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Biomedical subjects

M A Miller

Publications and source records attributed to M A Miller.

At least 109 records · Page 6Linked to original sources
PubMed1999

A syngeneic mouse glioma model for study of glioblastoma therapy.

Animal models of human tumors serve a vital role in the development and testing of new anticancer therapies. Since the immune system is likely to play an essential role in tumor eradication, there is a particular need for modeling human disease in immunocompetent hosts. Few models of glioma have been developed in immunocompetent mice that are commercially available and none of these tumors have histological and antigenic characteristics of human gliomas. We have used a cell line, 4C8, derived from a spontaneous glioma-like tumor that arose in a transgenic mouse to develop a new glioma model. The intracranial injection of 4C8 cells into immunocompetent syngeneic B6D2F1 mice resulted in tumors that were densely cellular, developed a pseudopallisading pattern of necrosis, and expressed GFAP; all important features of human malignant gliomas. The average neurological endpoint was 51 days after intracranial injection. The 4C8 cells also grew rapidly in the flank, retaining histologic features seen in intracranial tumors. Flank tumors reached an average volume of 100 mm3, a volume ideal for therapy testing, by 34 days postinjection. These results suggest that the 4C8 mouse glioma model is an excellent system in which to test new antiglioma therapies for use in humans.

Animals↗
PubMed1999

Management implications of evaluating the N2 and N3 neck after organ preservation therapy.

OBJECTIVES/HYPOTHESIS: To determine if metastatic squamous cell carcinoma with proliferative potential persists in N2 and N3 necks after conventional radiation. STUDY DESIGN: Retrospective case series. MATERIALS AND METHODS: We identified 17 patients from our head and neck tumor database who underwent organ-preserving radiotherapy for primary aerodigestive squamous cell cancer and N2-3 regional metastasis. Archival tissue from these 17 neck specimens was evaluated for routine histopathologic evidence of tumor, as well as immunohistochemically for cytokeratin and Ki-67 activity. An assay for apoptosis was also performed on 10 of the specimens. RESULTS: Routine H&E evaluation suggested metastatic cancer in 11 of 17 irradiated neck specimens. Cytokeratin immunostaining confirmed squamous cell carcinoma in these 11 necks as well as 1 additional specimen that had tested H&E negative. Ki-67 staining demonstrated proliferating tumor in 3 of 17 necks. The apoptosis assay confirmed regions of apoptosis in all of the specimens analyzed. CONCLUSIONS: The discovery of proliferating cancer cells in 3 of 17 irradiated specimens (18%) supports the practice of planned neck dissection after primary radiotherapy for patients with pretherapeutic N2+ metastatic disease.

Apoptosis↗
PubMed1999

Evaluation of meningococcal meningitis vaccination strategies for the meningitis belt in Africa.

BACKGROUND: Although the meningococcal polysaccharide vaccine has contributed to the control of Group A meningitis in the "meningitis belt" of Africa, recurrent large outbreaks have led to questions regarding vaccination strategy. We evaluated current and hypothetical vaccination strategies for the region. METHODS: A model was formulated to analyze the effectiveness and costs of vaccine campaigns in response to outbreaks based on 7 years of weekly incidence data from Burkina Faso. Additional models analyzed the potential impact and costs of either a 1- or 4-dose routine scheduled delivery of meningococcal polysaccharide vaccine based on data reported to the World Health Organization from 16 countries during 1948 through 1996. Vaccine efficacy, vaccination coverage and economic data from literature reviews provided model assumptions. RESULTS: For Burkina Faso neither 1- nor 4-dose vaccination schedules would prevent >30% of meningitis cases compared with the 42% prevented through an outbreak response program of vaccinating districts, which reach an incidence of 15 per 100000 persons for 2 weeks. For the entire meningitis belt, routine coverage with the 1- or 4-dose schedule meningococcal vaccine would require 4.9 and 19.6 million doses annually, respectively, for an annual net cost of $4.4 to $12.3 million and prevent an average 10300 to 12600 cases (23 to 28%), assuming a long term vaccine efficacy of 50%. In addition an initial "catch-up" campaign costing up to $72 million to vaccinate the population from 1 to 30 years of age would be required before achieving that level of effectiveness. CONCLUSION: Given the relatively poor routine vaccination coverage in this region, current strategies of vaccination campaigns that achieve higher coverage would generally be more effective and less costly than the modeled routine scheduled programs, assuming that campaigns can be rapidly implemented. Until a better vaccine is available, countries in this region would be more efficient in improving the response times to outbreaks, perhaps through improved surveillance, and in bolstering existing vaccination infrastructures rather than embarking on strategies of questionable effectiveness.

