Clinical dementia rating performed several years prior to death predicts regional Alzheimer's neuropathology.

AIMS: To assess the relationships between early and late antemortem measures of dementia severity and Alzheimer disease (AD) neuropathology severity. METHODS: 40 residents of a nursing home, average age at death 82.0, participated in this longitudinal cohort study with postmortem assessment. Severity of dementia was measured by Clinical Dementia Rating (CDR) at two time points, averaging 4.5 and 1.0 years before death. Densities of postmortem neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were measured in the cerebral cortex, hippocampus, and entorhinal cortex. RESULTS: For most brain areas, both early and late CDRs were significantly associated with NPs and NFTs. CDRs assessed proximal to death predicted NFTs beyond the contribution of early CDRs. NPs were predicted by both early and late CDRs. NPs were predictive of both early and late CDRs after controlling for NFTs. NFTs were only associated significantly with late CDR in the cerebral cortex after controlling for NPs. CONCLUSIONS: Even if assessed several years before death, dementia severity is associated with AD neuropathology. NPs are more strongly associated with dementia severity than NFTs. NFTs consistently associate better with late than early CDR, suggesting that these neuropathological changes may occur relatively later in the course of the disease.

Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology.

BACKGROUND: In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer's disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus. METHODS: The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD. RESULTS: Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p =.008) and NFTs (p =.047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p =.019), but the lower ratings of NFTs did not achieve statistical significance (p =.082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses. CONCLUSIONS: These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.

Left atrial function is unchanged by implantable defibrillator shocks on hearts in sinus rhythm.

Sixteen patients in sinus rhythm at baseline undergoing implantable cardioverter-defibrillator implantation were monitored with transesophageal echocardiography both before and after direct current cardioversion with currents of 15 to 20 J, for any direct current induced atrial dysfunction. We found no change in the indexes of atrial function or appearance of spontaneous echo contrast in the immediate postshock period by intraoperative transesophageal echocardiography.

Sternal blood flow during mobilization of the internal thoracic arteries.

A laser Doppler tissue perfusion monitor was used to measure sternal blood flow before, during, and after mobilization of the internal thoracic arteries in 24 patients undergoing coronary artery bypass grafting. To minimize chest wall injury, a narrow pedicle was mobilized. Bilateral flow data were available from 15 of the 24 patients. Analysis of these 39 studies showed no significant reduction of sternal blood flow as a consequence of mobilization of the internal thoracic arteries except in 2 patients who were both diabetic and obese.

A study of the human aortic valve orifice by transesophageal echocardiography.

The transverse short-axis plane of the aortic valve was imaged by transesophageal echocardiography at a relatively high frame rate in 25 anesthetized patients undergoing heart surgery. The effective, time-averaged aortic valve area (a-AVA) was compared with areas obtained with triangular and circular valve orifice models (t-AVA and c-AVA, respectively). The aortic valve orifice was circular during 33.6% +/- 17.5% of systole. The relations between the triangular or circular aortic valve areas and a-AVA were as follows: t-AVA = 1.04 x a-AVA - 0.14 (r = 0.90; standard error of the estimate = 0.24 cm2) and c-AVA = 1.37 x a-AVA + 0.00 (r = 0.90; SEE = 0.30 cm2). Bias analysis showed no significant difference between a-AVA and t-AVA (bias = -0.04 +/- 0.23 cm2; difference not significant) but a significant overestimation of the average valve area by c-AVA (bias = +0.88 +/- 0.30 cm2; p < 0.001). Thus the aortic valve orifice was not circular for the entire duration of systole and valve area calculations based on a triangular model approximated a-AVA more closely than did those based on a circular model. These findings suggest that, for echocardiographic measurements that incorporate the aortic valve orifice area (e.g., stroke volume determinations), the use of a triangular valve area model, rather than a circular model, may produce more accurate results in anesthetized patients with heart disease.

Pre-clamp cardioprotection by protein kinase C (PKC) inhibitor improves left ventricular function following canine normothermic arrest.

