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Biomedical subjects

M A Miller

Publications and source records attributed to M A Miller.

At least 163 records · Page 9Linked to original sources
PubMed1997

Amplification and expression of the cyclin D1 gene in anal and esophageal squamous cell carcinomas.

Cyclin D1 is a cell-cycle regulator and candidate proto-oncogene implicated in the pathogenesis of numerous tumor types. Amplification of the cyclin D1 gene occurs commonly in esophageal squamous cell carcinomas. However, no studies have examined the role of cyclin D1 in anal carcinogenesis. We examined 20 esophageal squamous cell carcinomas and 24 anal carcinomas for cyclin D1 alterations. Protein expression was evaluated by immunohistochemistry using the cyclin DIGM antibody (Novocastra, Newcastle upon Tyne, UK). Cyclin D1 amplification was examined by fluorescent in situ hybridization (FISH), using a cyclin D1 probe obtained from Toshiya Inaba at St. Jude Children's Research Hospital, Memphis, TN. The FISH sections were analyzed using a Leica (Deerfield, IL) confocal microscope. By immunohistochemistry, 75% of esophageal carcinomas showed evidence of cyclin D1 expression. Cyclin D1 amplification was detected by FISH in 65% of esophageal cancers. There was good correlation between cyclin D1 protein expression and gene amplification, although some tumors showed protein overexpression in the absence of gene amplification. Among the 24 anal carcinomas studied, 8% showed weak cyclin D1 immunoreactivity in rare tumor cells. None of the anal tumors showed cyclin D1 amplification. We conclude that cyclin D1 alterations are common in esophageal carcinomas but do not appear to be important in anal carcinogenesis. Immunohistochemical detection of cyclin D1 protein overexpression is a good predictor of cyclin D1 amplification.

Anus Neoplasms↗
PubMed1997

Plasma levels of parathyroid hormone that induce anabolic effects in bone of ovariectomized rats can be achieved by stimulation of endogenous hormone secretion.

Parathyroid hormone (PTH) administration increases bone mass in normal and osteopenic animals. However, this treatment currently requires the daily injection of large amounts of PTH, and the relationship of these doses to plasma levels of PTH that are achievable physiologically is unknown. We determined in ovariectomized (ovx) rats: 1) the plasma PTH levels that occur after the subcutaneous injection of graded doses of rat PTH, 2) whether similar PTH levels can be achieved by stimulation of endogenous PTH secretion, and 3) whether a plasma PTH profile that is achievable physiologically is anabolic on bone. Injection of 1, 5, or 25 micrograms/kg rat PTH-(1-34) increased plasma PTH by 46, 164, or 520 pg/mL, respectively, above basal levels within 60 min. Infusion of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid for 2 h reduced plasma Ca2+ by 0.36 mmol/L and produced a total plasma PTH response (area under the plasma PTH curve) similar to that with the 5 micrograms/kg rat PTH injection. Then, 1, 5, or 25 micrograms/kg doses of rat PTH-(1-34) were injected subcutaneously daily for 28 days in 19-week-old rats that were ovx 7 weeks earlier. The 5 and 25 micrograms/kg doses significantly increased bone mineral density in the distal femur and trabecular bone area and average trabecular thickness in the proximal tibia. All doses of PTH significantly increased indices of trabecular connectivity and cancellous bone formation, including double-labeled surface, mineralizing surface, and surface-referent bone formation rate. In conclusion, anabolic effects on bone can be achieved with a plasma PTH profile similar to that attained following stimulation of the parathyroid gland by induced hypocalcemia. These data suggest that agents that transiently increase endogenous PTH secretion may represent a novel means to promote anabolic effects in skeletal tissues.

Absorptiometry, Photon↗
PubMed1997

Comparison of scintigraphy and lactulose breath hydrogen test for assessment of orocecal transit: lactulose accelerates small bowel transit.

UNLABELLED: The lactulose breath test (LBT) and gastroenterocolonic scintigraphy (GECS) can both be used to measure orocecal transit time (OCTT). The aims of this study were (1) to measure OCTT by LBT and GECS and (2) to determine whether lactulose alters orocecal transit. METHODS: Eight normal subjects underwent simultaneous breath hydrogen testing, GECS, and duodenal manometry while receiving either 10 g lactulose or placebo with a radiolabeled solid/liquid test meal during two studies. There was a good correlation between OCTT by LBT and GECS when performed simultaneously (r = 0.95; P < 0.001). OCTT by GECS with lactulose was significantly faster (P = 0.004) than by GECS without lactulose, despite no change in gastric emptying of liquids and slowing of gastric emptying of solids (P = 0.02). The postprandial duodenal motility index was greater with lactulose than with placebo (P = 0.031). This study demonstrates that LBT and GECS (without lactulose) are not equivalent measures of OCTT. The standard LBT accelerates OCTT and slows gastric emptying. Therefore, lactulose has a direct accelerating effect on small intestinal transit.