Africa↗
PubMed1999

Structural relaxation in atomic clusters: master equation dynamics.

The role of the potential energy landscape in determining the relaxation dynamics of model clusters is studied using a master equation. Two types of energy landscape are examined: a single funnel, as exemplified by 13-atom Morse clusters, and the double funnel landscape of the 38-atom Lennard-Jones cluster. Interwell rate constants are calculated using Rice-Ramsperger-Kassel-Marcus theory within the harmonic approximation, but anharmonic model partition functions are also considered. Decreasing the range of the potential in the Morse clusters is shown to hinder relaxation toward the global minimum, and this effect is related to the concomitant changes in the energy landscape. The relaxation modes that emerge from the master equation are interpreted and analyzed to extract interfunnel rate constants for the Lennard-Jones cluster. Since this system is too large for a complete characterization of the energy landscape, the conditions under which the master equation can be applied to a limited database are explored. Connections are made to relaxation processes in proteins and structural glasses.

Journal Article↗
PubMed1999

Simple strategy for direct identification of medically important yeast species from positive blood culture vials.

We compared direct inoculation of the Auxacolor yeast identification system from positive blood culture vials to standard identification with the API 20C AUX (API 20C), using 44 prospectively collected clinical specimens and 25 seeded blood culture vials. Direct inoculation of the Auxacolor system was accurate and more rapid than standard identification with the API 20C.

Blood↗
PubMed1999

Epithelial sodium channel activity is not increased in hypertension in whites.

Abnormal renal sodium transport causing excess reabsorption of sodium may be one mechanism that causes high blood pressure. For example, increased activity of epithelial sodium channels in the distal tubule is the cause of high blood pressure in Liddle's syndrome, a rare familial form of hypertension. We have shown that the increase in sodium channel activity can be detected in the nose using transepithelial potential difference measurements in 1 family with Liddle's syndrome. We therefore used nasal potential difference measurements to look for increased sodium channel activity in white patients with essential hypertension. Transnasal potential difference was measured in 42 white hypertensive (HT) subjects and 38 white normotensive (NT) subjects before and after topical application of 10(-4) mol/L of amiloride. There was no difference in maximum potential between HT and NT subjects (HT, -18.8+/-0.9 mV; NT, -18.2+/-1.0 mV) (values mean+/-SEM; lumen-negative with respect to the submucosa). However, the postamiloride potential was significantly higher (HT, -12.6+/-0.7 mV; NT, -10.5+/-0.7 mV; P=0. 015) and the change in potential in response to amiloride significantly lower (HT, 6.2+/-0.5 mV, 33.1+/-2.0%; NT, 7.7+/-0.6 mV, 41.9+/-2.0%; P=0.046 and 0.003, respectively) in HT than in NT subjects. These results suggest that sodium channel activity is not increased in whites with essential hypertension and indicate that sodium channel overactivity similar to that seen in Liddle's syndrome is unlikely to be the cause of high blood pressure in this group. Increased postamiloride potential may reflect increased activity of chloride channels or amiloride-insensitive sodium channels.

Adult↗
PubMed1999

Inflammatory pseudotumor in a cat with cutaneous mycobacteriosis.

