Biomedical subjects
Publications and source records attributed to J F Brennan.
A maintenance hemodialysis patient developed metabolic alkalosis in the absence of vomiting or nasogastric suction. The cause of the metabolic alkalosis was ingestion of an exogenous alkali in the form of Bromoseltzer. The metabolic alkalosis improved with hemodialysis using a low-bicarbonate bath.
Coronary intravascular ultrasound (IVUS) can assess arterial wall architecture and localize large intravascular deposits, but it does not provide quantitative chemical information, which is essential in the evaluation of atherosclerotic lesions. Previously, it has been shown that Raman spectroscopy can be used to accurately quantify the relative weights of cholesterol, calcium salts, triglycerides, and phospholipids in homogenized arterial tissue. In the present study, we explore some benefits of combining IVUS and Raman spectroscopy to evaluate the intact arterial wall. IVUS images were collected in vitro from human coronary arterial segments in various stages of disease (n=7). The images were divided into radial segments (11 to 28 per image, 332 in total), each of which was classified visually as calcified or noncalcified tissue. The arteries were opened longitudinally, and Raman spectra were collected from locations at 0. 5-mm intervals across the arterial luminal circumference. The spectra were used to calculate the chemical composition of the arterial wall at the examined locations. Generally, locations containing large amounts of calcium salts, as determined with Raman spectroscopy, were classified as calcified with IVUS. However, small calcific deposits (<6% of weight) were not readily detected with IVUS. The amounts and location of cholesterol determined with Raman spectroscopy were correlated closely with the presence of cholesterol observed by histochemistry, but these deposits could not be located accurately by IVUS. The combination of Raman spectroscopy and IVUS applied in vitro provides detailed information about the amount and location of calcific deposits and lipid pools in atherosclerotic plaques. Future advances in optical fiber technology may allow simultaneous collection of Raman spectra and IVUS images through the same catheter in vivo.
On postnatal days (PND) 12 and 13, 90 male Swiss CD-1 mice were tested for orientation to 3 intensities of recorded ultrasounds while climbing an inclined wire grid surface. Motor responses and vocalization to replayed ultrasounds (55-75 kHz) of 20-, 40-, and 60-dB SPL indicated an intensity dependence. In Experiment 2, 138 pups were exposed to either contingent or noncontingent pairings of recorded ultrasounds of 55-75 kHz, averaging 40 dB, and mild inescapable footshocks, or taped vocalizations or footshocks only on PND 12, 14, or 16. At PND 18, subjects were tested for passive avoidance following exposure to the taped ultrasounds only upon entry into the dark side of a black-white compartment. Results suggested only overall, nonspecific effects of pretreatment to elicit responses antagonistic to motor activity. In Experiment 3, 36 pups at PND 15 were tested for passive avoidance with the ultrasound recordings of 40- or 80-dB onset upon entry to the dark compartment; a third group had no ultrasound exposure. A significant intensity effect confirmed that the ultrasounds had prepotent properties.
BACKGROUND: Lesion composition, rather than size or volume, determines whether an atherosclerotic plaque will progress, regress, or rupture, but current techniques cannot provide precise quantitative information about lesion composition. We have developed a technique to assess the pathological state of human coronary artery samples by quantifying their chemical composition with near-infrared Raman spectroscopy. METHODS AND RESULTS: Coronary artery samples (n=165) obtained from explanted recipient hearts were illuminated with 830-nm infrared light. Raman spectra were collected from the tissue and processed to quantify the relative weights of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts in the examined artery location. The artery locations were then classified by a pathologist and grouped as either nonatherosclerotic tissue, noncalcified plaque, or calcified plaque. Nonatherosclerotic tissue, which included normal artery and intimal fibroplasia, contained an average of approximately 4+/-3% cholesterol, whereas noncalcified plaques had approximately 26+/-10% and calcified plaques approximately 19+/-10% cholesterol in the noncalcified regions. The average relative weight of calcium salts was 1+/-2% in noncalcified plaques and 41+/-21% in calcified plaques. To make this quantitative chemical information clinically useful, we developed a diagnostic algorithm, based on a first set of 97 samples, that demonstrated a strong correlation of the relative weights of cholesterol and calcium salts with histological diagnoses of the same locations. This algorithm was then prospectively tested on a second set of 68 samples. The algorithm correctly classified 64 of these new samples, thus demonstrating the accuracy and robustness of the method. CONCLUSIONS: The pathological state of a given human coronary artery may be assessed by quantifying its chemical composition, which can be done rapidly with Raman spectroscopic techniques. When Raman spectra are obtained clinically via optical fibers, Raman spectroscopy may be useful in monitoring the progression and regression of atherosclerosis, predicting plaque rupture, and selecting proper therapeutic intervention.
