Simultaneous endocardial and epicardial monophasic action potential recordings during brief periods of coronary artery ligation in the dog: influence of adrenaline, beta blockade and alpha blockade

Local differences in the time course of recovery of excitability during the early phase of myocardial ischaemia are important in the genesis of arrhythmias. Catecholamines are known to encourage the formation of arrhythmias and adrenergic blockade is a recognised therapeutic regime. The purpose of this study was to compare the effect of short periods of coronary artery ligation on endocardial and epicardial repolarisation time, to assess any disparity between the two surfaces, and investigate the influence of catecholamines and adrenergic blockade. Simultaneous left ventricular endocardial and epicardial monophasic action potentials (MAPs) were recorded during short periods of left anterior descending coronary artery (LAD) ligation in 9 open chested dogs. Recordings were made during two 90 s periods of LAD ligation. Two further ligations were made during infusion of adrenaline (1 microgram.kg-1.min-1). Subsequently ligations were made after beta blockade with propranolol (0.25 mg.kg-1) and then in the presence of a combination of alpha blockade (phentolamine, 0.15 mg.kg-1) and beta blockade. MAP duration was measured at 90% repolarisation. LAD ligation produced a marked shortening of MAP duration epicardially with only minimal shortening endocardially, which resulted in a highly significant difference between the repolarisation times on the two surfaces. The disparity between surfaces tended to be augmented by adrenaline and was significantly minimised by either beta blockade alone or in combination with alpha blockade. Our results show rapid development of substantial regional differences in repolarisation time between endocardium and epicardium in response to "ischaemia".(ABSTRACT TRUNCATED AT 250 WORDS)     

Photodynamic therapy and endoscopic metal stent placement for esophageal papillomatosis associated with squamous cell carcinoma

Esophageal squamous papillomatosis is a rare condition associated with human papilloma virus infection and has been complicated by the development of squamous cell carcinoma. Photodynamic therapy using porfimer sodium has been used for the treatment of esophageal cancer but has not been utilized in the treatment of esophageal squamous papillomatosis. We report here the first case of papillomatosis and obstructing squamous cell carcinoma of the esophagus palliated with porfimer sodium photodynamic therapy indicating successful photosensitizer uptake in papilloma-laden tissue. Extensive debulking of papilloma and tumor allowed esophageal recanalization and placement of a self-expanding metal stent for long-term dysphagia palliation. This unique case highlights the combined use of endoscopic techniques for optimal treatment results.     

Effect of health beliefs on delays in care for abnormal cervical cytology in a multi-ethnic population

CONTEXT: Women from racial and ethnic minorities in the United States have higher rates of cervical cancer and present with later stage disease compared to whites. Delays in care for abnormal Papanicolaou (Pap) smears can lead to missed cases of cervical cancer or late-stage presentation and may be one explanation for these differences. OBJECTIVE: To determine if race and ethnicity, health beliefs, and cancer knowledge are associated with delays in care for abnormal Pap smears. DESIGN, PARTICIPANTS, AND SETTING: We conducted a mailed survey with telephone follow-up of all women with an abnormal Pap smear who received care at Kaiser Permanente Los Angeles Medical Center between October 1998 and October 1999 (n = 1,049). MEASUREMENTS AND MAIN RESULTS: A delay in care was defined as not attending the first scheduled clinic visit to follow up on an abnormal Pap smear, or requiring multiple contact attempts, including a certified letter, to schedule a follow-up visit. Our response rate was 70% (n = 733) and the sample was 51% Latina. Spanish-speaking Latinas and women of Asian descent were more likely to endorse fatalistic beliefs and misconceptions about cancer. Thirteen percent of the sample delayed follow-up on their abnormal Pap smear. Women who delayed care were more fatalistic and endorsed more misconceptions about cervical cancer. Delays in care were not independently associated with race and ethnicity. CONCLUSIONS: Health beliefs and cancer knowledge differed by race and ethnicity among women in a large managed care organization. Fatalistic health beliefs and misconceptions about cancer, but not race and ethnicity, were independently associated with delays in care.     

Functional and chronic anorectal and pelvic pain disorders

Several organic and functional disorders of the urinary bladder, reproductive tract, anorectum, and the pelvic floor musculature cause pelvic pain. This article describes functional disorders in which chronic pelvic and anorectal pain cannot be explained by a structural or other specified pathology. Currently, these functional disorders are classified into urogynecologic conditions or cystitis and painful bladder syndrome, anorectal disorders, and the levator ani syndrome. Although nomenclature suggests that these conditions are distinct, there is considerable overlap of their symptoms and these disorders have much in common.     

