Search PubMed⌕ Search

Biomedical subjects

B L Miller

Publications and source records attributed to B L Miller.

At least 19 recordsLinked to original sources
PubMed1995

Identification, activity, and structural studies of peptides incorporating the phorbol ester-binding domain of protein kinase C.

The family of homologous enzymes known as protein kinase C (PKC) has been the object of intense interest because of its crucial role in cellular signal transduction. Although considerable information about the activation of PKC has been gained through structure-activity, molecular modeling, and synthetic studies of both natural and designed activators, information about the structure of PKC itself has been limited by its large size and requirement for phospholipid cofactors. Additionally, difficulties in the purification of truncated mutants of PKC have thus far prevented their analysis by nuclear magnetic resonance (NMR) or x-ray crystallographic methods. We describe the identification, synthesis, ligand-binding analysis, cofactor requirements, and preliminary NMR evaluation of two subdomains (peptides B and C) of the regulatory domain of PKC-gamma. Peptides B and C bind [3H]phorbol 12,13-dibutyrate with good affinity (Kd = 6.4 microM and 414 nM, respectively) in the presence of phosphatidylserine. In comparison, the binding affinity of [3H]phorbol 12,13-dibutyrate for PKC was found to be 2.6 nM. Like PKC itself, these peptides also recognize other PKC activators, including dioctanoylglycerol and teleocidin B-4, and exhibit an ability to differentiate phorbol ester from its C-4 epimer. NMR studies of PKC subdomains are also described, indicating that both peptides B and C are well behaved in solution and do not exhibit any concentration-dependent changes. Finally, these studies reveal that peptide B becomes conformationally ordered only in the presence of phospholipid, suggesting that the regulatory domain of PKC itself might be organized for activation only when associated with the lipid bilayer, where its activator (diacylglycerol) is encountered.

Amino Acid Sequence↗
PubMed1995

Analysis of brain tumors using 1H magnetic resonance spectroscopy.

BACKGROUND: Magnetic resonance imaging (MRI) is superior in delineating anatomic and pathologic information and has subsequently been married to the ability of magnetic resonance spectroscopy (MRS) to provide insight into the biochemical changes underlying pathology. Proton magnetic resonance spectroscopy (1H MRS) allows the non-invasive in vivo collection and measurement of chemical information from a selected volume of tissue (voxel). METHODS: We conducted a prospective trial in 23 patients with brain mass lesions and 16 normal subjects using proton magnetic resonance spectroscopy (1H MRS). The spectra were analyzed for N-acetyl-aspartate (NAA), choline compounds (Cho), creatine (Cr), and lactate (Lac). The ratios of the compounds in tumors were compared to normals. RESULTS: The tumors showed significant decreases in the mean peak height ratios of NAA/Cho, NAA/Cr, and significant increases in Cho/Cr when compared to tissue from normal subjects. Cho was elevated in all of the meningiomas and gliomas. In benign tumors, Cho was usually elevated while in metastases Cho was often normal or decreased. The four metastatic tumors showed NAA/Cho, NAA/Cr, and Cho/Cr that were similar to controls. Lac varied with tumor type and was elevated in many malignant primary brain tumors. CONCLUSIONS: 1H MRS is a powerful tool for safe, noninvasive analysis of tissue chemistry in vivo. Analysis of intracranial tumors reveals significant trends that might eventually be used in the classification of tumor histology and evaluation of the efficacy of tumor treatment.

Adult↗
PubMed1995

SPECT in dementia: clinical and pathological correlation.

