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Biomedical subjects

D M Miller

Publications and source records attributed to D M Miller.

At least 19 recordsLinked to original sources
PubMed2006

Change in clinician-assessed measures of multiple sclerosis and subject-reported quality of life: results from the IMPACT study.

BACKGROUND: The IMPACT study demonstrated the benefit of interferon beta-1a (IFNbeta-1a, Avonex) two-year change in disability measured by the Multiple Sclerosis Functional Composite (MSFC) in secondary progressive multiple sclerosis (SP-MS) and health-related quality of life (HRQoL) measured by the Multiple Sclerosis Quality of Life Inventory (MSQLI). The IMPACT data permit a detailed assessment of the relation between clinical and self-reported measures. METHODS: IMPACT was an international randomized, double-blind, placebo-controlled trial of SP-MS patients. As the MSQLI is only in English, this report includes US and Canadian subjects. Subjects were randomized to weekly intramuscular (im) injections of INbeta-1a (60 microg) or placebo for 24 months. RESULTS: At baseline and follow-up, MSQLI correlations were generally stronger with the EDSS than with the MSQLI, MSFC but comparable with MSFC components. Combining the two groups, MSQLI changes for those in the best and worst MSFC change quartiles demonstrated a statistical difference for six of the 11 MSQLI scales. Linear regression demonstrated that EDSS change from baseline to month-24 scores was correlated with change in two MSQLI components. CONCLUSION: These data support the appropriateness of using the MSQLI with individuals who have SP-MS.

Adult↗
PubMed2005

Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients.

Two methods were used to estimate the long-term impact of disease-modifying drug therapy (DMDT) in patients with relapsing multiple sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of interferon beta-1a (IFNbeta-1a). The study cohort consisted of patients with ambulatory relapsing MS who had previously participated in a placebo-controlled clinical trial for two years. At its end, patients were managed in an unstructured fashion by their neurologists and re-evaluated at an average of 6.1 years after the end of the trial. Follow-up evaluation was obtained for 93% of the 172 eligible patients. Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of < or = 3.5 at entry, disability progression at follow-up was defined as EDSS > or = 6.0. Two methods were used to estimate the expected proportions that reached EDSS > or = 6.0 at follow-up. Estimates were compared with observed proportions. Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period. Method 2 used progression rates from a natural history comparison group of relapsing-remitting MS patients. At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFNbeta-1a patients reached an EDSS > or = 6.0, an observed treatment effect of approximately 30%. Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFNbeta-1a patients should have reached an EDSS > or = 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes. Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFNbeta-1a group. Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome. The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.

Adjuvants, Immunologic↗
PubMed2005

The pharmacokinetics of diminazene aceturate after intramuscular administration in healthy dogs.

The pharmacokinetics of diminazene aceturate following intramuscular (i.m.) administration at 4.2 mg/kg was evaluated in 8 healthy German Shepherd dogs. Blood samples were collected at 19 intervals over a period of 21 days. Diminazene plasma concentrations were measured using a validated HPLC method with UV detection and a sensitivity of 25 ng/ml. The in vitro and in vivo binding of diminazene to blood elements was additionally determined. Diminazene pharmacokinetics showed a large inter-individual variation after i.m. administration. It had a short absorption half-life (K01-HL of 0.11 +/- 0.18 h), resulting in a C(max) of 1849 +/- 268.7 ng/ml at T(max) of 0.37 h and a mean overall elimination half-life (T1/2beta) of 5.31 +/- 3.89 h. A terminal half-life of 27.5 +/- 25.0 h was measured. At 1 h after i.m. injection, 75% of the diminazene in whole blood was in the plasma fraction. The results of this study indicate that diminazene is rapidly distributed and sequestered into the liver, followed by a slower terminal phase during which diminazene is both redistributed to the peripheral tissues and/or renally excreted. It is recommended that diminazene administered i.m. at 4.2 mg/kg should not be repeated within a 21-day period.

Absorption↗
PubMed2004

A stomatin and a degenerin interact in lipid rafts of the nervous system of Caenorhabditis elegans.