Adult↗
PubMed1997

Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro.

OBJECTIVE: To investigate further the mechanisms of action of sildenafil, a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase (PDE5) that has proved effective in the treatment of erectile dysfunction, by assessing its effect on the in vitro formation of cGMP and cAMP in the corpus cavernosum of the rabbit. MATERIALS AND METHODS: Male New Zealand White rabbits (2.5 kg) were killed and their penises rapidly excised, cut into segments and pooled. Penile segments were then incubated with various concentrations of sildenafil or papaverine. The formation of cGMP was stimulated with increasing concentrations of sodium nitroprusside (SNP) and the cGMP and cAMP concentrations measured by radioimmunoassay. Responses were compared to those obtained with papaverine, which is used therapeutically as an erectogen. RESULTS: In the presence or absence of SNP, sildenafil increased cGMP concentrations in rabbit penile tissue with increasing dose; the increase was greatest (about 28-fold) when cGMP was stimulated with SNP (up to 10 mumol/L). At all stimulatory concentrations of SNP, the effective concentrations for 50% stimulation (EC50) of sildenafil were 430-520 nmol/L. Concentrations of cAMP were unaltered by sildenafil. Papaverine enhanced cGMP formation in response to SNP, but at much higher concentrations than did sildenafil (> or = 10 mumol/L). CONCLUSIONS: Sildenafil specifically increases cGMP levels in rabbit corpora cavernosa; the increase is greater in the presence of SNP indicating that, in vivo, sildenafil may enhance erection by the augmentation of nitric oxide-mediated relaxation pathways. The erectogenic effect of sildenafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known activity of sildenafil as a potent and highly selective inhibitor of cGMP-specific PDE.

Animals↗
PubMed1997

Severe hypospadias with genital ambiguity: adult outcome after staged hypospadias repair.

OBJECTIVE: To obtain the long-term follow-up information on children born with severe perineoscrotal hypospadias associated with genital ambiguity who underwent a staged surgical correction of their hypospadias and were raised as males. PATIENTS AND METHODS: The study comprised patients who had undergone a surgical correction of hypospadias before 1978 and were traced successfully. Postal questionnaires which were completed and returned by 19 patients and 28 general practitioners (GPs) were evaluated; in addition, nine cases were clinically reviewed. RESULTS: Of the 19 patients who completed and returned the questionnaire, four were married or living with a partner and 12 had had intercourse, with debut at a median age of 17 years. Satisfactory erection and orgasm were reported by 15 men but only seven had satisfactory ejaculation. Nine men had continued difficulties with micturition and urological function. Four men considered that their psychological well-being and quality of life had been markedly impaired by their condition and two other men had evidence of mild depression. Nine patients did not complete the questionnaires but allowed their GPs to provide information about them; only one was reported to have marked psychological impairment and impaired general health. Two of the patients who did not participate in the study are known to have significant psychiatric problems. CONCLUSIONS: Staged hypospadias repair in men with severe perineoscrotal hypospadias is associated with continued difficulty with both ejaculation and micturition, but is not usually associated with major psychiatric or psychological disturbance. The findings indicate the importance of follow-up in adolescence and adult life with adequate counselling when necessary.

Adolescent↗
PubMed1997

Electrogastrography and gastric emptying scintigraphy are complementary for assessment of dyspepsia.