A 5-year-old, castrated male, domestic Shorthair Cat had an ulcerated mass with fistulous tracts on the left hind paw. Homogeneous tan tissue diffusely infiltrated the dermis and subcutis of the paw and extended proximally so that, short of amputation, complete excision was not feasible. Biopsy specimens consisted of granulation tissue with marked proliferation of spindle cells. Neutrophils and histiocytic cells were scattered among the spindle cells. The histiocytic cells had abundant foamy or vacuolated cytoplasm, but features of granulomatous inflammation, such as epithelioid macrophages or granuloma formation, were not observed. The initial impression was inflammatory granulation tissue, but the degree of fibroplasia prompted inclusion of fibrosarcoma in the differential diagnosis. Cutaneous mycobacteriosis was diagnosed when numerous acid-fast bacteria were identified with Kinyoun's stain; Mycobacterium avium was subsequently cultured. The cat was euthanatized because of lack of response to enrofloxacin therapy. At necropsy, lesions were localized to the hind limb. Not only is mycobacteriosis an uncommon cause of cutaneous masses in cats, but this case was unusual because of the lack of granuloma formation and the similarity of the mass to a spindle cell tumor.

Animals↗
PubMed1999

Isolation and characterization of polyethylene wear debris associated with osteolysis following total shoulder arthroplasty.

We evaluated the interface membranes surrounding three total shoulder prostheses that had been removed because of progressive aseptic loosening associated with osteolysis. The mean time between the uncomplicated initial arthroplasty and the revision procedure was twelve years (10.5, 10.5, and 16.0 years). Membranes from around both the humeral and the glenoid component were obtained from all three shoulders and were studied histologically to determine the biological response involved in the development of aseptic loosening. For the purpose of comparison, periprosthetic tissue was also obtained from the sites of four failed total hip prostheses that were associated with osteolysis. Polyethylene particles were retrieved with an enzymatic digestion technique that involved the use of papain. Raman vibrational spectroscopy verified that the particles were ultra-high molecular weight polyethylene. The particles were isolated from the tissue, and a computerized image-analysis system characterized 582 of them in terms of size and morphology. Each particle was defined with the use of six shape descriptors: equivalent circle diameter, roundness, form factor, aspect ratio, elongation, and outline fractal dimension. The particles from the hips had a mean equivalent circle diameter (and standard error of the mean) of 0.62 +/- 0.03 micrometer, were predominantly globular in shape, and had low mean values for aspect ratio (1.46 +/- 0.02) and elongation (1.85 +/- 0.03) and relatively high values for roundness (0.74 +/- 0.01) and form factor (0.87 +/- 0.01). In contrast, the particles from the shoulders had a mean equivalent circle diameter of 1.04 +/- 0.03 micrometers. In addition, they had relatively high values for aspect ratio (2.36 +/- 0.07) and elongation (4.96 +/- 0.23) and correspondingly low values for roundness (0.54 +/- 0.01) and form factor (0.67 +/- 0.01), indicating that they were more fibrillar in shape. The particles from the shoulders and those from the hips were significantly different (p < 0.0001) with respect to all of the descriptors except outline fractal dimension. The particles from the shoulders, in general, were larger and more fibrillar than the particles from the hips.

Aged↗
PubMed1999

Overexpression of transforming growth factor-alpha and epidermal growth factor-receptor in idiopathic pulmonary fibrosis.

