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Biomedical subjects

C A Miller

Publications and source records attributed to C A Miller.

At least 73 records · Page 4Linked to original sources
PubMed1998

Therapeutic alternatives in metastatic neuroendocrine tumors.

In the treatment of neuroendocrine tumors that cannot be resected for cure two goals must be addressed: (1) the control of symptoms related to hormonal hypersecretion and (2) the prolongation of survival by destruction of tumor of the limitation of its growth. Clinical approaches, medical and surgical, have been developed in recent years to meet these goals. Surgical options in the face of metastatic disease include resection of hepatic metastases, cryoablation, and liver transplantation. Medical therapy includes treatment of symptomatic hypersecretory states and systemic chemotherapeutic and immunomodulatory regimes. Hepatic artery chemoembolization has also been used successfully in the treatment of hepatic metastases of neuroendocrine tumors.

Adjuvants, Immunologic↗
PubMed1997

Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds.

The human aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator protein (ARNT) were coexpressed in the yeast Saccharomyces cerevisiae to create a system for the study of this heterodimeric transcription factor. Specific transcriptional activation mediated by AHR/ARNT heterodimer, which is a functional indicator of receptor expression, was assessed by beta-galactosidase activity produced from a reporter plasmid. Yeast expressing AHR and ARNT displayed constitutive transcriptional activity that was not augmented by addition of AHR agonists in strains that required exogenous tryptophan for viability. In contrast, strains with an intact pathway for tryptophan biosynthesis responded to AHR agonists and had lower levels of background beta-galactosidase activity. Hexachlorobenzene, benzo(a)pyrene, and beta-naphthoflavone were effective AHR agonists in the yeast system, and had EC50 values of 200, 40, and 20 nM, respectively, for beta-galactosidase activity induction. Tryptophan, indole, indole acetic acid, and tryptamine activated transcription in yeast coexpressing AHR and ARNT (EC50 values approximately 300 microM). Indole-3-carbinol was an exceptionally potent AHR agonist (EC50 approximately 10 microM) in yeast. This yeast system is useful for the study of AHR/ARNT protein complexes, and may be generally applicable to the investigation of other multiprotein complexes.

Antioxidants↗
PubMed1997

Myoclonic epilepsy and ragged red fibers (MERRF) syndrome: selective vulnerability of CNS neurons does not correlate with the level of mitochondrial tRNAlys mutation in individual neuronal isolates.

Selective vulnerability of subpopulations of neurons is a striking feature of neurodegeneration. Mitochondrially transmitted diseases are no exception. In this study CNS tissues from a patient with myoclonus epilepsy and ragged red fibers (MERRF) syndrome, which results from an A to G transition of nucleotide (nt) 8344 in the mitochondrial tRNALys gene, were examined for the proportion of mutant mtDNA. Either individual neuronal somas or the adjacent neuropil and glia were microdissected from cryostat tissue sections of histologically severely affected brain regions, including dentate nuclei, Purkinje cells, and inferior olivary nuclei, and from a presumably less affected neuronal subpopulation, the anterior horn cells of the spinal cord. Mutant and normal mtDNA were quantified after PCR amplification with a mismatched primer and restriction enzyme digestion. Neurons and the surrounding neuropil and glia from all CNS regions that were analyzed exhibited high proportions of mutant mtDNA, ranging from 97.6 +/- 0.7% in Purkinje cells to 80.6 +/- 2.8% in the anterior horn cells. Within each neuronal group that was analyzed, neuronal soma values were similar to those in the surrounding neuropil and glia or in the regional tissue homogenate. Surprisingly, as compared with controls, neuronal loss ranged from 7% of the Purkinje cells to 46% of the neurons of the dentate nucleus in MERRF cerebellum. Thus, factors other than the high proportion of mutant mtDNA, in particular nuclear-controlled neuronal differences among various regions of the CNS, seem to contribute to the mitochondrial dysfunction and ultimate cell death.

Adolescent↗
PubMed1997

A comparison of patients with major depressive disorder recruited through newspaper advertising versus consultation referrals for clinical drug trials.