Since protein kinase C (PKC) has been proven to be a mediator of neutrophil activation and of intracellular calcium homeostasis, its inhibition could protect the myocardium from the deleterious effects of ischemic/reperfusion inury (IRI). The principal objective of this study was to evaluate the efficacy of the PK inhibitor SPC-100270 (2S,3S)-2-amino, 3-octadecanediol in a canine model of IRI. A double-blind study was conducted in which 19 coonhound dogs received either SPC-100270 or a vehicle before going on cardiopulmonary bypass (CPB). After 60 minutes of global normothermic (37 degree C) cardiac arrest (cross-clamp time 65-81 minutes for SPC-100270 and 65-72 minutes for control) and discontinuation of CBP, an epicardial short axis view echocardiogram was performed and reviewed by a double-blinded observer to determine the ejection fraction (EF). EF value exceeded 20% in 5 out of 9 SPC-100270 animals (27%-44%) and in 0 of 10 controls (0%-16%). These data show that SPC-10027 significantly (p=0.01 by Fisher's Exact Test) increased the probability that the animals would exhibit an EF greater than 20%.

Possible intra-aortic balloon pump "function-related" mechanism of embolic events in patient with protruding atheroma in the thoracic aorta.

A possible new functional mechanism of atheromatous embolus is presented resulting from reversed aortic blood flow during diastolic augmentation by balloon counterpulsation. This mechanism is different from mechanical disruption during insertion. Despite this, intra-aortic balloon remains an important asset in the management of hemodynamically challenged patients.

Left ventricular performance indices by transesophageal Doppler.

The purpose of this study was to assess whether blood flow velocity signals, obtained by esophageal continuous-wave Doppler, reflect changes in ventricular performance. Ventricular performance has previously been determined by analysis of blood flow velocity signals sampled in the ascending aorta. In this investigation velocity signals were acquired from the descending aorta, with the use of an esophageal Doppler transducer. Maximum blood flow velocity (Vm), maximum blood flow volume acceleration (Accv), and maximum linear blood flow acceleration (Acc) were the velocity signals used to evaluate left ventricular performance. Twenty-six patients scheduled for myocardial revascularization and anesthetized with fentanyl (50 micrograms/kg) and pancuronium (0.15 mg/kg) were studied. In seven patients (Group I) a good correlation (r = 0.91) was observed between Accv in the ascending and descending aorta. In 10 patients (Group 2), halothane (0.5 and 1.0 MAC end-tidal) was added to the anesthetic. At these halothane concentrations Vm, Accv, and Acc measured in the descending aorta remained unchanged. Decreases were noted in the product of mean arterial pressure (MAP) and Acc (P-Acc; decreased 20% at 0.5 MAC and 39% at 1 MAC) and the product of systemic vascular resistance and Acc (R-Acc; decreased 25% at 1 MAC). In nine patients (Group 3), phenylephrine was used to reverse the decrease in MAP induced by 1 MAC halothane. Under these conditions Vm, Accv, Acc, and P-Acc showed similar decreases (approximately 30% of baseline values), whereas R-Acc returned to baseline values. In summary, indices of blood flow in the descending aorta were easily determined with a commercial transesophageal continuous-wave Doppler device. Descending and ascending aortic blood flow Accv correlated well, and the changes in the product of MAP and Acc in the descending aorta reflected the anticipated, halothane-induced, changes in left ventricular performance. In conclusion, descending aortic blood flow acceleration contains information on left ventricular performance that can be derived by the minimally invasive transesophageal Doppler technique.

Photochemical cross-linking studies on the interaction of Escherichia coli RNA polymerase with T7 DNA.

We have identified the subunits of Escherichia coli RNA polymerase which are in close contact with the T7 phage DNA template using photochemical cross-linking. In nonspecific T7 DNA-enzyme complexes which occur in all regions of the DNA, subunits sigma, beta, and beta' were cross-linked to the DNA. In contrast, in specific binary complexes which presumably occur at promoter sites, and in the initiation complex (holoenzyme + T7 DNA + initiator dinucleotides + three nucleoside triphosphates), only sigma and beta were cross-linked to DNA, while cross-linking of beta' could not be demonstrated. These results (1) do not support the idea that alpha subunits are involved in the enzyme-template interaction, (2) raise the possibility that sigma subunit participates directly in promoter recognition even though isolated sigma does not bind to DNA, and (3) indicate different modes of interaction between RNA polymerase and DNA in nonspecific and specific complexes. These findings are relevant to the mechanism by which RNA polymerase carries out selective transcription.

Statistical interpretation of fluorescence energy transfer measurements in macromolecular systems.

