Soluble beta-amyloid precursor protein and pyramidal neuron loss.
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Biomedical subjects
Publications and source records attributed to R Doshi.
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OBJECTIVES: The goal of this study was to develop an accurate, simplified proximal isovelocity surface area (PISA) method for calculating volume flow rate using lower blue-red interface velocity produced by a color Doppler zero baseline shift technique. BACKGROUND: The Doppler color proximal isovelocity surface area method has been shown to be accurate for calculating the volume flow rate (Q) across a narrowed orifice by the formula Q = PISA x Blue-red interface velocity. A hemispheric model is generally used to calculate proximal isovelocity surface area (PISA = 2 pi a2, where a = the radius corresponding to the blue-red interface velocity). Although a hemispheric model is simple, requiring measurement of one radius, it may underestimate the actual volume flow rate because, in the general case, the shape of a proximal isovelocity surface area is hemielliptic. Although a hemielliptic model is generally more accurate for calculating proximal isovelocity surface area, it is more complex, requiring measurement of two orthogonal radii. METHODS: Sixteen in vitro constant flow model studies were performed using planar circular orifices (diameter range 6 to 16 mm). The blue-red interface velocity was changed from 3 to 54 cm/s using color Doppler zero baseline shift. RESULTS: 1) With decreasing blue-red interface velocity, the size of the proximal isovelocity surface area was increased, and its shape changed from hemielliptic to hemispheric. 2) With the blue-red interface velocity in the range 11 to 15 cm/s, the proximal isovelocity surface area became nearly hemispheric; however, it was difficult to determine the blue-red interface radius at a blue-red interface velocity < 10 cm/s because of interface fluctuations. 3) Calculated volume flow rate using the hemispheric proximal isovelocity surface area model with a single radius was relatively accurate at a blue-red interface velocity of 11 to 15 cm/s (mean percent difference from actual volume flow rate was -3.6%). CONCLUSIONS: Because the shape of the proximal isovelocity surface area is nearly hemispheric at a blue-red interface velocity of 11 to 15 cm/s, volume flow rate can be accurately calculated in this proximal isovelocity surface area interface velocity range (produced by zero baseline shift) by measuring a single-interface radius. This approach should be clinically useful for calculating the volume flow rate across stenotic and regurgitant valves and across shunt defects.
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Visual estimates of the intensity of the continuous wave (CW) Doppler regurgitant jet signal have been used to estimate the severity of valvular regurgitation. Theoretically, the strength of the reflected Doppler signal is a function of the number of scatterers. To test this approach quantitatively, free jets were produced in 27 experiments using a power injector and cornstarch suspension varying in concentration from 1% to 3%. Flow volume was varied from 5 to 15 ml, and orifice diameter varied from 2.5 to 10 mm. Machine settings were kept constant. Also, 22 patients with mitral regurgitation (MR)--5 mild, 11 moderate, and 6 severe by angiography--were studied. Average signal intensity under the CW Doppler flow curve was calculated using a computer image processor. In MR patients, average regurgitant flow (RF) intensity was compared with average mitral forward flow (FF) signal intensity. (1) The intensity under the CW flow signal in the free jet experiments correlated well with injection volume (r greater than 0.98). (2) RF average signal intensity did not correlate with angiographic MR severity (r = 0.21), but the ratio of RF to FF average signal intensity did correlate with MR severity (r = 0.73). (3) The sensitivity and the specificity of an RF/FF ratio greater than 0.65 for angiographically severe mitral regurgitation were both 83%. (4) The sensitivity and specificity of an RF/FF ratio less than 0.50 for angiographic mild mitral regurgitation were both 80%. The ratio of regurgitant to forward mitral flow CW Doppler signal intensity appears to be an accurate and clinically applicable method for estimating the severity of mitral regurgitation.
