Biomedical subjects
Publications and source records attributed to T W Smith.
We present three cases of desmoplastic infantile ganglioglioma in patients admitted to our institution in the past 8 years. CT and MR findings are discussed. Typically, these lesions are located in the frontal and parietal lobes, appearing as cystic tumors with a solid cortical component within the cerebrum, which enhances intensely, and moderate surrounding edema.
A major determinant of survival in patients with advanced viral or bacterial infection, or following severe trauma or burns complicated by multiple organ failure, is the combination of clinical signs termed the systemic inflammatory response syndrome (SIRS). SIRS is characterized by hypotension, tachypnea, hypo- or hyperthermia and leukocytosis as well as other clinical signs and symptoms, including a depression in myocardial contractile function. Heart failure complicating systemic sepsis or other causes of SIRS is usually not accompanied by coronary artery ischemia due to hypotension, myocardial necrosis, or marked cardiac interstitial inflammatory infiltrates, and thus the cause of cardiac contractile dysfunction in this syndrome has remained unclear. However, recent evidence has implicated an endogenous nitric oxide (NO) signalling pathway within cardiac myocytes and other cellular constituents of cardiac muscle, including the microvascular endothelium, as a possible contributor to the pathogenesis of heart failure in this syndrome. Cardiac myocytes are now known to express both constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) activities. Activation of cNOS appears to modulate cardiac myocyte responsiveness to muscarinic cholinergic and beta-adrenergic receptor stimulation. Induction of iNOS by soluble inflammatory mediators, including cytokines, causes a marked depression in myocyte contractile responsiveness to beta-adrenergic agonists. Thus, inappropriate activation of cNOS or excessive or prolonged induction of iNOS in the myocardium may contribute to cardiac dysfunction complicating SIRS.
The utility of measuring both positive and negative affective states for assessing rheumatoid arthritis (RA) patients was examined in 3 independent samples of male and female RA patients (Sample A: 179 women, 48 men; Sample B: 177 women, 24 men; Sample C: 134 women, 38 men). Confirmatory factor analyses of each sample indicated that positive and negative affect constituted separate, negatively correlated factors. The relations among disease variables, coping, and affects were consistent with a model in which coping mediates the relationship between disease variables and positive and negative affect. Patients with higher pain and limitation from RA had higher levels of maladaptive coping, and maladaptive coping was associated with lower positive affect and higher negative affect. Those RAs with higher activity limitation also reported less adaptive coping, which was associated with less positive affect.
Cell cycle-associated nuclear proteins may have more specialized functions in the adult nervous system in addition to those directly associated with cell proliferation, as suggested by a recent study showing that neurofibrillary tangles (NFT) and dystrophic neurites in Alzheimer's disease (AD) are immunoreactive for the proliferation-associated antigen p105. To further investigate this hypothesis, we studied the expression of another proliferation-associated antigen, Ki-67, in the brains of patients with AD and other neurodegenerative disorders. Formalin-fixed, paraffin-embedded sections from autopsy cases of AD, Down's syndrome with dementia and AD pathology (DS/AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), Lewy body disease (LBD), Parkinson's disease (PD), corticobasal degeneration (CBD), and young and aged normal brains, and from two surgically resected gangliogliomas were immunostained using antibodies to Ki-67 (MIB-1 clone equivalent) and tau (tau). Ki-67 staining was performed following antigen retrieval by microwave heating. Ki-67 labeled NFT that were observed in the AD, DS/AD, PiD, PSP, LBD, and PD cases, one aged normal brain, and one ganglioglioma. Ki-67 generally labeled fewer NFT compared to tau. Pick bodies, ballooned neurons (Pick cells) in CBD and PiD, and nigral corticobasal inclusions in CBD were immunoreactive for tau but not Ki-67. Neither antibody labeled cortical or subcortical Lewy bodies. Our findings suggest that Ki-67 may be involved in the pathogenesis of neurofibrillary degeneration in AD, other neurodegenerative disorders, normal aging, and neoplasms such as ganglioglioma. We postulate a possible role for Ki-67 in the production of the abnormally phosphorylated tau protein that leads to the formation of paired helical filaments within susceptible neurons.
