An analysis of breast cancer risk in women with single, multiple, and atypical papilloma

Breast papillomas may be single or multiple and associated with atypical ductal or lobular hyperplasias (ADH/ALH). The risk of breast carcinoma development in patients with papillomas, particularly those with multiple or atypical lesions, is incompletely defined. Fibrocystic lesions were histopathologically classified in a benign breast disease cohort of 9155 who underwent biopsy from 1967 to 1991, with papilloma assessment in 9108. Individuals with papillomas (N=480) were classified into 4 groups: single papilloma (SP, N=372), single papilloma with ADH or ALH (SP+A, N=54), multiple (>5) papillomas (MP, N=41), and multiple papillomas with ADH or ALH (MP+A, N=13). Those without papillomas were classified as nonproliferative (NP, N=6053), proliferative without atypia (PDWA, N=2308), and ADH/ALH [atypical hyperplasia (AH), N=267]. The relative risk of cancer development within our cohort was compared to that expected in the general population using standardized incidence ratios. The relative risk of breast cancer development associated with SP [2.04, 95% confidence interval (CI) 1.43-2.81] was greater than NP (1.28, 95% CI 1.16-1.42) but similar to PDWA (1.90, 95% CI 1.66-2.16). The risk associated with SP+A (5.11, 95% CI 2.64-8.92) was highly elevated but not substantively different than atypical hyperplasia (4.17, 95% CI 3.10-5.50). Patients with MP are at increased risk compared with PDWA or SP (3.01, 95% CI 1.10-6.55), particularly those with MP+A (7.01, 95% CI 1.91-17.97). There was a marginal increase in breast cancer risk (16%) among patients with proliferative disease if a papilloma was present, but this did not reach statistical significance (P=0.29). The observed frequency of ipsilateral (vs. contralateral) breast cancer development in papilloma subsets was not significantly different than other patient groups. We conclude that SP imparts a cancer risk similar to conventional proliferative fibrocystic change. The presence of papilloma in, or associated with, atypia does not modify the risk connotation of ADH/ALH overall. MP constitutes a proliferative breast disease subset having unique clinical and biologic behavior.     

Fixation, polyethylene wear, and pelvic osteolysis in primary total hip replacement

A multicenter retrospective review was performed analyzing 1081 primary total hip replacements in 944 patients using the Harris Galante-I cementless acetabular component with screw fixation. All patients were followed up for a minimum of 5 years with a mean followup of 81 months. Linear polyethylene wear averaged 0.11 mm/year (range, 0-0.86 mm/year). Pelvic osteolysis was seen in 25 patients (2.3%). Migration of the acetabular component was seen in four hips. A subgroup of patients was reanalyzed at a minimum followup of 10 years. The mean linear polyethylene wear rate remained 0.11 mm/year. In this group, only one socket had migrated. There was an association between wear rate and age. On average, younger patients had higher wear rates. The risk for having pelvic osteolysis develop and the need for revision surgery also was age-related. Twenty-two percent of hip replacements (15 hips) in patients younger than 50 years of age at the time of their index operation had pelvic osteolysis develop. In contrast, for patients older than 50 years of age at the time of surgery only 7.8% (eight hips) had osteolysis of the pelvis develop. For patients older than 70 years of age at the time of primary total hip replacement, none had pelvic osteolysis develop.     

Abnormal renal vasodilation to an amino acid infusion in congestive heart failure: normalization by enalapril

In congestive heart failure (CHF), the neurohormonal mechanisms that cause renal vasoconstriction, particularly those depending on the renin-angiotensin system, could interfere with renal vasodilating mechanisms. To elucidate this issue, we studied the kidney response to an amino acid infusion (known to cause renal vasodilation in healthy individuals) in eight patients with CHF. We found that the amino acid infusion (0.7 mL/kg/h of a 10% solution) elicited no renal hemodynamic response, in marked contrast to healthy subjects. We next hypothesized that the renin-angiotensin system (known to be activated in heart failure) has a role in the lack of response to the amino acid infusion. To test this hypothesis, we repeated the study after two 5-mg doses of enalapril, an inhibitor of the angiotensin-converting enzyme, administered 12 hours apart. After enalapril treatment, the amino acid infusion caused a 45% increase in mean renal blood flow (RBF) from 383 +/- 55 to 557 +/- 51 mL/min at the fifth hour (P < 0.05). This normalization of the renal response to the amino acid infusion occurred without changes in cardiac output or in systemic vascular resistance. Hence, the renal fraction of the cardiac output increased during the amino acid infusion. The recovery of the renal vascular response was not accompanied by an increase in glomerular filtration rate (GFR; filtration fraction decreased), suggesting a predominant efferent arteriole dilatation. Our study shows that, in heart failure, the kidney loses its ability to increase RBF in response to an amino acid load. This lack of renal vascular response can be restored by inhibiting the renin-angiotensin system and is unrelated to changes in systemic hemodynamics.     