Monophasic action potentials at discontinuation of cardiopulmonary bypass: evidence for contraction-excitation feedback in man

Mechanical dysfunction is the strongest predictor of sudden cardiac death due to arrhythmia. Contraction-excitation feedback whereby changes in myocardial length/tension influence the time course of repolarization and excitability would provide a possible mechanism. Such a relationship has been shown in animals but has yet to be demonstrated in man. A useful model for studying this relationship is provided by the process of weaning off cardiopulmonary bypass after routine coronary artery surgery. During this weaning period of approximately 1 min, the heart is converted from being partially empty and flaccid (i.e., a "nonworking" state) to being filled and stretched to support the circulation (i.e., a "working" state). Monophasic action potentials (MAPs) were recorded from the left ventricular epicardium as a measure of repolarization time in 16 patients at discontinuation of cardiopulmonary bypass. Systolic pressure was recorded from the radial artery line. Measurements were made at three stages that related to different dynamic states of the heart: (1) starting to come off bypass ("minimally working"), defined as the time of first appearance of an inflection on the arterial pressure trace indicating the start of left ventricular ejection and valve opening, when arterial pressures represent left ventricular pressure, (2) half off bypass ("partially working"), and (3) off bypass ("wholly working"). During the process of discontinuing bypass MAP duration shortened, while systolic pressure increased. MAP duration at 90% and 60% repolarization (MAP D90, MAP D60) decreased from 288.0 +/- 29.5 msec (mean +/- SEM) and 235.0 +/- 27.9 msec in the minimally working heart to 274.5 +/- 30.2 msec and 224.2 +/- 27.3 msec in the partially working heart (p less than .001), with a subsequent decrease to 261.0 +/- 28.8 and 214.0 +/- 28.7 when the heart was wholly working (p less than .001). Systolic pressure increased from 54.1 +/- 9.3 mm Hg in the minimally working heart to 65.9 +/- 13.8 mm Hg in the partially working heart (p less than .001) and subsequently increased to 75.5 +/- 13.3 mm Hg when the heart was wholly working (p less than .001). Mean heart rates did not change significantly. A strong correlation was obtained between absolute MAP duration and systolic pressure. Regression analysis revealed: MAP D90 vs systolic pressure (p less than .001) and MAP D60 vs systolic pressure (p less than .01).(ABSTRACT TRUNCATED AT 400 WORDS)     

Computer-aided diagnosis of the airways: beyond nodule detection

Although to date, the major impetus for the development of computer-assisted diagnosis (CAD) has been the detection of pulmonary nodules, CAD should properly be viewed as a potential tool for assisting radiologic interpretation of the entire gamut of chest diseases, including not just enhanced detection of disease but also characterization and quantification, ideally leading to improved patient management. The use of CAD to improve visualization of the airways using advanced computer techniques, including sophisticated methods for obtaining 3-dimensional segmentation of the central airways and, in particular, the development of virtual bronchoscopy has been recently studied. In this paper, the authors review the development of a specific series of CAD applications enabling automated identification and characterization of chronically inflamed airways. The advantages to the use of computer methodologies to quantify peripheral airway disease include reproducible visualization methods to display the location, severity, and extent of airway dilatation, bronchial wall thickening, and the presence of mucoid impacted airways. Currently, a number of semiquantitative global scoring systems have been proposed to assess disease extent and severity in patients with bronchiectasis. Unfortunately, with the exception of patients with cystic fibrosis, these are rarely if ever employed, largely owing to the considerable inconvenience of measuring individual airway dimensions and computing a global score. It is apparent that for this specific purpose, CAD may be ideally suited. Automated staging allows for more complete assessment of the entire bronchial tree while providing improved standardization and eliminating an otherwise tedious and time-consuming task.     