The computed tomographic and magnetic resonance appearance of a calvarial aneurysmal bone cyst is described. Both forms of imaging demonstrate an epidural mass in the right occiput. The fluid-fluid levels in the mass on the T2-weighted images are characteristic of, though not specific for, aneurysmal bone cyst.
Primary malignant fibrous histiocytomas are rare. The authors report on a 56-year-old man who presented with neurological symptoms due to cerebral metastasis of a primary malignant fibrous histiocytoma of the lung.
There are important phenotypic differences between endothelial cells of large vessels and the microvasculature and among microvascular endothelial cells isolated from different tissues and organs. In contrast to most macrovascular endothelial cells, we demonstrate that cultured cardiac microvascular endothelial cells (CMEC) have no detectable constitutive NO synthase (NOS) activity but have a robust increase in NOS activity in response to specific inflammatory cytokines. To determine the identity of the inducible NOS (iNOS) isoform(s) induced by cytokines, we used reverse-transcription polymerase chain reaction techniques to clone and sequence a 217-bp cDNA fragment from CMEC cultures pretreated with interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) that was identical to the corresponding portion of the murine macrophage iNOS cDNA. By use of this CMEC iNOS cDNA as a probe in Northern analyses, IL-1 beta, but not IFN-gamma, increased iNOS mRNA content in CMEC, although IFN-gamma markedly potentiated iNOS induction in these cells. In IL-1 beta- and IFN-gamma-pretreated CMEC, dexamethasone only minimally suppressed the rise in iNOS mRNA, protein abundance, or maximal iNOS enzyme activity in whole cell lysates but suppressed nitrite production by 60% in intact CMEC. Dual labeling of cytokine-pretreated CMEC in primary culture with an anti-iNOS antiserum and a fluorescein-labeled lectin specific for the microvascular endothelium of rat heart (GS-1) confirmed the presence of iNOS expression in these cells. iNOS was also detected in microvascular endothelium in situ in ventricular muscle from lipopolysaccharide-, but not sham-injected, rat hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
Unlike large-vessel endothelial cells in cell culture, cardiac microvascular endothelial cells (CMEC) isolated from adult rat ventricular muscle exhibit little detectable constitutive nitric oxide (NO) synthase activity after isolation in vitro but respond to specific combinations of inflammatory mediators with an increase in inducible NO synthase (iNOS; type 2 NO synthase) activity. CMEC iNOS is induced by soluble inflammatory mediators in lipopolysaccharide-activated rat alveolar macrophage-conditioned medium at 24 hours, and this induction can be partially prevented by either interleukin-1 (IL-1) receptor antagonist or a polyclonal anti-rat tumor necrosis factor-alpha (TNF-alpha) antiserum. Interferon-gamma (IFN-gamma), which by itself does not induce iNOS in CMEC, potentiates and accelerates iNOS induction by IL-1 beta. Transforming growth factor-beta (TGF-beta) decreases iNOS activity, protein content, and mRNA abundance in IL-1 beta- and IFN-gamma-pretreated CMEC. To determine whether NO released by CMEC would affect myocyte contractile function in vitro, freshly isolated ARVM were allowed to settle onto confluent, serum-starved CMEC that had been pretreated for 24 hours with IL-1 beta, a cytokine that alone does not affect myocyte contractile function in vitro. Baseline contractile amplitude, at 2 Hz and 37 degrees C, of myocytes in heterotypic culture with IL-1 beta-pretreated CMEC was not different from that of myocytes in control, homotypic myocyte cultures. However, cocultured myocytes exhibited decreased contractile responsiveness to 2 nmol/L isoproterenol compared with control cells, and this could be reversed by the addition of 1 mmol/L NG-monomethyl-L-arginine, an inhibitor of NOS.(ABSTRACT TRUNCATED AT 250 WORDS)