BACKGROUND: The clinical diagnosis of dementia continues to be flawed. Although the diagnosis of Alzheimer's disease (AD) is better than 90% at research centers in highly selected patients, the diagnosis of patients with non-AD dementias and atypical AD patients is poor. Single photon emission computed tomography (SPECT) is a functional imaging technique touted as a diagnostic technique for the degenerative disorders. However there have been few clinicopathological studies using SPECT. METHODS: Twenty-seven consecutive dementia patients were evaluated clinically at a University-based specialty dementia clinic, and a diagnosis of a specific dementia was made. SPECT imaging was used in helping to select a clinical diagnosis. The correlations between clinical, SPECT and autopsy diagnoses were analyzed. RESULTS: Single photon emission computed tomography predicted pathologic diagnosis in 25 of 27 patients with dementia (92.6%), compared with clinical diagnosis, which was confirmed in 20/27 (74.1%). Distinct patterns were associated with dementia caused by AD, Fronto-Temporal Dementia (FTD), and Jakob-Creutzfeldt Disease (JCD). Vascular insults not seen with computerized tomography (CT) or magnetic resonance imaging (MRI) were found with SPECT. Three different pathologies were found in patients with Parkinsonian-Dementias (PD): Lewy-Body Variant of AD, Diffuse Lewy-bodies without plaques, and substantia nigra neuronal loss without plaques or Lewy-bodies. All showed a temporal-parietal pattern with SPECT that was similar to AD. CONCLUSION: SPECT provides useful positive information in dementia, particularly the differentiation of AD, FTD, and JCD. However, it does not distinguish PD from AD.

Adult↗
PubMed1995

Localized in vivo 1H magnetic resonance spectroscopy and in vitro analyses of heterogeneous brain tumors.

Results of magnetic resonance spectroscopic (MRS) studies of the chemical patterns in brain tumors have been inconsistent. Actual biochemical correlations are needed. In 2 patients with heterogeneous intracranial tumors, in vivo 1H MRS and in vitro biochemical analyses were correlated. Histology confirmed the tumor heterogeneity. Choline was elevated in the cellular portion of both tumors but decreased in the necrotic or cystic portions. Creatine was diffusely decreased while lactate was elevated in all regions of both tumors. Furthermore, the increase in the choline peak on 1H MRS appeared to be due to increases in water-soluble choline compounds. This study illustrates the value of small localized voxels for differentiating regional chemical differences in tumors.

Adult↗
PubMed1995

Brain lesions in patients with AIDS: H-1 MR spectroscopy.

PURPOSE: To evaluate the role of proton (hydrogen-1) magnetic resonance (MR) spectroscopy in the differential diagnosis of focal brain lesions in patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Twenty-six men with 35 AIDS-related brain lesions underwent MR imaging and localized H-1 MR spectroscopy. Lesions consisted of 11 toxoplasmic abscesses, 12 progressive multifocal leukoencephalopathic lesions, eight lymphomas, and four cryptococcomas. Metabolite peak areas in the lesions were compared with those in the contralateral hemisphere in each patient. RESULTS: H-1 MR spectroscopic findings showed significantly different biochemical profiles for each diagnostic group (P = .0001) with regard to N-acetyl compounds, total creatine pool, choline-containing compounds, myoinositol, and lactate. H-1 MR spectroscopy alone helped correctly diagnose 94% (84% with jackknifed classification) of the brain lesions, without overlap between toxoplasmosis and lymphoma. CONCLUSION: H-1 MR spectroscopy is a sensitive and potentially specific noninvasive adjunctive method for differential diagnosis of focal brain lesions in AIDS.

AIDS Dementia Complex↗
PubMed1994

Reduction of cerebral blood flow in older depressed patients.

BACKGROUND: We investigated regional cerebral blood flow in older, drug-free depressed patients and examined factors that might be related to rCBF. METHODS: We studied 39 physically healthy depressed patients over the age of 50 years and 20 psychiatrically healthy control subjects. Regional cerebral blood flow was measured with single photon emission computed tomography, using both xenon 133 (to quantify regional cerebral blood flow) and 99mTc-hexamethylpropylene amine oxime (to make regional comparisons). From magnetic resonance imaging, we derived a semiquantitative measure of areas of white matter hyperintensity and a ventricle-to-brain ratio. RESULTS: Patients exhibited a global reduction in regional cerebral blood flow compared with controls, with the orbital frontal and inferior temporal areas affected bilaterally. Regional cerebral blood flow was also reduced in higher brain slices in the right but not the left hemisphere. Significant predictors of lowered regional cerebral blood flow were being depressed, being male, and having a greater ventricle-to-brain ratio. There appeared to be a subgroup of patients who demonstrated large areas of white matter hyperintensity and low regional cerebral blood flow. CONCLUSIONS: Cerebral blood flow was lower in older, medication-free depressed patients than in age-matched control subjects, involved the orbital frontal and anterior temporal regions, and was more reduced in the right hemisphere.