Difficulties in recruiting patients for clinical trials have plagued investigators for many years. One concern is the generalizability of clinical trial results to community practice, that is, whether volunteers recruited through advertising are homogeneous with those seeking treatment in a clinical setting. This article retrospectively compares the baseline characteristics of patients recruited through newspaper advertisements with those recruited through consultation referrals by reviewing the charts of 54 patients enrolled in two clinical trials for major depressive disorder (MDD). We examined demographic data, background information, clinical histories, and baseline status. Results indicated homogeneity for most variables. The consultation group was significantly more likely to have had previous treatment for the current episode of depression. These results suggest that, although the advertisement and consultation groups were very similar, the drug naivety of the advertisement group may make them a preferred source in terms of generalizability to community practice.

Adult↗
PubMed1997

Fast onset: an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy.

Pindolol, a beta-adrenergic and presynaptic 5-HT1 vA antagonist, when added to specific serotonin reuptake inhibitors, potentiates the antidepressant action, leading to an earlier onset of effect. Following on from the suggestion that nefazodone, a specific serotonin reuptake inhibitor and antagonist of 5-HT2, improves 5-HT1A-mediated transmission, we used a pindolol and nefazodone combination treatment for major depressive disorder. Twenty outpatients underwent a 4-week trial. Patients were seen twice a week, and completed efficacy and safety measures including the 17-item Hamilton Depression Scale, the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression scales. Results demonstrated significant improvement in all efficacy measures after one visit (2-4 days of treatment), with decreasing depression scores on all measures continuing throughout the trial. After 1 week of treatment, 15 out of 20 patients had experienced a 50% or greater reduction in their 17-item Hamilton Depression Scale scores. Remission rates were dramatic, with 40% of patients in remission after 1 week of treatment and 90% after 4 weeks. This open study of nefazodone-pindolol combination therapy suggests that this may be a new treatment option for patients with major depressive disorder; however, it needs to be replicated in a double-blind trial before conclusions regarding efficacy and safety can be made.

Adrenergic beta-Antagonists↗
PubMed1997

A comparison of placebo response with major depressive disorder in patients recruited through newspaper advertising versus consultation referrals.

Recent evidence indicates few differences between patients recruited through advertising and by consultation referral, and there is some suggestion that those recruited through advertising are more representative of the target community population. However little has been reported on differences in placebo response and compliance in these two patient groups. We conducted a retrospective chart review of 49 patients with major depressive disorder (MDD), recruited through advertising or consultation, randomized to placebo in five clinical trials. Variables included demographics, clinical history, efficacy, compliance, and completion data. Homogeneity was demonstrated for most variables. Differences in placebo groups included significantly lower Hamilton Rating Scale for Depression (HAM-D) scores for the advertisement group throughout the trials. Advertisement patients were also more likely to be early placebo responders and in remission at Days 14 and 28. No differences were found in completion rates or reasons for early termination. Compliance was excellent for both groups. Early placebo response of the advertisement group reinforces the need for trials of at least 8 weeks. In addition, consultation patients may have a more severe illness and be treatment resistant, suggesting they are less generalizable to community practice populations.

Adult↗
PubMed1996

Prostanoid receptors of murine NIH 3T3 and RAW 264.7 cells. Structure and expression of the murine prostaglandin EP4 receptor gene.

