defects proves the relevance of this novel mechanism in humans.     

Urothelial cell DNA adducts in rubber workers

Workers employed in the rubber industry appear to have a significant excess cancer risk in a variety of sites, including cancer of the urinary bladder. In this cross-sectional study, we investigated the occurrence of DNA adducts in exfoliated bladder cells of currently exposed, nonsmoking rubber workers (n = 52) and their relationship with occupational exposure estimates and acetylation phenotype (NAT2). Four DNA adducts were identified, with the proportion of positive samples (e.g., DNA samples with quantifiable levels of a specific DNA adduct) ranging from 3.8 to 79%. The highest proportion of positive samples and the highest relative adduct labeling levels were in workers involved in the production functions "mixing" and "curing," areas with potential for substantial exposure to a wide range of chemical compounds used in rubber manufacturing (P < 0.05 for adducts 2 and/or 3, compared to all other departments). No statistically significant relationships were found between identified DNA adducts and urinary mutagenicity or personal inhalable and dermal exposure estimates. Interestingly, subjects with a fast NAT2 acetylation phenotype tended to have higher levels of DNA adducts. This study suggests that rubber workers engaged in mixing and curing may be exposed to compounds that can form DNA adducts in urothelial cells. Larger studies among rubber workers should be conducted to study in more detail the potential carcinogenicity of exposures encountered in these work areas.     

Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus

Primary ciliary dyskinesia (PCD), also known as Kartagener's syndrome, is a human syndrome that results from ciliary dysfunction. This syndrome is characterized by recurrent respiratory infections, situs inversus and infertility. In some cases, hydrocephalus is also observed. We have characterized an insertional mutation in a mouse axonemal dynein heavy chain gene (Mdnah5) that reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility. These mice also suffer from hydrocephalus and die perinatally. Electron microscopic studies demonstrate the loss of axonemal outer arms. These results show that mutations in Mdnah5 are a primary cause of PCD and provide direct evidence that mutations in an axonemal dynein can cause hydrocephalus. Mutations in the human DNAH5 have recently been identified in PCD patients. Comparison of the mouse model and the human data suggests that the degree of ciliary dysfunction is causally related to the severity of human PCD, particularly the presence of hydrocephalus.     

Effect of gonadectomy on the follicular cell and inclusions in mitochondria of rabbit thyroid gland.

Thyroid glands of male rabbits were studied 2, 4, and 6 weeks after gonadectomy. In the gonadectomized group of animals, at the end of 2 weeks the follicular cell did not present any significant change except for the reduction of the supranuclear portion of the cell. By the end of 4 weeks there was a marked decrease in the microvilli of the apical border, dense granules, colloid droplets, ribosomes, and ergastoplasmic sacs. The lateral and basal cell margins were less convoluted. These changes reached a peak by the end of 6 weeks. The mitochondria with the inclusions also showed an apparent decrease in incidence at the end of 4 weeks and were rarely encountered by the end of 6 weeks. The thyroid gland morphologially resembled a hypothroid state, indicating that gonadectomy depresses the function and, therefore, may affect the metabolic process controlled by the gland.     

Previous abdominal colectomy affects functional results after ileal pouch-anal anastomosis

We assessed the effect of previous abdominal colectomy on functional results after ileal J pouch-anal anastomosis (IPAA) in patients with ulcerative colitis. Twenty-five patients with colectomy prior to IPAA were compared with 22 patients who underwent noncolonic abdominal operations prior to IPAA. No differences were observed in pre- or postoperative resting anal sphincter pressure, squeeze pressure, or rectal inhibitory reflex. Previous colectomy was associated with a greater incidence of postoperative small bowel obstruction. Mean ± SEM daily stool frequency at 1 and 12 months postoperatively, respectively, was 8.9±0.8 and 5.7±0.3 for patients who had undergone previous colectomy, and 8.2±0.7 and 6.0±0.5 for the no previous colectomy group (p=not significant). At the same postoperative intervals, nocturnal stool frequency was 1.9±0.3 and 1.1±0.2 for the colectomy group and 1.5±0.3 and 0.6±0.1 for the no colectomy group (p=0.05 at 1 year). More patients in the previous colectomy group had greater than or equal to 1 nocturnal stool after 1 year (71% versus 33%,p=0.03). Although pouch capacity at 1 year was not different in the 2 groups, pouch capacity was directly related to stool frequency in the no colectomy group (r²=0.48,p=0.01), but not in the previous colectomy group (r²= 0.08,p=not significant). We conclude that previous abdominal colectomy may be associated with a higher overall incidence of small bowel obstruction. Moreover, previous colectomy is a determinant of postoperative nocturnal stool frequency after IPAA, most likely due to altered ileal pouch function. When possible, single-stage colectomy, mucosal proctectomy, and endorectal ileal pouch-anal anastomosis should be performed in patients requiring colectomy for ulcerative colitis.