Age Factors↗
PubMed1994

In vivo proton spectroscopy of intracranial infections and neoplasms.

The chemical characteristics of 10 neoplastic and 11 infectious brain masses were studied by in vivo 1H magnetic resonance spectroscopy. In tumors, peak height ratios of n-acetyl-L-aspartate to choline were decreased compared to those in normal brain tissue and infectious masses (p < 0.02), but the ratios in normal brains and those with infections did not differ. N-acetyl-L-aspartate-to-creatine/phosphocreatine ratios were significantly lower in infectious masses and tumors compared to normal brain tissue (p = 0.003). However, in progressive multifocal leukoencephalopathy, N-acetyl-L-aspartate appeared relatively unchanged. Lactate was greater than choline in 9 of 11 brains with infection, 0 of 14 control brains, and 1 of 10 tumors. Lactate-to-choline ratios were significantly elevated in infectious masses compared with tumors (p < 0.01). 1H magnetic resonance spectroscopy is promising for the noninvasive diagnosis of focal brain masses.

Analysis of Variance↗
PubMed1994

Cerebral blood flow changes with acute cocaine intoxication: clinical correlations with SPECT, CT, and MRI.

In summary, these data suggest that widespread primary or secondary cerebral vasoconstriction is common in patients with neurological complications from cocaine. In most patients, SPECT showed wide-spread hypoperfusion in regions that had no clear clinical significance (e.g., the periventricular area). In many, the SPECT was performed more than 24 hours after the onset of neurological symptomatology. These findings raise several questions. It has been assumed that these SPECT changes in patients with acute neurological symptoms are temporary, although it will be important to determine whether these areas of hypoperfusion persist after symptoms have abated. Recently, Holman and colleagues (1991) found multifocal and deep areas of hypoperfusion with SPECT in 16 of 18 patients with a history of chronic cocaine abuse. Although most of the subjects tested positive for cocaine, several had abstained from cocaine use for weeks prior to the study. All 18 subjects had neuropsychological deficits, 13 mild and 5 moderate. Similarly, Pascual-Leone and colleagues (1991) have shown that CT scan atrophy strongly correlates with the duration of cocaine abuse, suggesting that brain injury may occur with continued use of cocaine. It is the authors' concern that cocaine abuse might produce permanent changes in cerebral perfusion. In conclusion, brain SPECT was found to be a useful procedure in the evaluation of acute cocaine intoxication. Brain SPECT revealed focal cortical lesions not seen on head CT or MRI, which corresponded to clinical deficits. In addition, [99mTc]HMPAO brain SPECT had a characteristic scalloped appearance, and this may be a marker for acute intoxication with cocaine. This study further supports the contention that cocaine causes neurological disease by its vasoconstrictive action.

Adult↗
PubMed1993

Brain imaging in late-life schizophrenia and related psychoses.

Despite disagreements about nomenclature, patients who develop schizophrenic or schizophrenia-like symptoms in later life are often seen in clinical practice. Questions about the etiology of late-life psychotic disorders and about their similarities or differences from early-onset disorders remain unanswered. Neuro-imaging techniques have been used to study patients with late onset of psychosis, and in substantial subgroups of patients (from 25% to 100% in various studies) compared with age-matched control subjects, structural and functional abnormalities have been found. We review the literature on imaging in late-life schizophrenia and related psychotic disorders, and we present data from our own investigations of patients with these disorders. We discuss the potential usefulness of imaging evaluations in patients with late-onset disorders, and we offer suggestions for future investigations.

