Survival after aortic valve replacement for severe aortic stenosis with low transvalvular gradients and severe left ventricular dysfunction

OBJECTIVE: We sought to assess whether aortic valve replacement (AVR) among patients with severe aortic stenosis (AS), severe left ventricular (LV) dysfunction and a low transvalvular gradient (TVG) is associated with improved survival. BACKGROUND: The optimal management of patients with severe AS with severe LV dysfunction and a low TVG remains controversial. METHODS: Between 1990 and 1998, we evaluated 68 patients who underwent AVR at our institution (AVR group) and 89 patients who did not undergo AVR (control group), with an aortic valve area < or = 0.75 cm(2), LV ejection fraction < or = 35% and mean gradient < or = 30 mm Hg. Using propensity analysis, survival was compared between a cohort of 39 patients in the AVR group and 56 patients in the control group. RESULTS: Despite well-matched baseline characteristics among propensity-matched patients, the one- and four-year survival rates were markedly improved in patients in the AVR group (82% and 78%), as compared with patients in the control group (41% and 15%; p < 0.0001). By multivariable analysis, the main predictor of improved survival was AVR (adjusted risk ratio 0.19, 95% confidence interval 0.09 to 0.39; p < 0.0001). The only other predictors of mortality were age and the serum creatinine level. CONCLUSIONS: Among select patients with severe AS, severe LV dysfunction and a low TVG, AVR was associated with significantly improved survival.     

The ontogeny of iodothyronine deiodinase systems in liver and intestine of the rat

The ontogeny of the iodothyronine deiodinase systems has been studied by several investigators in recent years, but our understanding of the subject is far from complete. The present study was conducted to obtain kinetic information concerning 5' deiodinase (5'D) and 5 deiodinase (5D) activities in fetal rat liver and intestine, and to examine reduced glutathione (GSH)-activated 5'D activity in the two tissues. When dithiothreitol (DTT) was used as cofactor in concentrations up to 100 mM, 5'D activity was not clearly detected in liver or intestine until day 16 of gestation. Activity increased markedly in both tissues between fetal day 18-21, due primarily to an increase in maximum velocity (Vmax) of the enzyme. However, whereas 5'D activity was much higher in adult liver than in fetal liver [due to both an increase in Vmax and a decrease in the Michaelis-Menten constant (Km)], activity was barely detectable in adult intestine. When GSH was used as cofactor, the temporal development of activity in both tissues was comparable to that observed with DTT, but kinetic values were very different; with DTT mean values for Vmax in liver ranged from 3.7-1264 pmol I-/h.mg protein, and values for Km ranged from 0.1-0.5 microM; with GSH, values for Vmax ranged from 0.4-16.7 pmol I-/h.mg protein, and values for Km were less than 1 nM. A comparable difference was observed also in intestine. When either DTT or GSH was used as cofactor, 5'D activity was inhibited in the presence of 6n-propyl-2-thiouracil or iopanoic acid. Using T3 as substrate it was found that 5D activity was much higher in intestine than in liver, and the amount of 5D activity in intestine paralleled that in brain in that it was much higher in fetal than in adult tissue. Moreover, values for Vmax and Km in fetal intestine were comparable to those in fetal brain. These findings suggest that thyroid hormone is important in the developing rat intestine and raise the possibility that GSH could be the activator of 5'D systems in vivo.     

Dobutamine stress cardiac magnetic resonance imaging to detect myocardial ischemia in women

This study sought to evaluate dobutamine stress cardiac magnetic resonance imaging (DCMRI) in women with abnormal stress nuclear testing results. Women with findings on stress nuclear exams, including electrocardiography and/or perfusion, thought to require further evaluation with invasive coronary angiography were prospectively enrolled. Multiplane cine imaging was obtained at rest and at each stage of inotropic stress with atropine as needed to achieve target heart rate. DCMRI results were compared with stress nuclear and invasive cardiac catheterization results. Of 23 patients enrolled successfully, 22 completed DCMRI examination without complications. In all cases, DCMRI imaging demonstrated appropriate stress response with no ischemia despite abnormalities on stress nuclear testing. In the 18 patients who also underwent invasive coronary angiography, no significant obstructive disease was identified. DCMRI may be a useful alternative to stress nuclear examination in women; larger studies are warranted to determine its potential to more accurately predict obstructive coronary artery disease.     