BACKGROUND AND AIM: A recent transgenic mouse model overexpressing transforming growth factor alpha (TGF-alpha) led to a phenotype of pulmonary fibrosis. In order to validate this mouse as a model for idiopathic pulmonary fibrosis in humans, we studied the expression of TGF-alpha in lung tissue of patients with idiopathic pulmonary fibrosis compared to control lung tissue. METHODS: Tissue from both groups was obtained from operative specimens and immediately formalin-fixed and paraffin embedded. Contiguous four micron sections were prepared for conventional histochemical staining and staining with antibodies to either TGF-alpha or the epidermal growth factor-receptor (EGF-R). Immunostaining was performed using the Ventana ES automated immunohistochemistry system. Four cell types were examined (vascular endothelium, bronchial epithelium, type 2 pneumocytes, and fibroblasts) and stain activity was scored on a six point scale. RESULTS: Eleven patients with IPF were compared to seven control subjects. TGF-alpha immunoreactivity was significantly higher in the IPF patients than in controls in the vascular endothelium, type 2 pneumocytes, and fibroblasts (P < 0.005). [IPF (4(2-4) Median (Range)) than the controls (0.5(0-2), p < 0.0005).] The differences in EGF-R, one of the receptors for TGF-alpha, between these two patient populations were not as striking. There was a small but significantly greater expression of EGF-R in the bronchial epithelium and type 2 pneumocytes of the IPF patients. CONCLUSIONS: TGF-alpha is overexpressed in patients with IPF, especially in the vascular endothelial cells.

Adult↗
PubMed1999

Preservation of noradrenergic neurons in the locus ceruleus that coexpress galanin mRNA in Alzheimer's disease.

Galanin (GAL) innervation is hypertrophied in the basal forebrain and cortex of patients with Alzheimer's disease (AD). Increased GAL could exacerbate the cognitive and behavioral deficits of AD because GAL acts as an inhibitory modulator of cholinergic and noradren-ergic neurotransmission. The locus ceruleus (LC) may be a source of increased GAL in AD because (a) GAL is coexpressed in a subset of LC neurons, (b) GAL expression is up-regulated with neuronal injury, and (c) the LC undergoes extensive degeneration in AD. Therefore, we have used in situ hybridization histochemistry to measure GAL gene expression in the LC of AD patients and sex- and age-matched nondemented controls. Despite the extensive loss of norepinephrine neurons with AD, GAL mRNA-expressing neurons in the LC did not differ between groups. This resulted in a significant increase in the percentage of neuromelanin-pigmented cells that coexpressed GAL in AD patients compared with controls. These findings raise the possibility that the increased incidence of GAL expression among remaining LC neurons contributes to the hyperinnervation of GAL fibers in AD. Furthermore, GAL may be neuroprotective in the LC.

Aged↗
PubMed1999

Angiogenic growth factors in preinvasive breast disease.

Recently, we showed that preinvasive breast pathologies, such as usual hyperplasia, atypical hyperplasia, and carcinoma in situ, have an increased vascularity when compared with normal breast tissue (S. C. Heffelfinger et al., Clinical Cancer Res., 2: 1873-1878, 1996). To understand the mechanism of this increased vascularity, we examined by immunohistochemistry each of these pathological lesions for the expression of angiogenic growth factors. These studies showed that normal breast tissue contains numerous angiogenic agents, particularly vascular endothelial cell growth factor and basic fibroblast growth factor. At the transition from normal epithelium to proliferative breast disease, insulin-like growth factor (IGF) II expression was increased, primarily in the stroma and infiltrating leukocytes. However, among proliferative tissues, IGF I decreased with increasing vascularity. Finally, both epithelial vascular endothelial growth factor and epithelial and leukocytic platelet-derived endothelial cell growth factor increased at the transition to carcinoma in situ, whereas stromal and leukocytic basic fibroblast growth factor were elevated only in invasive carcinoma. Therefore, during histological progression there is also a complex progression of angiogenic growth factors. For CIS, two forms of vascularity are found: stromal microvascular density (MVD), and vascularity associated with the epithelial basement membrane (vascular score). There was 35% discordance between these two measurement systems. Among carcinoma in situ cases, decreases in stromal IGF II were associated with increasing vascular scores but not MVD, and increases in platelet-derived endothelial cell growth factor were associated with increasing MVD but not the vascular score. The presence of discordance and differential association with specific angiogenic agents suggests that these two forms of vascularity may be differentially regulated.