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Resumen Hemos valorado el efecto de una colectomía abdominal previa sobre los resultados funcionales después de anastomosis ileoanal de bolsa en J (AIAB) en pacientes con colitis ulcerativa. Veinticinco pacientes con colectomía previa a la AIAB fueron comparados con 22 pacientes sometidos a operaciones abdominales no colónicas antes de la AIAB. No se hallaron diferencias en cuanto a la presión en reposo del esfínter anal (preoperatoria o postoperatoria), a la presión de compresión, o al reflejo rectal inhibitorio. La colectomía previa apareció asociada con una mayor incidencia de obstrucción del intestino delgado. La frecuencia de defecación diaria a 1 y a 12 meses postoperatorios, respectivamente, fue 8.9±0.8 y 5.7±0.3 para los pacientes que habían sido sometidos a colectomía previa, y 8.2 ±0.7 y 6.0±0.5 para el grupo sin colectomía previa (p=NS). En los mismos períodos postoperatorios la frecuencia de defecación nocturna fue 1.9±0.3 y 1.1±0.2 para el grupo con colectomía previa y 1.5±0.3 y 0.6 ±0.1 para el grupo sin colectomía (p=0.05 a 1 año). Más pacientes en el grupo de colectomía previa presentó más de una o una deposición nocturna después de un año (71% versus 33%, p=0.03). Aunque la capacidad de la boisa a un ano no apareció diferente en los 2 grupos, la capacidad de la bolsa apareció directamente relacionada con la frecuencia de la deposición en el grupo sin colectomía (r²=0.48,p=0.01), pero no en el grupo con colectomía previa (r²=0.08,p=NS). Nuestra conclusión es que una colectomía abdominal previa puede estar asociada con una mayor incidencia de obstrucción del intestino delgado. Además, la colectomía previa aparece como un factor determinante de la frecuencia de defecación nocturna después de AIAB, muy probablemente por alteración de la función de la bolsa ileal. En cuanto sea posible, se debe realizar la colectomía, proctectomía mucosal, y anastomosis ileal endorrectal en una sola etapa en los pacientes que requieran colectomía por colitis ulcerativa.

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Résumé Nous avons chercher à savoir si le fait d'avoir déjà effectué une colectomie retentissait sur les résultats de fonctionnement de l'anastomose iléo-anale avec réservoir en J (AIAR) chez le patient avec rectocolite hémorragique. Vingt cinq patients ayant eu une colectomie avant d'être opérés de leur AIAR ont été comparés à 22 patients ayant une intervention abdominale sans colectomie avant d'être opérés de leur AIAR. Aucune différence dans la pression sphinctérienne au repos pré ou post-opératoire, dans la pression de contraction ou dans le réflexe inhibiteur rectal n'a été observée. La colectomie préalable était associée à une incidence élevée d'occlusion intestinale post-opératoire. Le nombre de selles à 1 et à 12 mois post-opératoires était de 8.9±0.8 et 5.7±0.3, respectivement, chez le patient sans chirurgie colique antérieure (NS). Aux mêmes intervalles, la fréquence de selles nocturnes était de 1.9 ±0.3 et de 1.1±0.2 pour le groupe à colectomie préalable et de 1.5±0.3 et 0.6±0.1 pour le groupe sans chirurgie colique préalable (p=0.05 à un an). Dans le groupe à colectomie préalable, il y avait plus de patients qui avaient une ou plusieurs selles nocturnes après la première année (71% versus 33%;p= 0.03). Bien que la capacité du réservoir ne différait pas à 1 an entre les 2 groupes, la capacité était directement en rapport avec la fréquence des selles dans le groupe sans chirurgie colique préalable (r²=0.48; p=0.01), mais sans rapport dans le groupe avec chirurgie colique préalable (r²=0.08, p=NS). Nous concluons que la colectomie préalable est asscoiée à une incidence d'occlusion post-opératoire supérieure. De plus, la colectomie préalable est associée à une fréquence plus élevée de selles nocturnes après AIAR, probablement liée à un dysfonctionnement du réservoir. Lorsque la colectomie totale avec mucosectomie rectale, avec anastomose iléo-anale et réservoir est indiquée chez le patient ayant une rectocolite hémorragique, il vaut mieux la faire en un seul temps.

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Presented at the Société Internationale de Chirurgie, Toronto, Ontario, Canada, September, 1989.