The vasa vasorum and angioplasty

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.     

Speech-controlled generation of radiology reports

Voice entry has been successfully employed to generate radiology reports with a word recognizer with a 1,000-word lexicon capacity. About 50% of reports were able to be dictated with a single 900-word lexicon. This was split into five sections by anatomic or subspecialty application. Each was augmented to 900 words. By switching from one lexicon to another, it was possible to dictate more than 70% of reports. With exclusive use of three lexicons in subspecialty areas (gastrointestinal radiology, neuroradiology, and mammography), and with further modification of the respective vocabulary, it has been possible to employ the system 88% of the time. Twelve percent of cases included wording that was beyond the scope of the lexicon. Computer subsets that allow different translations of some words when used in different contexts have been used. Some of these are used as triggers that will print whole lines, sentences, or even complete reports. Dictation times with voice entry take about 20% longer. Recognition reliability has been greater than 95%.     

Do epigenetic pathways initiate late onset Alzheimer disease (LOAD): towards a new paradigm

Late onset Alzheimer's disease (LOAD) is a non-familial, progressive neurodegenerative disease and the most prominent form of dementia in the elderly. Accumulating evidence suggests that LOAD not only results from the combined effects of variation in a number of genes and environmental factors, but also from epigenetic abnormalities such as histone modifications or DNA methylation. In comparison to monogenic diseases, LOAD exhibits numerous anomalies that suggest an epigenetic component in disease etiology. Evidence against a monogenic course and for an epigenetic component include: 1) the dominance of sporadic cases over familial ones and the low estimated concordance rates for monozygotic twins; 2) gender specific susceptibility and course of disease; 3) parent-of-origin effects, and late age of onset; 4) brain chromatin abnormalities, non-Mendelian inheritance patterns, and atypical levels of folate and homocysteine; and 5) monoallelic expression patterns of susceptibility genes [1]. The epigenome is particularly susceptible to deregulation during early embryonic and neonatal periods and thus disturbances during these periods can have latent lasting effects. The Latent Early-life Associated Regulation (LEARn) model attempts to explain these consequences from a brain specific point of view. In the present review we present the evidence that support the role of epigenetics in the development of AD and explore the potential pathways and mechanisms that may be involved.     

Applying epigenetics to Alzheimer's disease via the latent early-life associated regulation (LEARn) model

Alzheimer's disease (AD) is a leading cause of aging related dementia and has been extensively studied by several groups around the world. A general consensus, based on neuropathology, genetics and cellular and animal models, is that the 4 kDa amyloid β protein (Aβ) triggers a toxic cascade that induces microtubule-associated protein τ (MAPT) hyperphosphorylation and deposition. Together, these lesions lead to neuronal dysfunction and neurodegeneration, modeled in animals, that ultimately causes dementia. Genetic studies show that a simple duplication of the Aβ precursor (APP) gene, as occurs in Down syndrome (trisomy 21), with a 1.5-fold increase in expression, can cause dementia with the complete AD associated neuropathology. The most fully characterized form of AD is early onset familial AD (FAD). Unfortunately, by far the most common form of AD is late onset AD (LOAD). FAD has well-identified autosomally dominant genetic causes, absent in LOAD. It is reasonable to hypothesize that environmental influences play a much stronger role in etiology of LOAD than of FAD. Since AD pathology in LOAD closely resembles FAD with accumulation of both Aβ and MAPT, it is likely that the environmental factors foster accumulation of these proteins in a manner similar to FAD mutations. Therefore, it is important to identify environmentally driven changes that "phenocopy" FAD in order to find ways to prevent LOAD. Epigenetic changes in expression are complex but stable determinants of many complex traits. Some aspects are regulated by prenatal and early post-natal development, others punctuate specific periods of maturation, and still others occur throughout life, mediating predictable changes that take place during various developmental stages. Environmental agents such as mercury, lead, and pesticides can disrupt the natural epigenetic program and lead to developmental deficits, mental retardation, feminization, and other complex syndromes. In this review we discuss latent early- life associated regulation (LEARn), where apparently temporary changes, induced by environmental agents, become latent and present themselves again at maturity or senescence to increase production of Aβ that may cause AD. The model provides us with a novel direction for identifying potentially harmful agents that may induce neurodegeneration and dementia later in life and provides hope that we may be able to prevent age-related neurodegenerative disease by "detoxifying" our environment.