Screening flexible sigmoidoscopy

Objective: To measure patients’ expectations and attitudes about screening flexible sigmoidoscopy and their discomfort during the procedure, and to identify factors affecting compliance among patients scheduled for sigmoidoscopy. Design: Patient survey at the time sigmoidoscopy was ordered and again one week after the procedure was performed. Setting: An academic general internal medicine practice. Patients: 105 consecutive patients scheduled for screening flexible sigmoidoscopy. Main results: Seventy-five percent of patients (79/105) scheduled for sigmoidoscopy complied with the procedure. Compliance was higher among men and among patients who had family histories of colon cancer. Although many patients experienced moderate to extreme embarrassment (27%), discomfort (42%), and pain (31%), patients experienced less embarrassment (p=0.03) and pain (p=0.02) than they had expected. Patients aged 65 years and older were twice as likely as younger ones (52% versus 25%) to experience moderate to extreme pain (p=0.04). Only 1.4% of patients reported that they would probably not have the test again. Conclusion: Although flexible sigmoidoscopy is an uncomfortable procedure for some patients, especially those aged 65 and older, in general it is not as bad as patients expect and most would have the test again. Therefore, rather than assuming sigmoidoscopy is too uncomfortable for all patients to tolerate as a screening test, clinicians should inform their patients about the potential benefits and risks of sigmoidoscopy and about what the patient can expect during the procedure, thus enabling the patient to make an informed decision about whether to undergo screening sigmoidoscopy. Received from the Section of General Internal Medicine, Evans Department of Clinical Research and the Department of Medicine, University Hospital, Boston University Medical Center, Boston, Massachusetts. Dr. McCarthy is currently at the Division of General Internal Medicine, Center for Clinical Effectiveness, Department of Medicine, Henry Ford Hospital, Detroit, Michigan. Presented at the annual meeting of the Society of General Internal Medicine, April 26–28, 1989, Arlington, Virginia.     

How do patients perceive the British orthodontic society online information resource about orthognathic treatment? A qualitative study

Objectives: To explore the accessibility, usability and relevance of the British Orthodontic Society (BOS) online information resource (OIR), Your Jaw Surgery.

Design: Qualitative, cross-sectional study.

Setting: 5 UK sites.

Participants: Patients before, during and after treatment for non-cleft skeletal discrepancy.

Methods: Patients were identified at joint clinics and recruited after having time to view the OIR. Semi-structured interviews were conducted with 17 patients (aged 16–46 years). The interviews were transcribed and thematic analysis was undertaken using a framework approach.

Results: The main themes identified were the overall usefulness, personal relevance and positive perceptions of the OIR. The OIR was seen to be useful for patients considering treatment, and potentially useful for patients undergoing treatment. Participants were looking for a personally relevant resource that would give them the best possible idea of how they would look and feel after surgery. The OIR was perceived as trusted, positive and reassuring.

Conclusions: Patients at different stages of treatment found the OIR helpful and reassuring. Clinicians may find it useful to direct patients to the OIR to complement a professional consultation, but should be aware that patients may perceive it as presenting a positive image of the long-term benefits of orthognathic surgery.     