Recent evidence has documented that increased activity of an inducible nitric oxide synthase (iNOS; type 2 NO synthase) in primary isolates of adult rat ventricular myocytes after exposure to soluble mediators in medium conditioned by lipopolysaccharide-activated macrophages is associated with a decrease in their contractile responsiveness to beta-adrenergic agonists. It remained unclear which specific inflammatory cytokines in this medium contribute to the induction of iNOS activity in myocytes and whether induction of iNOS would result in an obligatory decline in contractile function. Interleukin (IL)-1 beta and tumor necrosis factor-alpha (TNF-alpha) were both present in the lipopolysaccharide-activated macrophage-conditioned medium. However, only IL-1 receptor antagonist and not an anti-rat TNF-alpha antiserum diminished the extent of iNOS induction in myocytes exposed to this medium and prevented a decline in contractile responsiveness to isoproterenol. When recombinant cytokines were used, IL-1 beta, TNF-alpha, and IFN-gamma each induced iNOS activity in cardiac myocytes at 24 hours. However, only the combination of IL-1 beta and IFN-gamma reproducibly caused contractile dysfunction in cardiac myocytes. Among the constituents of the defined medium routinely used for maintenance of adult rat ventricular myocytes in primary culture, it was noted that insulin (10(-7) mol/L) was required for NO production, as detected by nitrite release in cytokine-pretreated myocytes, although insulin had no effect on the extent of induction of iNOS mRNA or maximal enzyme activity in myocyte cell lysates.(ABSTRACT TRUNCATED AT 250 WORDS)
In vitro studies indicate that muscarinic cholinergic inhibition of beta-adrenergic cardiac responses may be modulated in part by nitric oxide (NO). To evaluate the role of NO in parasympathetic inhibition of the beta-adrenergic contractile response in vivo, we assessed the inotropic response to dobutamine before and during bilateral vagus nerve stimulation in closed-chest dogs. Dobutamine administration and vagal stimulation were repeated during intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mumol/min) and again following infusion of L-arginine (100 mg/kg). In eight dogs, intracoronary dobutamine infusion at rates of 25 and 50 micrograms/min increased peak +dP/dt by 131 +/- 24 and 168 +/- 22%, respectively (P < 0.0001). Vagal stimulation (2.5 Hz) attenuated the responses to dobutamine (25 and 50 micrograms/min) by 23 +/- 4 and 21 +/- 4%, respectively (P < 0.001). L-NMMA reduced (by 44-62%; P < 0.001) and L-arginine restored vagal inhibition of the dobutamine-stimulated inotropic response. In a second group of nine dogs, dobutamine was administered systemically to assure a constant concentration in the coronary circulation. Vagal stimulation (2.5 Hz) attenuated the dobutamine-stimulated inotropic response (2.5 and 5.0 micrograms/kg per min) by 40 +/- 12% and 57 +/- 8%, respectively (P < 0.004). As with intracoronary dobutamine, L-NMMA diminished and L-arginine restored vagal inhibition of the inotropic response to dobutamine. Intracoronary infusion of atropine (12 micrograms/min) abolished the vagal inhibitory effect, and intracoronary infusion of 8-bromo-cyclic GMP (1 and 10 mM) caused a dose-dependent attenuation of the dobutamine-stimulated increase in +dP/dt. These data suggest that NO mediates, at least in part, vagal inhibition of the inotropic response to beta-adrenergic stimulation by dobutamine, and thus may play a role in normal physiologic regulation of myocardial autonomic responses.