Doppler color flow mapping of a proximal isovelocity surface area (PISA), calculated from a blue-red aliasing radius, has been shown in vitro to be accurate for estimating volume flow rate across a narrowed orifice. Volume flow rate (in cm 3/sec) can be calculated as PISA (in cm 2) x aliasing velocity (in cm/sec). This method has advantages over other color Doppler approaches in that PISA-derived volume flow rate calculations appear to be independent of machine parameter settings and orifice shape. We evaluated the clinical applicability of the PISA method in 49 patients with native valve mitral regurgitation (MR). Color Doppler flow mapping was performed at color aliasing velocities of 54-72 cm/sec. Twenty-four patients were excluded because a color aliasing radius was not clearly seen: 20 of these 24 patients had mild MR. In the remaining 25 patients, the ratio of maximum regurgitant jet area-to-left atrial area, as well as the regurgitant stroke volume estimated using the time-velocity integral method, were compared to regurgitant stroke volume calculated from the PISA method. Maximum PISA was calculated using a formula derived from previous in vitro studies: PISA = 8.05 x r 2, where r is the maximum color Doppler aliasing radius in the apical four-chamber view.(ABSTRACT TRUNCATED AT 250 WORDS)
beta-Adrenergic receptor downregulation is the end result of cellular adaptation to prolonged agonist exposure. The factors mediating receptor downregulation include receptor phosphorylation, receptor movement from the plasma membrane to intracellular sites, and alterations in nascent receptor synthesis. We have previously demonstrated a downregulation of the left ventricular beta-receptor during chronic hypoxia in vivo. To determine the mechanism of this downregulation, we produced chronic hypoxia in seven newborn lambs by creating right ventricular outflow obstruction and an atrial septal defect. Oxygen saturation was reduced to 65-74% for 2 weeks. Six lambs served as normoxic controls. Sarcolemmal membrane and cytosolic fractions were prepared from left ventricular free wall samples. beta-Receptor density in each fraction was determined with the radioligand [125I]iodocyanopindolol. Steady-state levels of beta-receptor mRNA were determined by Northern blot analysis using a beta 1-adrenergic receptor cDNA probe. During chronic hypoxia, left ventricular membrane beta-adrenergic receptor density decreased by 55% (153 +/- 28 fmol/mg for hypoxic lambs versus 342 +/- 79 fmol/mg for control lambs, p < 0.05). There was no corresponding increase in beta-receptor density in the cytosolic fraction (23 +/- 3 fmol/mg for hypoxic lambs versus 33 +/- 9 fmol/mg for control lambs, p = NS), nor was there a significant change in the ratio of beta 1-receptor/beta 2-receptor subtypes as assessed by radioligand binding (beta 1 subtype, 84.1 +/- 10.1% for hypoxic lambs versus 93.2 +/- 8.8% for control lambs; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
This is the case report of an eighty-seven-year-old woman who was seen because of swelling of her left upper extremity and breast of one week's duration. She had a history of severe arthritis of the knees and had been wheelchair-bound for seven years. Venography showed compression of the cephalic vein and thrombosis of the distal basilic vein with extension into the axillary and subclavian veins. To the author's knowledge, this is the first case report of venous thrombosis in association with subluxation of the shoulder.
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Previously described Doppler color flow mapping methods for estimating the severity of valvular regurgitation have focused on the distal jet. In this study, a newer Doppler color flow technique, focusing on the flow proximal to an orifice, was used. This method identifies a proximal isovelocity surface area (PISA) by displaying an aliasing interface. Volume flow rate (cm3/s) can be calculated as PISA (cm2) x aliasing velocity (cm/s). For planar circular orifices, a hemi-elliptic model accurately approximated the shape of PISA. Clinically, however, orifice shapes may be noncircular. In vitro flow experiments (n = 226) using orifices of various shapes (ellipse, square, triangle, star, rectangle) were performed. Volume flow rate calculated using a hemi-elliptic model for PISA was accurate, with average percent differences from actual flow rate = +4.3% for a square, -4.2% for a triangle, -4.7% for a star, -4.5% for an ellipse and -2.8% for a rectangle. However, average percent differences for calculated volume flow rates using a hemispheric model for PISA shape ranged from -11.6% (square) to -34.8% (rectangle). In addition, to evaluate whether PISA is influenced by machine factors, in vitro studies (n = 83) were performed.(ABSTRACT TRUNCATED AT 250 WORDS)
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During chronic hypoxemia, left ventricular beta-adrenergic receptor density is decreased and a dissociation occurs between increased chronotropic and decreased inotropic responses to chronically elevated sympathetic tone. To determine whether this dissociation was related to alterations in autonomic receptor populations in the right atrium, we studied right atrial cholinergic and beta-adrenergic receptors in chronically hypoxemic newborn lambs and in normoxemic controls. Heart rate response was determined by infusing isoproterenol at 0.1 or 0.5 microgram.kg-1.min-1. Muscarinic receptors were quantified with [3H]quinuclidinyl benzilate and beta-adrenergic receptors with [125I]iodocyanopindolol. Competition with ICI 118,551 was used to determine beta 1- vs. beta 2-receptor subtypes. In the hypoxemic lambs, isoproterenol resulted in a lesser percentage increase in heart rate (hypoxemic, 46 +/- 6% vs. control, 89 +/- 17%, P less than 0.05); however, because baseline heart rate was higher in the hypoxemic lambs (213 +/- 7 vs. 177 +/- 12 beats/min, P less than 0.05), maximal heart rate responses were similar (310 +/- 7 vs. 326 +/- 6 beats/min, NS). There was no change in receptor density or affinity of either muscarinic or beta-adrenergic receptors and no change in the proportion of beta 1- vs. beta 2-receptor subtypes. Thus the dissociation between the chronotropic and inotropic responses to chronic hypoxemia may be in part secondary to a differential regulation of beta-adrenergic receptors between the left ventricle and the right atrium.