Prostaglandin endoperoxide H synthase-1 (PGHS-1) is expressed constitutively in murine NIH 3T3 cells and RAW 264.7 cells. PGHS-2 is inducibly expressed in these cells following stimulation with serum or bacterial lipopolysaccharide (LPS), respectively. Reverse transcription-polymerase chain reaction (RT-PCR) analysis established that a variety of G protein-linked and peroxisomal proliferator-activated prostanoid receptors are expressed in both of these cell types. The levels of the EP2 and EP4 prostaglandin E2 (PGE2) receptors and the prostaglandin I2 receptor were changed in these cells by serum or LPS stimulation. Quantitative RT-PCR indicated that the mRNA for the murine EP4 receptor, the butaprost-insensitive PGE2 receptor that couples to Gs, increases 1.5-3-fold in response to serum (NIH 3T3) or LPS (RAW 264.7) with a time course approximating the induction of PGHS-2 expression. To study expression of the EP4 receptor we isolated the mouse EP4 receptor gene; the gene is 10 kilobase pairs (kb) in length and, like other known prostanoid receptor genes, contains three exons and two introns. The first intron is 0.5 kb and is located 16 base pairs (bp) downstream of the translational start site. This is a different location than that of the first introns of other prostanoid receptor genes. The second intron is located immediately following the sixth transmembrane domain at the same position as the second intron of the thromboxane A2 receptor, prostaglandin D2 receptor, prostaglandin I2 receptor, and one of the PGE2 (EP1) receptor genes. A major transcriptional start was detected at -142 bp upstream of the translational start. There are a variety of putative cis-acting elements within 1.5 kb upstream of the translational start site and within the first intron. Promoter analyses of the EP4 receptor gene promoter in RAW 264.7 cells indicated that there is a constitutive negative regulatory region between -992 and -928 bp, a constitutive positive region between -928 and -554 bp, and an LPS/serum-responsive region between -554 and -116 bp.

3T3 Cells↗
PubMed1996

Determination of the step duration of gait initiation using a mechanical energy analysis.

The analysis of gait initiation (the transient state between standing and walking) is an important diagnostic tool in the study of pathologic gait and the evaluation of prosthetic devices. Therefore it is important to know the step duration of gait initiation. However, there is little agreement in the literature regarding this step duration, since each author has based their conclusion on a different biomechanical parameter. In this study, gait initiation in seven normal subjects was studied using a mechanical energy analysis. The number of steps necessary to reach steady state was determined based on the fact that in steady-state gait, the net mechanical work of the body over one stride is zero (Winter et al. J. Biomechanics 9, 253-257, 1976). The variance of the work for a stride during steady-state walking was calculated for 100 steady-state trials from a separate database of normal subjects. The stride work was normalized to the subject's body weight (BW) and leg length (LL), and 95% confidence limits were defined from this data at -1.68%BW * LL < epsilon < 1.28%BW * LL. Total body energy during gait initiation was then computed for the seven test subjects. The energy analysis of gait initiation showed that steady state was attained by the end of three full steps. Therefore, a researcher studying gait initiation must allow his/her subject to take three full steps when recording data to ensure that the full event is included.

Adult↗
PubMed1996

Developmental expression in the mouse nervous system of the p493F12 SAP kinase.

Mitogen-activated protein (MAP) kinases are proline-directed, serine/threonine kinases that respond to a variety of extracellular signals. A subgroup of these kinases, stress-activated protein (SAP) kinases, phosphorylate c-jun in response to cellular stress. Using monoclonal antibody (MAb) 3F12, we have cloned and partially characterized p493F12 kinase, a mouse homologue of the rat SAP beta kinase and described its expression in the adult and developing mouse. Unlike previously reported MAP and SAP kinases, it is primarily expressed as a 2.7 kb transcript in neurons in the nervous system of the adult mouse. A 2.4 kb transcript is also expressed in the testis. Immunocytochemically, MAb 3F12 decorates a loop-like structure encircling the nucleus in the cytoplasm of neurons in the adult brain, and distinct perinuclear dots in the embryos. In situ hybridization first reveals expression in post-mitotic neurons, on embryonic day 11. The mRNA is also expressed in the Neuro-2A neuroblastoma cell line and is not upregulated in response to differentiating agents. The neuronal specificity of this kinase suggests the presence of a signal transduction cascade unique to neurons. As the amino acid sequence is highly conserved in the human and mouse, the latter may serve as a model for regulation and expression of this kinase.

Aging↗
PubMed1996

Matrix metalloproteinases in the neocortex and spinal cord of amyotrophic lateral sclerosis patients.