On the source of Ca(2+) activating the tonic component of contraction of myocytes of guinea pig heart

OBJECTIVE: Contractions of isolated, single myocytes of guinea pig heart stimulated at 37 degrees C consist of a phasic component and a voltage dependent tonic component. In this study we investigated the source of Ca(2+) activating the tonic component. METHODS: Experiments were performed at 37 degrees C in ventricular myocytes of guinea pig heart. Voltage-clamped cells were stimulated by the pulses from the holding potential of -40 to +5 mV. [Ca(2+)](i) was monitored as fluorescence of Indo 1-AM and contractions were recorded with the TV edge-tracking system. RESULTS: Superfusion of 5 mmol/l Ni(2+) during 30 s pause did not inhibit subsequent biphasic Ca(2+) transients and contractions despite inhibition of Ca(2+) current and Na(+)/Ca(2+) exchange. KB-R7943 (5 micromol/l) or intracellular dialysis with 0 Na(+) solution, both of which inhibit reversed Na(+)/Ca(2+) exchange, decreased amplitude of Ca(2+) transients and contractions by approximately 40%. The ratio of amplitudes of tonic to phasic component was increased by Ni(2+) and was not changed by KB-R7943 or 0 Na(+)(i). Ryanodine (200 micromol/l) inhibited both components of contractions in cells superfused with Ni(2+). The phasic component but not the tonic component was inhibited by 20 micromol/l nifedipine in cells superfused with Ni(2+). CONCLUSIONS: Tonic component of contraction of single myocytes of guinea pig heart is not activated by Ca(2+) current or by the reverse mode Na(+)/Ca(2+) exchange as currently proposed in literature. Rather, it is activated by Ca(2+) released from the sarcoplasmic reticulum. However, kinetics and mechanism of release seem to be quite different from those of Ca(2+) fraction activating the phasic component of contraction.     

High molecular weight complex analysis of Epstein–Barr virus Latent Membrane Protein 1 (LMP-1): Structural insights into LMP-1's homo-oligomerization and lipid raft association

LMP-1 is a constitutively active Tumor Necrosis Factor Receptor analog encoded by Epstein–Barr virus. LMP-1 activation correlates with oligomerization and raft localization, but direct evidence of LMP-1 oligomers is limited. We report that LMP-1 forms multiple high molecular weight native LMP-1 complexes when analyzed by BN-PAGE, the largest of which are enriched in detergent resistant membranes. The largest of these high molecular weight complexes are not formed by purified LMP-1 or by loss of function LMP-1 mutants. Consistent with these results we find a dimeric form of LMP-1 that can be stabilized by disulfide crosslinking. We identify cysteine 238 in the C-terminus of LMP-1 as the crosslinked cysteine. Disulfide crosslinking occurs post-lysis but the dimer can be crosslinked in intact cells with membrane permeable crosslinkers. LMP-1/C238A retains wild type LMP-1 NF-κB activity. LMP-1's TRAF binding, raft association and oligomerization are associated with the dimeric form of LMP-1. Our results suggest the possibility that the observed dimeric species results from inter-oligomeric crosslinking of LMP-1 molecules in adjacent core LMP-1 oligomers.     

Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production

The increased life expectancy of people living with HIV-1/AIDS is accompanied by increased prevalence of HIV–1-associated neurocognitive disorder. As well, these individuals are increasingly experiencing Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased deposition of amyloid beta (Aβ) protein. Findings that Aβ production occurs largely in endolysosomes, that HIV-1 transactivator protein (Tat) disrupts endolysosome function—an early pathological feature of AD—and that HIV-1 Tat can increase Aβ levels prompted us to test the hypothesis that endolysosome dysfunction is associated with HIV-1 Tat-induced increases in neuronal Aβ generation. Using primary cultured rat hippocampal neurons, we found that treatment with HIV-1 Tat caused such morphological changes as enlargement of endolysosomes identified with LysoTracker dye and such functional changes as elevated endolysosome pH measured ratiometrically with LysoSensor dye. The HIV-1 Tat-induced changes in endolysosome function preceded temporally HIV-1 Tat-induced increases in Aβ generation measured using enzyme-linked immunosorbent assay. In addition, we demonstrated that HIV-1 Tat increased endolysosome accumulation of Aβ precursor protein and Aβ identified using immunostaining with 4G8 antibodies. Furthermore, we demonstrated that treatment of neurons with HIV-1 Tat increased endolysosome accumulation of beta amyloid-converting enzyme, the rate-limiting enzymatic step for Aβ production, and enhanced beta amyloid-converting enzyme activity. Together, our findings suggest that HIV-1 Tat increases neuronal Aβ generation and thereby contributes to the development of AD-like pathology in HIV–1-infected individuals by disturbing endolysosome structure and function.