Aged↗
PubMed1993

Cerebral perfusion and neuropsychological consequences of chronic cocaine use.

Research indicates that cocaine significantly constricts the cerebral vasculature and can lead to ischemic brain infarction. Long-term effects of intermittent or casual cocaine use in patients without symptoms of stroke or transient ischemic attack were investigated. Single-photon emission computed tomography with xenon-133 and [99mTc]hexamethylpropyleneamine oxime, magnetic resonance imaging, and selected neuropsychological measures were used to study cerebral perfusion, brain morphology, and cognitive functioning. Patients were drug free for at least 6 months before evaluation. All showed regions of significant cerebral hypoperfusion in the frontal, periventricular, and/or temporal-parietal areas. Deficits in attention, concentration, new learning, visual and verbal memory, word production, and visuomotor integration were observed. This study indicates that long-term cocaine use may produce sustained brain perfusion deficits and persistent neuropsychological compromise in some subgroups of cocaine-abusing patients.

Adult↗
PubMed1992

Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect.

The clinical significance of white-matter lesions (WMLs) detected by computed tomography and magnetic resonance imaging in healthy elderly subjects has been controversial, with some studies reporting associated deficits in cognition and others failing to document cognitive disturbance. In our sample of 100 healthy elderly individuals, almost half (n = 46) had no WMLs, approximately one fourth had minimal (less than or equal to 1 cm2; n = 27) or moderate (greater than 1 cm2 but less than or equal to 10 cm2; n = 21) WML areas, and six subjects had large WML areas (greater than 10 cm2). Substantial disturbances in basic attention and selected frontal lobe skills were detected in the six subjects with the large WML areas. These findings suggest that a "threshold" of WML area must be present before cognitive deficits are observed. Surprisingly, no significant relationships between duration of hypertension or cholesterol levels and WMLs were detected, suggesting that factors other than vascular disturbances are involved in the origin of at least some WMLs.

Aged↗
PubMed1992

Emergency room evaluation of cocaine-associated neuropsychiatric disorders.

The widespread abuse of cocaine has produced an alarming number of cocaine-related emergency room visits in the last several years. The authors discuss the various issues involved in emergency rom evaluation of patients who abuse cocaine and manifest signs and symptoms suggesting neuropsychiatric disease. Appropriate triage is emphasized, and a discussion of impediments to the accurate assessment of these patients ensues. The unique features of cocaine-induced mood, psychotic, and organic disorders are then detailed and contrasted with other functional and organic disorders. Strategies for the emergency room treatment of patients exhibiting symptomatology consistent with cocaine intoxication and withdrawal are outlined. The issues of psychiatric comorbidity and dual diagnosis in the cocaine-abusing population are examined. In addition, the neurological complications associated with the use of cocaine are reviewed. Finally, emerging data from single photon emission computerized tomography (SPECT) analysis of cocaine abusers is reported.

Brain Damage, Chronic↗
PubMed1992

StuA is required for cell pattern formation in Aspergillus.

The stunted (stuA) gene product is required for the orderly differentiation and spatial organization of cell types of the Aspergillus nidulans conidiophore. Expression of the stuA gene is complex. Two transcripts, stuA alpha and stuA beta, are initiated from separate promoters. Transcription of both RNAs increases approximately 50-fold during the establishment of developmental competence. Induction-dependent transcriptional and post-transcriptional regulatory mechanisms further enhance expression 15-fold. Consistent with the latter observation, both transcripts have structural features characteristic of RNAs subject to translational control. Conidiophore morphogenesis requires regulatory interactions between the products of the stuA, bristle (brlA), and abacus (abaA) genes. Enhanced stunted expression is cell type specific and dependent on a functional BrlA protein. StuA affects the spatial localization of AbaA by acting directly, or indirectly, to repress abaA expression.

Amino Acid Sequence↗