To determine whether apolipoprotein E (APOE) genotype affects neuropathology in Lewy body disease (LBD), we examined 18 cases of LBD that did not have concurrent Alzheimer's disease by the CERAD criteria. We obtained APOE genotypes, determined diffuse beta-amyloid plaque (A beta P) and Lewy body densities in multiple brain regions, and graded the intensity of CA2-3 ubiquitin-positive neurites, vacuolar change, nigral pathology, amyloid angiopathy, and subpial amyloid deposition. The APOE allele frequencies were as follows: epsilon 2, 0.14 +/- 0.07; epsilon 3, 0.64 +/- 0.08; and epsilon 4, 0.22 +/- 0.03. The mean A beta P density was lower in APOE epsilon 3/3 cases (14.5 A beta Ps per mm2) than in the groups with the APOE epsilon 2 (67.0) or APOE epsilon 4 (46.6) alleles. This difference was due largely to the difference between A beta P density in the APOE epsilon 2 group and the APOE epsilon 3/3 group (F = 5.525, p < 0.02). CA2-3 neuritic degeneration was greater in those with the APOE epsilon 4 allele than in those with the APOE epsilon 3/3 genotype (grade = 1.9 +/- 1.3 versus 0.938 +/- 0.9; Kruskal-Wallis test statistic = 6.962, p < 0.05). These data are consistent with the hypothesis that APOE genotype may affect neuropathology in LBD.
We compared immunohistochemical expression of the transforming growth factor-betas (TGF-beta 1, TGF-beta 2, and TGF-beta 3) using brain tissue from patients with nondominantly inherited Alzheimer's disease (NDAD) (n = 9), autosomal dominantly inherited Alzheimer's disease with linkage to 14q24.3 (FAD-14) (n = 4), and cognitively normal controls (n = 10) to determine whether their pathologic changes are associated with an altered distribution of the TGF-betas. We found increased expression of TGF-beta 2 in large, tangle-bearing neurons with widespread staining of glia in NDAD and FAD-14 patients compared with control cases. This result was confirmed with sandwich ELISA assays of brain tissue, which showed TGF-beta 2 levels in AD and NDAD to average 3.2 times the average level of control cases. Despite proximity of TGF-beta 1 and TGF-beta 3 to the sites of susceptibility loci on chromosomes 19 and 14, we did not find that TGF-beta 1 and TGF-beta 3 were selectively altered in any AD subtypes. However, selective induction of TGF-beta 2 may occur in NDAD and FAD-14.
The bcl-2 protooncogene encodes a 26-kD protein that extends cell survival by blocking apoptosis. This protein has been found to be overexpressed in neoplastic neural cell lines, although its expression in reactive and neoplastic astrocytes in vivo has not been well characterized. The authors hypothesized that bcl-2 oncoprotein expression in gliomas might be positively correlated with the tumor's degree of malignancy. Sixty-three gliomas of various subtypes and histological grades were immunostained by bcl-2 protein and the percentage of positive cells was quantitatively assessed. All tumors contained neoplastic cells that were immunoreactive for the bcl-2 protein (range of cell positivity 1%-53%). It was found that bcl-2 expression did not vary significantly as a function of tumor subtype or grade (p < 0.1, one-way analysis of variance (ANOVA) on ranks) as compared to the cell proliferation marker Ki-67 (MIB-1) in which a very significant correlation with tumor grade was noted (p < 0.0000001, one-way ANOVA on ranks). In fact, the highest percentage of bcl-2 immunoreactive cells was noted in low-grade gliomas, that is, in juvenile pilocytic astrocytomas and oligoastrocytomas. The specificity of bcl-2 overexpression was also assessed in 10 nonneoplastic lesions associated with prominent reactive astrocytosis. In nine of these cases (90%), bcl-2-positive reactive astrocytes were observed, often in large numbers, whereas relatively few Ki-67 immunoreactive cells were noted. The authors conclude that bcl-2 oncoprotein expression as assessed immunohistochemically does not correlate with glial tumor type or grade and its overexpression is not confined only to neoplastic conditions. Instead, the finding of robust bcl-2 expression in low-grade glial tumors and in reactive astrocytes warrants the inference that resistance to apoptosis is a nonspecific finding in astrocytes associated with both reactive and neoplastic conditions.
Explore the source record for details and available documents.