A statistical method is presented for the interpretation of intramolecular distance measurements by the fluorescence energy transfer technique in systems for which the detailed geometries of the donor-acceptor pairs are unknown. This method enables calculation of the probability that a specified distance range corresponds to the actual distance to be measured. It makes use of the numerically calculated probability density function for the distance of interest. The two general systems considered are the single donor-acceptor pair and the multi-donor-single-acceptor transfer. In both systems, the statistical method incorporates the uncertainty in the orientation of the donor and acceptor dipoles. In addition, it can take into account the rotational mobility of the donor dipoles determined by time-dependent emission anisotropy measurements. When more than one donor is involved in the transfer process, the uncertainties associated with the number and location of individual donors and the size and shape of the donor distribution are also incorporated in calculating the distance ranges. Application of the method was demonstrated for a wide range of transfer efficiency and Ro values for the single donor-acceptor system. Specific examples are also presented for interpretation of both single donor-acceptor and multi-donor-single-acceptor energy transfer measurements performed in order to reveal the spatial relationship of the sigma subunit and the rifampicin binding site in the Escherichia coli RNA polymerase (see Wu, C.-W., Yarbrough, L. R., Wu, F. Y.-H., and Hillel, Z. (1976), Biochemistry, preceding paper in this issue). Analysis of these energy transfer data by methods which use average values of the unknown geometrical parameters of the system yielded results similar to those obtained by the statistical method. However, the statistical method represents a more realistic approach to the interpretation of energy transfer measurements since it provides information concerning the entire range of possible distances and their relative likelihood.

Subunit topography of RNA polymerase from Escherichia coli. A cross-linking study with bifunctional reagents.

The quaternary structures of Escherichia coli DNA-dependent RNA polymerase holenzyme (alpha 2 beta beta' sigma) and core enzyme (alpha 2 beta beta') have been investigated by chemical cross-linking with a cleavable bifunctional reagent, methyl 4-mercaptobutyrimidate, and noncleavable reagents, dimethyl suberimidate and N,N'-(1,4-phenylene)bismaleimide. A model of the subunit organization deduced from cross-linked subunit neighbors identified by dodecyl sulfate-polyacrylamide gel electrophoresis indicates that the large beta and beta' subunits constitute the backbone of both core and holoenzyme, while sigma and two alpha subunits interact with this structure along the contact domain of beta and beta' subunits. In holoenzyme, sigma subunit is in the vicinity of at least one alpha subunit. The two alpha subunits are close to each other in holoenzyme, core enzyme, and the isolated alpha 2 beta complex. Cross-linking of the "premature" core and holoenzyme intermediates in the in vitro reconstitution of active enzyme from isolated subunits suggests that these species are composed of subunit complexes of molecular weight lower than that of native core and holoenzyme, respectively. The structural information obtained for RNA polymerase and its subcomplexes has important implications for the enzyme-promoter recognition as well as the mechanism of subunit assembly of the enzyme.

DNA strand specificity in promoter recognition by RNA polymerase.

DNA strand and enzyme subunit specificities involved in the interaction between E. coli RNA polymerase and T7 DNA were studied by photo-crosslinking techniques. In non-specific enzyme-DNA complexes, subunits, sigma, beta, and beta' were crosslinked to both strands of the DNA. Under conditions leading to specific enzyme-promoter complexes, however, only sigma and beta subunits were crosslinked. The sigma subunit was crosslinked preferentially to the non-sense strand at promoter sites. No such strand specificity was observed for the beta subunit. These results provide insight into the molecular mechanism of promoter recognition and indicate that the interaction between RNA polymerase and DNA template is different at promoters and at non-specific sites.

Molecular mechanism of promoter selection in gene transcription. I. Development of a rapid mixing-photocrosslinking technique to study the kinetics of Escherichia coli RNA polymerase binding to T7 DNA.

A combined rapid mixing-photocrosslinking technique has been developed to investigate the kinetics of the interaction between Escherichia coli RNA polymerase and T7 DNA. The reactants were rapidly mixed in a modified Durrum stopped-flow apparatus, and the intermediates formed at different stages of the binding process were "frozen" by photocrosslinking with a UV light pulse of 10-mus duration at various times after mixing. The results indicate that the initial binding between RNA polymerase and T7 DNA is a diffusion-controlled reaction. Furthermore, the extents of initial contracts with DNA made with the beta, beta', and sigma subunits of RNA polymerase are roughly proportional to the sizes of these subunits, suggesting that complex formation occurs through random collision between the two reactants. After the initial complex formation, the rate of transfer of polymerase between individual DNA molecules is slow, implying that the polymerase molecules are undergoing predominantly intramolecular transfer during the promoter search. From the kinetic studies of subunit-DNA contacts during RNA polymerase binding to T7 DNA, it can be inferred that the beta, beta', and sigma subunits are directly participating in the promoter search process.