We have tried to correlate abnormalities in electrogastrography (EGG) and gastric emptying (GE) with symptom severity in patients with functional dyspepsia. Seventy-two patients with functional dyspepsia underwent EGG, GE, and symptom severity quantitation. EGGs were assessed for dominant frequency (DF), percentage of time of DF in the 2 to 4 cpm range, and postprandial-fasting DF power ratio. Solid-phase GE scintigraphy was assessed for 2-hour percentage retention. Symptoms of upper abdominal discomfort, early satiety, postprandial abdominal distension, nausea, vomiting, and anorexia were graded as none (0), mild (1), moderate (2), and severe (3); the sum represented a total symptom score. The EGG was abnormal in 11 of 22 (50%) patients with delayed GE compared with 11 of 50 (22%) with normal GE (p < 0.025). The total symptom scores were higher in patients with both delayed GE and abnormal EGG compared with patients with normal GE and EGG, normal GE and abnormal EGG, and delayed GE and normal EGG. We conclude that EGG abnormalities are more common in dyspeptic patients with delayed GE. Patients with both delayed GE and abnormal EGG have more severe symptoms. Our results suggest that EGG and GE complement each other in correlating symptoms to gastric dysmotility.

Adult↗
PubMed1997

Effects of the program-management model: a case study on professional rehabilitation nursing.

In an attempt to increase organizational innovation and flexibility, Cardinal Hill Rehabilitation Hospital moved from the traditional discipline-management model to the program-management model. In the restructuring, the integrity of professional nursing practices was put to the test when the director of nursing position and numerous staff nursing positions were eliminated. This article evaluates statistics from the three years that have elapsed since the restructuring event in order to determine the new program-management model's compatibility with patient outcomes associated with professional nursing standards.

Disease Management↗
PubMed1997

Renal cysts and cystic neoplasms.

This article reviews the imaging approach to cystic renal lesions. Imaging characteristics of lesions ranging from simple cysts to cystic renal cell carcinomas are discussed. The MR appearance of cystic renal masses is described and the role of MR imaging in the evaluation of these lesions is discussed.

Carcinoma, Renal Cell↗
PubMed1997

Delayed gastric emptying and decreased antral contractility in normal premenopausal women compared with men.

OBJECTIVES: The effects of gender on gastric emptying have not been fully elucidated. The aims of this study were to determine how gender affects gastric emptying and to see whether any of the observed differences in gastric emptying correlate with alterations in antral motility as measured by dynamic antral scintigraphy (DAS), cutaneous electrogastrography (EGG), and antroduodenal manometry (ADM). METHODS: Nine normal women [age 27.9 +/- 2.2 (mean +/- SEM) yr] in the first 10 days of the menstrual cycle and 13 normal men (age 27.5 +/- 1.7 yr) underwent simultaneous gastric emptying scintigraphy, DAS, EGG, and ADM. After an overnight fast and placement of an ADM catheter and EGG electrodes, a 60-min fasting recording was obtained, followed by ingestion of a 99m Tc-labeled solid meal. Measurements for all modalities were acquired every 10-15 min for 180 min. RESULTS: The gastric T1/2 was longer in women than in men [102 +/- 18 min vs. 71 +/- 4 (mean +/- SEM) min, p < 0.05]. A comparison of the gastric emptying pattern in women with that in men revealed no difference in proximal gastric emptying and lag phase, but in women the terminal slope of emptying was decreased compared with that in men (p < 0.05). The contractility measured in mid-antrum by DAS was significantly lower for women (p < 0.05). A decrease was also seen in the strength of contractions as measured by ADM. CONCLUSIONS: These data demonstrate that gastric emptying of solid food in normal young, premenopausal women is slower than in age-matched men, even during the first 10 days of the menstrual cycle. The findings suggest that the delay is due primarily to altered distal gastric motor function. This hypothesis was corroborated by finding decreased antral contractility as recorded by both dynamic antral scintigraphy and ADM. This study demonstrates the need to use appropriate control values to evaluate symptomatic female patients.

Adolescent↗
PubMed1996

A complete mechanism for steady-state oxidation of yeast cytochrome c by yeast cytochrome c peroxidase.

Steady-state oxidation of yeast cytochrome c (yCc) was monitored as a function of ionic strength (mu) for mutants of a cloned cytochrome c peroxidase [CcP(MI)]. The data are best interpreted in the context of a two binding site model, where the affinity of the two sites for yCc differs by approximately 1000-fold and rapid intracomplex electron transfer (ET) occurs only at the high-affinity site identified in the crystal structure. At low mu, catalysis is apparently limited by the rate of yCc dissociation from the reactive high-affinity site (koff). Binding of yCc at the low-affinity site increases koff and therefore increases the rate of catalysis. Mutations at the high-affinity site also increase the rate of catalysis by the 1:1 CcP(MI):yCc complex by increasing koff. Mutations at residues that interact strongly with yCc at the high-affinity site (Asp 34, Glu 290, and Ala 193) cause the greatest increase in koff (25-38-fold at mu = 20 mM). Mutations at residues that interact less strongly with yCc (Glu 32 and Glu 291) cause smaller increases in koff (10- and 3-fold, respectively, at mu = 20 mM). The results provide additional evidence that the high-affinity site formed in solution is similar to the one identified in the crystal structure and that yCc dissociation from this site limits enzyme turnover at low ionic strength. Numerical integration simulations show that the model accurately predicts enzyme turnover rates at the high-affinity site, using published rate constants for the elementary reaction steps.