Angiogenesis Inducing Agents↗
PubMed1999

The cost of unsafe injections.

Unsafe injection practices are associated with substantial morbidity and mortality, particularly from hepatitis B and C and human immunodeficiency virus (HIV) infections. These inadvertently transmitted bloodborne diseases become manifest some considerable time after infection and hence may not be appropriately accounted for. Annually more than 1.3 million deaths and US$ 535 million are estimated to be due to current unsafe injection practices. With the global increase in the number of injections for vaccination and medical services, safer injecting technologies such as auto-disable syringes must be budgeted for. Investment in health education and safer disposal will also reduce infections associated with unsafe injecting practices. Safer injecting practices are more expensive than current less safe practices, but the additional cost is more than offset by the reduction in disease that would result.

Cross Infection↗
PubMed1999

p53 immunoreactivity and single-strand conformational polymorphism analysis often fail to predict p53 mutational status.

The intent of this study was to investigate the ability of p53 expression and single-strand conformational polymorphism analysis (SSCP) to predict p53 mutational status in archival, paraffin-embedded tissues of gastric cancer. We evaluated paraffin-embedded tissues from 78 patients with advanced gastric cancer. The mutational status of the p53 gene (exons 5-9) was examined by SSCP analysis and by direct sequencing. These results were compared with p53 expression as assessed by immunohistochemical analysis (IHC). We graded p53 expression on a scale from 0 to 8 on the basis of both the intensity and the number of cells staining. Overall, we detected p53 immunoreactivity in 75.6% of the gastric cases; 19 (32.2%) of these cases scored from 1 to 4, and 40 (67.8%) cases scored from 5 to 8. p53 gene mutations were detected in 18 cases (23.1%) by SSCP and in 28 cases (36%) by direct sequencing. Thus, SSCP failed to detect 38% of the mutations found by sequencing. The majority of missed mutations involved exons 7 and 8. The concordance between IHC and SSCP was 37%, and the concordance between IHC and direct sequencing was 50%. Forty-five percent of cases positive by IHC failed to show mutations in exons 5 through 9. Five percent of cases negative by IHC (4 cases) contained mutations. One had a 1-base pair insertion; one had a mutation that resulted in a stop codon; the third had a mutation in exon 8; and the fourth had a mutation in both exons 5 and 8. Our findings indicate that p53 immunoreactivity correlates with the presence or absence of gene mutations in 50% of advanced gastric cancers when exons 5 through 9 are examined and that IHC cannot be reproducibly used as a marker of mutation in the most commonly mutated exons of the p53 gene. Furthermore, the sensitivity of SSCP for detecting mutations is only 62%. Thus, SSCP analysis cannot be used reliably to screen for p53 mutations.

Base Sequence↗
PubMed1998

Regulation of galanin in memory pathways.

Based on early immunocytochemical findings, galanin (GAL) was postulated to function as an inhibitory cotransmitter in rat cholinergic memory pathways. However, recent studies indicate that in the basal state GAL is not widely expressed by forebrain cholinergic neurons in rats. Inhibition of cholinergic transmission by cosecreted GAL may be enhanced under certain conditions, because GAL gene expression in the cholinergic basal forebrain is significantly increased prior to puberty and following nerve growth factor treatment. Other sources of GAL in rat septohippocampus that could interact with cholinergic pathways include noradrenergic neurons in the locus ceruleus and vasopressinergic neurons in the bed nucleus of the stria terminalis (BST) and medial amygdala (Me). GAL is extensively colocalized within these steroid-sensitive cell groups where its expression is upregulated by gonadal hormones. GAL, acting via the GALR1 receptor subtype, does not appear to directly regulate the activity of cholinergic neurons, but it may regulate the release of vasopressin and GAL into septohippocampus from BST/Me neurons.

Animals↗