A rapid mixing-photocrosslinking technique to study the dynamics of nucleic acid-protein interactions.

A rapid mixing-photocrosslinking technique has been developed to investigate the kinetics of protein-nucleic acid interactions. With this technique, binding of nucleic acid to protein is first synchronized by rapid mixing in a stopped-flow apparatus. The intermediates formed at different stages of the binding process are then "frozen" by photocrosslinking with a 10-microseconds uv light pulse at various times after mixing. By analyzing structural changes of these intermediates as a function of time, one can obtain the information concerning the dynamic aspects of the interaction. This technique may also be applied to other macromolecular interactions in biological systems.

A comparison of hemodynamic indices derived by invasive monitoring and two-dimensional echocardiography.

Intraoperative two-dimensional echocardiography (2D-echo) is useful for monitoring global and regional left ventricular function. The 2D-echo view most frequently utilized during intraoperative monitoring is the short-axis view at the level of the papillary muscles. To determine whether hemodynamic data can be derived from this single 2D-echo short-axis view, 12 patients undergoing coronary artery bypass grafting (CABG) were studied. All patients had normal left-ventricular function preoperatively (ejection fraction = 64% +/- 12%). Echo-data were obtained before and after cardiopulmonary bypass (CPB) by epicardial placement of a 5 MHz echo-transducer. The correlation between thermodilution and echo-derived cardiac indices was good (r = 0.8), and not significantly different from the correlation between stroke indices (r = 0.68). A strong positive correlation was established between end-diastolic volume index and echo cardiac index (CIE) (r = 0.93 before CPB; r = 0.91 after CPB) and end-diastolic area index and CIE (r = 0.94 before CPB; r = 0.91 after CPB). The pulmonary capillary wedge pressure was not a determinant of cardiac index before or after cardiopulmonary bypass. No correlation was observed between systemic vascular resistance and echo-derived wall stress. These findings demonstrate that, in patients with good left-ventricular function undergoing CABG surgery, 2D-echo provides a better index of left-ventricular preload than conventional invasive hemodynamic monitoring.

The association between Doppler transmitral flow variables measured by transesophageal echocardiography and pulmonary capillary wedge pressure.

The association between Doppler transmitral flow variables, measured by transesophageal echocardiography (TEE), and pulmonary capillary wedge pressure (PCWP) was studied in 88 patients undergoing coronary artery surgery. The Doppler flow variables and PCWP were measured after sternotomy by blinded investigators. In the first part of the study, patients were divided into two groups according to left ventricular (LV) ejection fraction (EF): Group A, EF > 35% (n = 38) and Group B, EF < or = 35% (n = 34). In Group B, significant correlations were found between deceleration time of early filling (DCT-E) and PCWP (r2 = 0.899) and deceleration slope of early filling and PCWP (r2 = 0.692), (P < 0.001 for both). When the relationship between DCT-E and PCWP was tested prospectively in a third group of patients [Group C; EF < or = 35% (n = 16)], a close agreement between the calculated and measured PCWP (bias = -0.55 +/- 3.87 mm Hg) was noted. The sensitivity, specificity, and positive predictive value of DCT-E > or = 150 ms for PCWP < 10 mm Hg were 93.3%, 100%, and 100%, respectively. In summary, patients with decreased left ventricular systolic function undergoing coronary artery surgery demonstrated high, statistically significant, correlations between PCWP and the deceleration time or deceleration slope of early diastolic filling as measured by transesophageal Doppler echocardiography.

Importance of atrial systole to ventricular filling predicted by transesophageal echocardiography.