Binding Sites↗
PubMed1996

The pattern of cell proliferation in neoplastic and nonneoplastic lesions of ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by repeated episodes of inflammation and epithelial regeneration. Patients with long-standing UC have an increased risk for the development of dysplasia and subsequent colon carcinoma. Because dysplasia likely results from deregulatec cell proliferation, the authors examined Ki-67 immunoreactivity in tissues from UC patients to examine patterns of proliferation in neoplastic and nonneoplastic lesions. METHODS: One hundred and eighty-seven specimens were obtained from 41 patients with UC and each lesion evaluated according to the International Classification for Dysplasia in Inflammatory Bowel Disease. All sections were stained with a monoclonal antibody directed against the proliferation marker Ki-67, and evaluated by three observers. RESULTS: Statistically significant differences in the pattern of Ki-67 immunoreactivity were observed between nonneoplastic and neoplastic lesions. In regenerative mucosa, Ki-67 immunoreactivity localized to the bases of the crypts, and the proliferative zone appeared expanded. In dysplasia, Ki-67 staining was prominent in cells in the superficial mucosa, as well as in cells at the crypt bases. In some dysplasias and all invasive carcinomas, Ki-67 staining was diffusely distributed throughout the crypts, suggesting complete deregulation of normal cell proliferation. CONCLUSIONS: Cell proliferation is markedly increased in patients with UC, and appears abnormally regulated in neoplastic lesions. Furthermore, Ki-67 staining helps delineate areas of dysplasia in cases in which the distinction from regenerative mucosa is unclear. The increased cell proliferation that occurs in patients with UC may predispose the mucosa to mutational events, thereby increasing cancer risk in these patients.

Adult↗
PubMed1996

Design of a ruthenium-cytochrome c derivative to measure electron transfer to the radical cation and oxyferryl heme in cytochrome c peroxidase.

A new ruthenium-labeled cytochrome c derivative was designed to measure the actual rate of electron transfer to the Trp-191 radical cation and the oxyferryl heme in cytochrome c peroxidase compound I {CMPI(FeIV = O,R.+)}. The H39C,C102T variant of yeast iso-1-cytochrome c was labeled at the single cysteine residue with a tris (bipyridyl)ruthenium(II) reagent to form Ru-39-Cc. This derivative has the same reactivity with CMPI as native yCc measured by stopped-flow spectroscopy, indicating that the ruthenium group does not interfere with the interaction between the two proteins. Laser excitation of the 1:1 Ru-39-Cc-CMPI complex in low ionic strength buffer (2 mM phosphate, pH 7) resulted in electron transfer from RuII* to heme c FeIII with a rate constant of 5 x 10(5) s-1, followed by electron transfer from heme c Fe II to the Trp-191 indolyl radical cation in CMPI(FeIV = O,R*+) with a rate constant of k(eta) = 2 x 10(6) s-1. A subsequent laser flash led to electron transfer from heme c to the oxyferryl heme in CMPII-(FeIV = O,R) with a rate constant of k(etb) = 5000 s-1. The location of the binding domain was determined using a series of surface charge mutants of CcP. The mutations D34N, E290N, and A193F each decreased the values of k(eta) and k(etb) by 2-4-fold, consistent with the use of the binding domain identified in the crystal structure of the yCc-CcP complex for reduction of both redox centers [Pelletier, H., & Kraut, J. (1992) Science 258, 1748-1755]. A mechanism is proposed for reduction of the oxyferryl heme in which internal electron transfer in CMPII(FeIV = O,R) leads to the regeneration of the radical cation in CMPII-(FeIII,R*+), which is then reduced by yCcII. Thus, both steps in the complete reduction of CMPI involve electron transfer from yCcII to the Trp-191 radical cation using the same binding site and pathway. Comparison of the rate constant k(eta) with theoretical predictions indicate that the electron transfer pathway identified in the crystalline yCc-CcP complex is very efficient. Stopped-flow studies indicate that native yCcII initially reduces the Trp-191 radical cation in CMPI with a second-order rate constant ka, which increases from 1.8 x 10(8) M-1 s-1 at 310 mM ionic strength to > 3 x 10(9) M-1 s-1 at ionic strengths below 100 mM. A second molecule of yCcII then reduces the oxyferryl heme in CMPII with a second-order rate constant kb which increases from 2.7 x 10(7) M-1 s-1 at 310 mM ionic strength to 2.5 x 10(8) M-1 s-1 at 160 mM ionic strength. As the ionic strength is decreased below 100 mM the rate constant for reduction of the oxyferryl heme becomes progressively slower as the reaction is limited by release of the product yCcIII from the yCcIII-CMPII complex. Both ruthenium photoreduction studies and stopped-flow studies demonstrate that the Trp-191 radical cation is the initial site of reduction in CMPI under all conditions of ionic strength.