The chemical composition of vascular lesions, an important determinant of plaque progression and rupture, can not presently be determined in vivo. Prior studies have shown that Raman spectroscopy can accurately quantify the amounts of major lipid classes and calcium salts in homogenized coronary artery tissue. This study determines how the relative cholesterol content, which is calculated from Raman spectra collected at the luminal surface of an artery, is related to its depth in an intact arterial wall. Raman spectra of human atherosclerotic plaques were measured after thin tissue layers were successively placed on them. From these spectra, relative cholesterol contents were calculated and used to determine how cholesterol signal strength is attenuated by overlaying tissue. Then, intact artery samples (n = 13) were examined spectroscopically, sectioned and stained specifically for cholesterol. Images of these sections were digitized, and image intensities were related to cholesterol content. These cholesterol amounts were weighed appropriately for depth into the tissue and area-integrated for comparison with spectroscopy results. A decaying exponential curve was fit to the layer study data (r2 = 0.97) and showed that approximately 300 microm of tissue attenuates cholesterol signals by 50%. In intact plaques, the spectroscopically-determined cholesterol amounts correlated strongly and linearly with those determined by digital microscopy (r2 = 0.94). With Raman spectroscopy techniques, the cholesterol content of a lesion can be determined by properly accounting for its depth into an arterial wall. Our results suggest that chemical concentrations in an artery wall could be mapped throughout its thickness, possibly by combining Raman spectroscopy methods with other techniques.
PURPOSE: Near-infrared Raman spectroscopy provides an important new means of analyzing the chemical composition of the arterial wall. The objective of this study was to show that Raman spectroscopy can be used to evaluate the lipid and calcium salt contents of human peripheral arteries. The results extend a recently developed Raman-based method for analyzing the chemical composition of coronary arteries. METHODS AND RESULTS: We studied 167 segments of carotid and femoral artery wall in various pathologic states. The Raman spectra from these samples was accurately modeled. The resulting chemical concentrations were compared with the amounts of cholesterol and calcium mineral determined at histologic evaluation by an experienced cardiovascular pathologist. Strong correlations between spectroscopic measurements and morphologic findings were demonstrated and validated the applicability of the method to peripheral arteries. CONCLUSIONS: Raman spectroscopy can provide reliable histochemical information about peripheral and coronary arteries. Such information may help identify rupture-prone plaques before the onset of symptoms and allow aggressive and directed intervention. Accurate knowledge of the chemical composition of a lesion may be useful in selecting the most appropriate treatment.
BACKGROUND: We present a method for in situ chemical analysis of human coronary artery using near-infrared Raman spectroscopy. It is rapid and accurate and does not require tissue removal; small volumes, approximately 1 mm3, can be sampled. This methodology is likely to be useful as a tool for intravascular diagnosis of artery disease. METHODS AND RESULTS: Human coronary artery segments were obtained from nine explanted recipient hearts within 1 hour of heart transplantation. Minces from one or more segments were obtained through grinding in a mortar and pestle containing liquid nitrogen. Artery segments and minces were excited with 830 nm near-infrared light, and Raman spectra were collected with a specially designed spectrometer. A model was developed to analyze the spectra and quantify the amounts of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts present. The model provided excellent fits to spectra from the artery segments, indicating its applicability to intact tissue. In addition, the minces were assayed chemically for lipid and calcium salt content, and the results were compared. The relative weights obtained using the Raman technique agreed with those of the standard assays within a few percentage points. CONCLUSIONS: The chemical composition of coronary artery can be quantified accurately with Raman spectroscopy. This opens the possibility of using histochemical analysis to predict acute events such as plaque rupture, to follow the progression of disease, and to select appropriate therapeutic interventions.
Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level.
BACKGROUND: Laser-induced fluorescence spectroscopy has the potential to detect colonic dysplasia in vivo. However, previous studies have limited their analyses to multivariate regression techniques and unblinded retrospective evaluation. The purpose of this study was to develop a probability-based algorithm to detect colonic dysplasia using laser-induced fluorescence spectroscopy and to evaluate it in a blinded manner. METHODS: Fluorescence spectra were collected from normal mucosa and colonic polyps during colonoscopy using 370 nm excitation. Tissue was classified as normal, hyperplastic, or adenomatous by histologic examination. Preliminary data was used to devise an algorithm to differentiate tissue type based on probability distributions of the fluorescence intensity at 460 nm and the ratio of the intensity at 680 nm to that at 600 nm. The algorithm was then tested in a blinded fashion. RESULTS: The algorithm correctly determined the tissue type in 88% of cases, equal to the agreement of independent pathologists. Sensitivity, specificity, and positive predictive value for the detection of dysplasia was 90%, 95%, and 90%, respectively. CONCLUSIONS: Dysplasia was detected in vivo using fluorescence spectroscopy and a probability-based algorithm. This method may form the basis for a new surveillance technique for patients with increased risk for dysplastic transformation.
Protection from the deleterious effects of the interaction of environmental stress and salicylate by calcium supplement was investigated in 96 pigmented rats. Within a 2 x 2 x 4 factorial design, rats were assigned to groups defined by: A) ad lib access to 1) plain tap water, or 2) 50 mM calcium chloride solution; B) exposure to stressors consisting of daily 10 h periods of 1) 98 dB SPL noise, or 2) confinement precluding movements; C) daily injections of 233, 350, or 410 mg/kg of sodium salicylate or the saline vehicle. For subjects maintained on tap water, weight loss and mortality increased with salicylate levels, with all subjects dying in the group drinking water and injected with 410 mg/kg. Calcium protected all of the subjects in the noise stress group but not in the confined group.
The myc family DNA copy number of 291 specimens (183 tumors and 108 tumor cell lines) from patients with small-cell lung cancer has been reported in 15 different studies. Thirty-five of 108 (32%) cell lines from small-cell lung cancer patients have myc family DNA amplification (16 c-myc, 7 N-myc, and 12 L-myc). Thirty-seven of 183 (20%) tumors from patients with small-cell lung cancer have myc family DNA amplification (3 c-myc, 13 N-myc, and 18 L-myc). The myc family DNA copy number in tumors from patients with small-cell lung cancer is similar in the majority of sites from the same patient. The presence of myc family DNA amplification in the tumor cell line is also typically present in the tumor from the same patient. myc family DNA amplification is present in a minority of patients with small-cell lung cancer, and the data on its association with shorter survival of patients are meager at present. Future studies on the biology of the myc family in small-cell lung cancer may require use of newer technologies that can work with small tissue samples typically available at the start of therapy.
Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.
Acquired cystic kidney disease has become increasingly recognised as a significant risk in patients with end-stage renal disease, especially in those maintained on chronic haemodialysis and peritoneal dialysis. A review of the literature indicates that nearly 50% of patients on dialysis for more than 3 years develop renal cystic changes. The major complications of this condition are neoplasia and spontaneous renal haemorrhage. The risk of developing renal carcinoma has been estimated to be more than 30 times higher in dialysis patients with cystic changes than in the general population. Our experience with 5 patients is reported, including 3 with renal tumours and 1 with metastatic disease. Careful surveillance of dialysis patients using yearly ultrasonography and computed tomography is recommended. The evolving indications for radical nephrectomy in this disease are discussed.