AGE‐modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival

Biomechanical strain imposed by age‐related thickening of the basal lamina and augmented tissue stiffness in the prostate gland coincides with increased cancer risk. Here we hypothesized that the structural alterations in the basal lamina associated with age can induce mechanotransduction pathways in prostate epithelial cells (PECs) to promote invasiveness and cancer progression. To demonstrate this, we developed a 3D model of PEC acini in which thickening and stiffening of basal lamina matrix was induced by advanced glycation end‐product (AGE)‐dependent non‐enzymatic crosslinking of its major components, collagen IV and laminin. We used this model to demonstrate that antibody targeted blockade of CTLD2, the second of eight C‐type lectin‐like domains in Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) that can recognize glycosylated collagens, reversed actinomyosin‐based contractility [myosin‐light chain‐2 (MLC2) phosphorylation], loss of cell polarity, loss of cell–cell junctions, luminal infiltration and basal invasion induced by AGE‐modified basal lamina matrix in PEC acini. Our in vitro results were concordant with luminal occlusion of acini in the prostate glands of adult Endo180^{ΔEx2–6/ΔEx2–6} mice, with constitutively exposed CTLD2 and decreased survival of men with early (non‐invasive) prostate cancer with high epithelial Endo180 expression and levels of AGE. These findings indicate that AGE‐dependent modification of the basal lamina induces invasive behaviour in non‐transformed PECs via a molecular mechanism linked to cancer progression. This study provides a rationale for targeting CTLD2 in Endo180 in prostate cancer and other pathologies in which increased basal lamina thickness and tissue stiffness are driving factors. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Bioluminescent Imaging Reveals Novel Patterns of Colonization and Invasion in Systemic Escherichia coli K1 Experimental Infection in the Neonatal Rat

Key features of Escherichia coli K1-mediated neonatal sepsis and meningitis, such as a strong age dependency and development along the gut-mesentery-blood-brain course of infection, can be replicated in the newborn rat. We examined temporal and spatial aspects of E. coli K1 infection following initiation of gastrointestinal colonization in 2-day-old (P2) rats after oral administration of E. coli K1 strain A192PP and a virulent bioluminescent derivative, E. coli A192PP-lux2. A combination of bacterial enumeration in the major organs, two-dimensional bioluminescence imaging, and three-dimensional diffuse light imaging tomography with integrated micro-computed tomography indicated multiple sites of colonization within the alimentary canal; these included the tongue, esophagus, and stomach in addition to the small intestine and colon. After invasion of the blood compartment, the bacteria entered the central nervous system, with restricted colonization of the brain, and also invaded the major organs, in line with increases in the severity of symptoms of infection. Both keratinized and nonkeratinized surfaces of esophagi were colonized to a considerably greater extent in susceptible P2 neonates than in corresponding tissues from infection-resistant 9-day-old rat pups; the bacteria appeared to damage and penetrate the nonkeratinized esophageal epithelium of infection-susceptible P2 animals, suggesting the esophagus represents a portal of entry for E. coli K1 into the systemic circulation. Thus, multimodality imaging of experimental systemic infections in real time indicates complex dynamic patterns of colonization and dissemination that provide new insights into the E. coli K1 infection of the neonatal rat.     

The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis

Background

The chemokine interleukin-8 (CXCL8) is a key mediator of inflammation in airways of patients with cystic fibrosis (CF). Glycosaminoglycans (GAGs) possess the ability to influence the chemokine profile of the CF lung by binding CXCL8 and protecting it from proteolytic degradation. CXCL8 is maintained in an active state by this glycan interaction thus increasing infiltration of immune cells such as neutrophils into the lungs. As the CXCL8-based decoy PA401 displays no chemotactic activity, yet demonstrates glycan binding affinity, the aim of this study was to investigate the anti-inflammatory effect of PA401 on CXCL8 levels, and activity, in CF airway samples in vitro.

Methods

Bronchoalveolar lavage fluid (BALF) was collected from patients with CF homozygous for the ΔF508 mutation (n = 13). CXCL8 in CF BALF pre and post exposure to PA401 was quantified by ELISA. Western blot analysis was used to determine PA401 degradation in CF BALF. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post exposure to PA401 by use of a Boyden chamber-based motility assay.

Results

Exposure of CF BALF to increasing concentrations of PA401 (50–1000 pg/ml) over a time course of 2–12 h in vitro, significantly reduced the level of detectable CXCL8 (P < 0.05). Interestingly, PA401 engendered release of CXCL8 from GAGs exposing the chemokine susceptible to proteolysis. Subsequently, a loss of PA401 was observed (P < 0.05) due to proteolytic degradation by elastase like proteases. A 25% decrease in neutrophil chemotactic efficiency towards CF BALF samples incubated with PA401 was also observed (P < 0.05).

Conclusion

PA401 can disrupt CXCL8:GAG complexes, rendering the chemokine susceptible to proteolytic degradation. Clinical application of a CXCL8 decoy, such as PA401, may serve to decrease the inflammatory burden in the CF lung in vivo.