2,2'-Dipyridyl↗
PubMed1996

Protective immunity to Listeria monocytogenes elicited by immunization with heat-killed Listeria and IL-12. Potential mechanism of IL-12 adjuvanticity.

The results presented here demonstrate the striking potentiating effects of IL-12 when it is combined with listerial immunogens. Although HKLM alone does not elicit strong T-cell responses, the results presented here demonstrate that the combination of HKLM and IL-12 elicited vigorous Listeria-specific Th1-type T-cell responses when administered intraperitoneally. The intensity of these responses, as well as the cytokine profiles of the Listeria-specific peritoneal T cells and macrophages, was remarkably similar to that of Listeria-infected/immune mice. These studies also revealed that typically nonimmunogenic forms of soluble listerial antigen preparations (cLLO, SLP) and LLO peptide homologs (M. A. Miller et al., manuscript in preparation) elicited intense Listeria-specific T-cell responses when administered with IL-12. In conjunction with the generation of specific T-cell responses following injection of IL-12 in combination with either killed Listeria or soluble listerial antigen preparations, macrophages from these mice expressed upregulated quantities of class II MHC and produced increased amounts of IL-12 following restimulation in vitro. Protection studies established that the Listeria-specific T-cell responses elicited by the HKLM + IL-12 mixture conferred protective immunity of mice to a lethal dose of viable L. monocytogenes. Studies designed to investigate the regulation of IL-12 production by peritoneal macrophages revealed that activated macrophages are particularly sensitive to bacterial products. However, nonviable or replication-incompetent bacteria or bacterial products injected alone were unable to influence the ability of macrophages to produce IL-12. The ability of activated macrophages to respond to HKLM was dramatically upregulated upon addition of IFN-gamma and markedly downregulated in the presence of the Th2 cytokines, IL-4 and IL-10. In light of what is known about the ability of IL-12 to induce IFN-gamma production by NK cells and gamma delta T cells, these results suggest that the exogenous addition of IL-12 may help initiate a cytokine cascade which enables the immune system to interact productively with an antigen that is typically nonimmunogenic when administered alone. These findings demonstrate that IL-12 may prove to be a powerful and broadly useful adjuvant component of particulate and soluble antigen-based vaccines directed towards many types of intracellular pathogenic microorganisms. Studies aimed at determining the generality of these findings in other infectious disease models as well as experiments designed to further elucidate the mechanism(s) of IL-12 adjuvanticity are continuing.

Adjuvants, Immunologic↗
PubMed1996

Leptospira interrogans serovar grippotyphosa infection in dogs.

Leptospirosis attributed to infection with serovar grippotyphosa was diagnosed in 11 dogs. In naturally and experimentally infected dogs, a stereotypic serologic response to infection with Leptospira serovar grippotyphosa was detected. Although the highest serum antibody titers developed against serovar grippotyphosa, most dogs also had lower titers against serovars bratislava and pomona. Acute renal failure was evident in 10 dogs. One dog died prior to initiation of treatment; the remaining 10 dogs were treated with antibiotics and fluids. Two dogs were euthanatized, 2 dogs recovered without clinical or biochemical evidence of residual renal dysfunction, and 6 dogs recovered but had varying degrees of renal insufficiency. Hepatic involvement appeared to be a minor component of the disease in these dogs. Our results indicate that Leptospira serovar grippotyphosa infection is an important problem in dogs and should be considered when evaluating a dog with renal failure.

Acute Kidney Injury↗