Tonal frequency generalization was examined in a total of 114 pigmented male rats, 60 of which were tested under the influence of salicylate-induced phantom auditory perception, introduced before or after lick suppression training. Thirty control subjects received saline injections, and the remaining 24 subjects served as noninjected controls of tonal background effects on generalization. Rats were continuously exposed to background noise alone or with a superimposed tone. Offset of background noise alone (Experiment I), or combined with onset or continuation of the tone (Experiments II and III) served as the conditioned stimulus (CS). In Experiment I, tone presentations were introduced only after suppression training. Depending on the time of salicylate introduction, a strong and differential influence on generalization gradients was observed, which is consistent with subjects' detection of salicylate-induced, high-pitched sound. Moreover, when either 12- or 3 kHz tones were introduced before or after Pavlovian training to mimic salicylate effects in 24 rats, the distortions in generalization gradients resembled trends obtained from respective salicylate injected groups. Experiments II and III were aimed at evaluating the masking effect of salicylate-induced phantom auditory perception on external sounds, with a 5- or a 10-kHz tone imposed continuously on the noise or presented only during the CS. Tests of tonal generalization to frequencies ranging from 4- to 11- kHz showed that in this experimental context salicylate-induced perception did not interfere with the dominant influence of external tones, a result that further strengthens the conclusion of Experiment I.
Stereotypical behavior or response perseveration dominating early mammalian responding, especially under conditions of aversive motivation, may be radically modified through damage in the prefrontal and hippocampal systems. These observations contribute evidence to the notion that changes in neural circuitry may be supporting behavioral recovery of function after selective brain damage. The extent of behavioral deficits as well as the prognosis for recovery are governed by task-specific variables, usually related to a discriminative element in stimulus control. Conversely, reversion to earlier, stereotypical behavior may be produced in adult rats exposed to damage at points within the same sites. Specific experiments tested weanling and adult rats within tasks that differed in the (1) extent and site of damage, (2) variety of signalling stimuli, (3) complexity of the task requirements, and (4) time since surgery for initiation of training. Experiments on 1-way active avoidance, alternation and reversal learning indicated that performance deficits are attributed to developmental immaturity early in ontogeny, and enhanced neurophysiological growth with age provides a reliable predictor of recovery. However with increasing age, variables related to the subtleties of damage site and task also emerge as salient factors in behavioral deficiencies. Interestingly, the cue properties or information value contained in the conditioned stimulus (CS) and the environmental context provide differential compensation for selected types of injury-induced deficits, and there was some evidence that the utility of environmental signals can be improved over long-term recovery periods. The results support the view that relationships between age at the time of injury and extent of recovery are perhaps best explained within developmentally determined constraints.(ABSTRACT TRUNCATED AT 250 WORDS)
Survival as a function of salicylate dose and the intensity of environmental noise was investigated in 150 adult female pigmented rats. Rats were assigned to groups (n = 6/group) defined by combinations of salicylate levels from 0-(saline) to 300 mg/kg, injected subcutaneously, and noise levels from ambient noise to 98 dB SPL, presented daily for 10-h periods for up to 17 days. Mortality occurred in groups exposed to the higher combinations of salicylate and noise.
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In four experiments, 54 pigmented rats were used to examine the time course of sodium salicylate uptake in serum, cerebrospinal fluid, and perilymph. Subjects were tested under sodium pentobarbital anesthesia or while conscious. Compared with previously reported data from albino rats, pigmented subjects generally showed increased salicylate uptake. Moreover, the data suggested two different, time-dependent clearance mechanisms in conscious animals not observed in anesthetized rats. Daily injections of salicylate did not produce an accumulation of salicylate in serum. Systematically higher levels of salicylate were observed in perilymph compared with cerebrospinal fluid. Behavioral procedures, including water deprivation and conditioned suppression of ongoing drinking levels, had no effect on salicylate levels.