A series of closely related peptide analogues of Lys-Pro-Thr [(interleukin-1 beta-(193-195)] have been investigated in two models of antinociception in mice (acetic acid-induced abdominal constrictions and formalin tests) and compared with morphine, aspirin and indomethacin. Formalin-induced nociceptive responses in the mouse showed early (0-5 min) and late (15-30 min) phases of peak activity. Lys-D-Pro, Lys-D-Pro-Thr, Lys-D-Pro-Arg, Lys-D-Pro-Val, morphine and aspirin, were antinociceptive in both phases after intraperitoneal (i.p.) and oral (p.o.) administrations. Lys-D-Pro-Leu inhibited the early phase response only after i.p. injection. Lys-D-Pro-Val-NH2, Lys-D-Pro-Gln, Lys-D-Pro-Tyr, Lys-D-Pro-Asn, Asp-Lys-D-Pro-Val and indomethacin were active only against the late phase (ED50 values of 64, 32, 44, 94, 67 and 25 mg/kg i.p., respectively). Several of the peptides showed good bio-availability, e.g. Lys-D-Pro-Asn (ED50: 10 mg/kg i.p.; 11.4 mg/kg p.o.) in the abdominal constrictions test, where two modes of action were apparent, non-opioid and opioid; non-opioid (naloxone-insensitive antinociception) mechanisms were illustrated by Lys-D-Pro-Thr and Lys-D-Pro-Asn; opioid (naloxone-sensitive antinociception) mechanisms by Lys-D-Pro-Val and Lys-D-Pro-Leu. These data identify orally active antinociceptive peptides in both antinociceptive tests with varied relative potency profiles to morphine, indomethacin and aspirin in the mouse formalin test.
The transcriptional regulatory protein Id, a negatively trans-acting protein with a helix-loop-helix motif that is expressed in many proliferating tissues early in development, continues to be expressed in postmitotic adult cardiac myocytes and vascular smooth muscle. Following the observation of a "doublet" band of 1.1 and 1.25 kilobases on Northern hybridizations of Id1 cDNA with mRNA isolated from both cardiac muscle and vascular smooth muscle cells, we identified and sequenced an alternatively spliced Id1 gene product containing an insert of 214 base pairs within the coding domain of the original Id1 cDNA. A protein with a molecular mass corresponding to that predicted by the Id1.25-kilobase mRNA sequence could be identified on immunoblots of cell lysates from neonatal and adult rat ventricular myocytes. The insert appears to be a "coding intron," based on the presence of intron-exon consensus sequences at the insert boundaries and the presence of the originally described Id1 carboxyl-terminal coding sequence immediately downstream from, and out of frame with, this insert. In contrast to Id1 and Id2, which do not form homodimers, the carboxyl-terminal sequence of this alternatively spliced Id1 transcript, termed Id1.25, permits homodimerization. Thus, alternative splicing of Id1 may allow for tissue-specific expression of Id1, while formation of homodimers could provide a post-translational mechanism to regulate the ability of Id1.25 to bind and inactivate E2A gene products.
The exact nature of the relationship between Lewy body disease and Alzheimer's disease (AD) is unknown. To investigate this, we compared cases of pure Lewy body disease, mixed Lewy body disease with AD, and pure AD to see what pathological features were shared and how they differed. We counted neurons, Lewy bodies, diffuse and neuritic senile plaques, neurofibrillary tangles, and neuropil threads in the frontal and medial temporal cortex and hippocampus from 5 autopsied cases of Lewy body disease (without AD histopathology), 7 with combined Lewy body disease and AD, 6 with AD, and 5 age-matched normal control subjects. Average neuronal counts in the cases with Lewy body disease were indistinguishable from those of control subjects, but higher than those for AD and combined Lewy body disease and AD. Diffuse plaque densities were similar in all disease forms. Neuritic senile plaques, neurofibrillary tangles, and neuropil threads were numerous in AD and combined Lewy body disease and AD, but sparse or absent in Lewy body disease and controls. Pure Lewy body disease and AD appear to be distinct clinicopathological entities except for the common feature of diffuse plaques in both disorders.
Explore the source record for details and available documents.