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To determine whether chronic hypoxemia secondary to an intracardiac right-to-left shunt alters regulation of the myocardial beta-adrenergic receptor/adenylate cyclase system, we produced chronic hypoxemia in nine newborn lambs by creating right ventricular outflow obstruction and an atrial septal defect. Oxygen saturation was reduced to 65-74% for 2 wk. Eight lambs served as normoxemic controls. beta-receptor density (Bmax) and ligand affinity (KD) were determined with the radio-ligand [125I]iodocyanopindolol and adenylate cyclase activity determined during stimulation with isoproterenol, sodium fluoride (NaF), and forskolin. During chronic hypoxemia, Bmax decreased 45% (hypoxemic, 180.6 +/- 31.5 vs. control, 330.5 +/- 60.1 fmol/mg) in the left ventricle (exposed to hypoxemia alone) but was unchanged in the right ventricle (exposed to hypoxemia and pressure overload). KD was not different from control in either ventricle. Left ventricular isoproterenol-stimulated adenylate cyclase activity was decreased by 39% (30.0 +/- 4.3% increase vs. 44.1 +/- 9.5% increase) whereas right ventricular adenylate cyclase activity was unchanged. Stimulation of adenylate cyclase with NaF or forskolin was not different from control in either ventricle. Circulating epinephrine was increased fourfold whereas circulating and myocardial norepinephrine were unchanged. These data demonstrate a down-regulation of the left ventricular beta-adrenergic receptor/adenylate cyclase system during chronic hypoxemia secondary to an intracardiac right-to-left shunt.
Manganese-deficient rats exhibited seven-fold lower preproinsulin mRNA levels compared to control, as detected by dot blot hybridization of both total and poly(A)+ RNA using a preproinsulin cDNA probe. No differences in the size of the insulin mRNA were observed. Thus, decreased mRNA levels may be a major contributing factor to the decreased insulinogenesis observed in manganese-deficient rats.
Excitatory dicarboxylic amino acids previously have been ascribed several functions in the brain. Here their total concentration and proposed neurochemical markers of neurotransmitter function have been measured in brain from patients with Alzheimer's disease (AD) and controls. Specimens were obtained antemortem (biopsy) approximately 3 years after emergence of symptoms and promptly (less than 3 h) postmortem some 10 years after onset. Early in the disease a slight elevation in aspartic acid concentration of cerebral cortex was observed in the patients with AD. A reduction in glutamic acid concentration of a similar magnitude was found. It is argued that this, together with a decrease in CSF glutamine content and lack of change in the phosphate-activated brain glutaminase activity of tissue, reflects an early metabolic abnormality. Later in the disease evidence of glutamatergic neurone loss is provided by the finding that in many regions of the cerebral cortex the Na+-dependent uptake of D-[3H]aspartic acid was almost always lowest in AD subjects compared with control when assessed by a method designed to minimise artifacts and epiphenomena. Release of endogenous neurotransmitters from human brain tissue postmortem did not appear to have the characteristics of that from human tissue antemortem and rat brain.
A healthy adult presented with severe neurological disturbance 4 d after developing chicken-pox. Although pneumonic and renal problems were also present the neurological state dominated the clinical picture. After the patient's sudden death an autopsy revealed that renal and cerebral problems were secondary to myocardial involvement. This was of an unusual type for varicella with features of dilated cardiomyopathy resembling that previously related to Coxsackie infections. We conclude that cardiac problems in this patient produced anoxic brain damage and subsequently death.
Fourteen previously reported cases of the fetal alcohol syndrome (FAS) showed anomalies of brain structure varying in severity from microscopic disorganization of tissue structure, or abnormalities in neuronal or glial migration only visible microscopically, to complete or partial agenesis of regions such as the corpus callosum or cerebellum and large neuronal heteropias. The difficulty is illustrated of differentiating this type of damage, lacking in specificity and uniformity, from other syndromes of uncertain aetiology, such as De Lange, DiGeorge and Dubowitz, in at least one of which (DiGeorge syndrome) maternal alcoholism has been implicated. Similar brain damage is also seen in other conditions with known causes. In FAS and syndromes with this type of brain damage, most of the non-CNS features which make the conditions clinically recognizable may well be determined by timing or ancillary factors. Alcohol-related antenatal effects should not be identified to restrictively with FAS but should be considered in any condition of unknown aetiology with disorganization of brain structure and mental retardation.