Matrix metalloproteinases (MMPs) were analyzed by immunohistochemistry and zymography in amyotrophic lateral sclerosis (ALS) and control brain and spinal cord specimens. Three major bands of enzyme activity (70, 100, and 130 kDa) were consistently observed and were subsequently identified as MMP-2 (70 kDa; also known as EC 3.4.24.24 or gelatinase A) and MMP-9 (100 and 130 kDa; also known as EC 3.4.24.35 or gelatinase B). Immunohistochemical studies established the presence of MMP-2 in astrocytes and MMP-9 in pyramidal neurons in the motor cortex and motor neurons in the spinal cord of ALS patients. Although a significant decrease in MMP-2 activity was noticed in the ALS motor cortex, statistically significant increases in MMP-9 (100-kDa) activity were observed in ALS frontal and occipital cortices (BA10 and 17) and all three spinal cord regions when compared with control specimens. The highest MMP-9 (100-kDa) activities in ALS were found in the motor cortex and thoracic and lumbar cord specimens. The abnormally high amount of MMP-9 and its possible release at the synapse may destroy the structural integrity of the surrounding matrix, thereby contributing to the pathogenesis of ALS.

Aged↗
PubMed1996

Temporal bone findings in Alzheimer's disease.

Sensorineural hearing loss has been reported in Alzheimer's disease (AD) and a topographically specific pattern of degeneration in the central auditory system has been described. Although peripheral visual and olfactory systems have been extensively studied, there is no report of peripheral auditory system abnormalities in AD patients. Comparison of temporal bones from eight AD patients with those from eight non-AD controls revealed a significant difference in the percentage of remaining hair cells, peripheral processes, and spiral ganglion cells in the basal cochlear turn but no significant differences in the overall percentage between the two groups. Furthermore, special stains (thioflavin S and Bielschowsky's silver impregnation) of temporal bone nervous tissue from AD patients did not show neuritic plaques and neurofibrillary tangles. It is unclear whether the differences between the two groups in the basal portion of the cochlea are due to AD or some other process, such as presbycusis. However, lack of significant degeneration in other parts of the cochlea and absence of neurofibrillary tangles and neuritic plaques in all eight patients may suggest that the peripheral auditory system, unlike the peripheral visual and olfactory systems, is not involved in AD. A larger sample of AD patients is necessary to clarify the peripheral auditory system findings in the present study.

Aged↗
PubMed1996

Performing public health functions: the perceived contribution of public health and other community agencies.

As public health struggles to define its role within health care reform, the need to examine carefully the component organizations providing and/or supporting health care for the public appears critical. This article identifies the nature and extent of involvement by agencies other than the official local public health department in performing public health practices and functions within 63 local public health jurisdictions. Adequacy of overall public health performance is significantly related to the extent of participation of outside agencies. Outside agencies contribute over 26 percent to the total public health performance for the jurisdictions surveyed. Other agencies of government, both at the state and local level, are the predominant outside contributors to public health practice. Private and voluntary agencies are perceived as minor contributors. Little variation exists among communities in which outside agencies tend to perform particular public health activities. Findings suggest that local public health departments can maximize their impact by understanding better the nature of working relationships within multi-institutional arrangements, encouraging greater levels of collaboration and integration and acting as catalysts for increased support of public health activities.

Community Health Centers↗
PubMed1995

Calcitonin gene-related peptide (CGRP) upregulates the restitution of rat gastric mucosa in vitro.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with many significant effects on gastrointestinal function. Among these are gastroprotective effects such as inhibition of acid secretion and increase in gastric mucosal blood flow. To evaluate whether CGRP has a direct protective effect on gastric mucosa, we examined the influence of the peptide on restoration of mucosal integrity following mild damage. Mucosal integrity was assayed by measurement of the transmucosal potential difference of tissue mounted in an Ussing chamber perfusion system. Undamaged mucosa maintained a potential difference of approximately -64 mV in both control tissues and tissues serosally treated with CGRP. Damage was induced by exposure of the gastric mucosa to solutions of 0.5, 1.0, and 2.0 M sodium chloride. Each of the hyperosmolar solutions caused mucosal injury as evidenced by a rapid decrease in PD, with the most concentrated solution causing the greatest decrease and the slowest and least complete recovery. CGRP treatment led to a significantly more complete recovery of PD when injury was caused by 0.5 M but not by either 1.0 or 2.0 M NaCl. We conclude that CGRP is capable of directly enhancing recovery of mucosal integrity after mild but not severe damage of rat gastric mucosa in vitro.

Animals↗