This study documented mitral flow velocity patterns in anesthetized patients with ischemic heart disease and left ventricular dysfunction and investigated the relationship between transmitral flow velocity measurements and the hemodynamic response to ventricular pacing. Twenty-four patients in sinus rhythm without evidence of mitral valve disease undergoing elective myocardial revascularization were studied. Anesthesia consisted of a high-dose opioid-muscle relaxant-oxygen technique. After endotracheal intubation a 3.5-MHz phased-array transesophageal echocardiographic probe was inserted and positioned to obtain a long-axis view of the left atrium and left ventricle. The Doppler sample volume was placed at the mitral annulus with minimal cursor angulation, and the biphasic velocity tracing of transmitral blood flow was recorded. A hemodynamic profile was obtained, and cardiac output was measured in triplicate by thermodilution. Ventricular pacing was then instituted and the hemodynamic and thermodilution measurements were repeated. The peak early filling (E) velocity was 0.34 +/- 0.11 m/s, and the peak atrial (A) velocity was 0.38 +/- 0.09 m/s. The mean E:A ratio was 0.91 +/- 0.3, and the median value was 0.88. In sinus rhythm the cardiac index of those patients with an E:A greater than 0.88 (group 1) was 1.97 +/- 0.32 l/min and those with an E:A less than 0.88 (group 2) was 1.76 +/- 0.50 (NS). During ventricular pacing the patients in group 1 (1.56 +/- 0.32 l/min) had significantly higher cardiac indices than those in group 2 (1.21 +/- 0.31 l/min) (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

An algorithm for real-time, continuous evaluation of left ventricular mechanics by single-beat estimation of arterial and ventricular elastance.

We describe a computer algorithm that allows continuous, real-time evaluation of ventricular elastance (Ees), arterial elastance (Ea), and their coupling ratio in a clinical setting. In the conventional pressure-volume analysis of left ventricular (LV) contractility, invasive methods of volume determination and a significant, rapid preload reduction are required to generate Ees. With the help of automated border detection by transesophageal echocardiography, and a technique of estimating peak LV isovolumic pressure, Ea and Ees were determined from a single cardiac beat without the need for preload reduction. A comparison of results obtained by a conventional approach and the new algorithm technique, showed good correlation for Ea (r = 0.86, p < 0.001) and Ees (r = 0.74, p = 0.001). Bias analysis showed a bias (d) of 1.47 mmHg/cm2 for Ea with a standard deviation (SD) of 7.03 mmHg/cm2, and upper (d+2SD) and lower(d-2SD) limits of agreement of 15.24 mmHg/cm2 and -12.31 mmHg/cm2, respectively. Bias analysis showed a bias of -1.42 mmHg/cm2 for Ees with a SD of 4.88 mmHg/cm2, and limits of agreement of 8.15 mmHg/cm2 and -10.98 mmHg/cm2. The algorithm's stability to artifacts was also analyzed by comparing magnitudes of residuals of Ea and Ees from source signals with and without noise. With Ea differing by an average of 1.036 mmHg/cm2 and Ees differing by an average of 0.836 mmHg/cm2, the algorithm was found to be stable to artifacts in the source signals.

Cardiac output by transesophageal echocardiography using continuous-wave Doppler across the aortic valve.

BACKGROUND: The use of transesophageal echocardiography for the determination of cardiac output (CO) has been limited to date. We assessed the capability of aortic continuous-wave Doppler transesophageal echocardiography to determine CO (DCO) in a transgastric long-axis imaging plane of the heart by comparing DCO to thermodilution CO (TCO). METHODS: DCO was determined in 63 consecutive patients undergoing cardiac surgery. Aortic valve area was obtained from the transverse short-axis view of the valve assuming a triangular shape for the valve orifice. Stroke volume was calculated as the product of velocity-time integral and aortic valve area: stroke volume = velocity-time integral x aortic valve area. DCO was calculated off-line, by multiplying stroke volume with heart rate: DCO = stroke volume x heart rate. RESULTS: The aortic valve orifice was easily imaged in all patients. Excellent-quality continuous-wave Doppler flow profiles were obtained in nearly all (62 of 63). A total of 109 DCO determinations were performed. Mean DCO was 4.35 +/- 1.18 l.min-1 (range 2.02-7.42 l.min-1), and mean TCO was 4.41 +/- 1.17 l.min-1 (range 2.24-8.94 l.min-1). Very high correlation and agreement were found between the two methods: DCO = 0.94 x TCO + 0.19, r = 0.94, SEE (standard error of the estimate) = 0.41 l.min-1; 95% confidence interval = 0.06 +/- 0.83 l.min-1. Relative changes from pre- to postbypass CO (delta) also showed a strong correlation (delta DCO = 0.93 x delta TCO + 5.4%, r = 0.82, SEE = 17.8%). For CO changes greater than 10%, Doppler was in accordance with thermodilution in 43 of 45 measurements. DCO repeatability coefficient was 0.51 l.min-1. CONCLUSIONS: Compared to thermodilution, continuous-wave Doppler measurements of blood flow velocity across the aortic valve in the transesophageal echocardiographic transgastric view allow accurate CO determination.