In Caenorhabditis elegans, the gene unc-1 controls anesthetic sensitivity and normal locomotion. The protein UNC-1 is a close homolog of the mammalian protein stomatin and is expressed primarily in the nervous system. Genetic studies in C. elegans have shown that the UNC-1 protein interacts with a sodium channel subunit, UNC-8. In humans, absence of stomatin is associated with abnormal sodium and potassium levels in red blood cells. Stomatin also has been postulated to participate in the formation of lipid rafts, which are membrane microdomains associated with protein complexes, cholesterol, and sphingolipids. In this study, we isolated a low-density, detergent-resistant fraction from cell membranes of C. elegans. This fraction contains cholesterol, sphingolipids, and protein consistent with their identification as lipid rafts. We then probed Western blots of protein from the rafts and found that the UNC-1 protein is almost totally restricted to this fraction. The UNC-8 protein is also found in rafts and coimmunoprecipitates UNC-1. A second stomatin-like protein, UNC-24, also affects anesthetic sensitivity, is found in lipid rafts, and regulates UNC-1 distribution. Mutations in the unc-24 gene alter the distribution of UNC-1 in lipid rafts. Each of these mutations alters anesthetic sensitivity in C. elegans. Because lipid rafts contain many of the putative targets of volatile anesthetics, they may represent a novel class of targets for volatile anesthetics.

Animals↗
PubMed2004

Cost and efficacy comparison of integrated pest management strategies with monthly spray insecticide applications for German cockroach (Dictyoptera: Blattellidae) control in public housing.

The long-term costs and efficacy of two treatment methodologies for German cockroach, Blattella germanica (L.), control were compared in the public housing environment. The "traditional" treatment for German cockroaches consisted of monthly baseboard and crack and crevice treatment (TBCC) by using spray and dust formulation insecticides. The integrated pest management treatment (IPM) involved initial vacuuming of apartments followed by monthly or quarterly applications of baits and insect growth regulator (IGR) devices. Cockroach populations in the IPM treatment were also monitored with sticky traps. Technician time and the amount of product applied were used to measure cost in both treatments. Twenty-four hour sticky trap catch was used as an indicator of treatment efficacy. The cost of the IPM treatment was found to be significantly greater than the traditional treatment, particularly at the initiation of the test. In the first month (clean-out), the average cost per apartment unit was dollar 14.60, whereas the average cost of a TBCC unit was dollar 2.75. In the second month of treatment, the average cost of IPM was still significantly greater than the TBCC cost. However, after month 4 the cost of the two treatments was no longer significantly different because many of the IPM apartments were moved to a quarterly treatment schedule. To evaluate the long-term costs of the two treatments over the entire year, technician time and product quantities were averaged over all units treated within the 12-mo test period (total 600 U per treatment). The average per unit cost of the IPM treatment was (dollar 4.06). The average IPM cost was significantly greater than that of the TBCC treatment at dollar 1.50 per unit. Although the TBCC was significantly less expensive than the IPM treatment, it was also less effective. Trap catch data indicated that the TBCC treatment had little, if any, effect on the cockroach populations over the course of the year. Cockroach populations in the TBCC treatment remained steady for the first 5 mo of the test and then had a threefold increase during the summer. Cockroach populations in the IPM treatment were significantly reduced from an average of 24.7 cockroaches per unit before treatment to an average 3.9 cockroaches per unit in month 4. The suppressed cockroach populations (< 5 per unit) in the IPM treatment remained constant for the remaining 8 mo of the test.

Animals↗
PubMed2004

Laboratory assays evaluate the influence of physical guidelines on subterranean termite (Isoptera: Rhinotermitidae) tunneling, bait discovery, and consumption.

Laboratory assays were conducted to determine whether physical guidelines could direct subterranean termite foraging behavior. Several materials (wood, plastics, and wood thermoplastic composites) were evaluated for their potential to serve as termite guidelines. Termite tunneling along the different types of guidelines was measured. The proportion of baits discovered when connected by a guideline was compared with the proportion of unconnected baits discovered. Termite consumption of baits also was quantified. Assay results indicated that the termites did not respond to all guideline materials in the same way. Termites built significantly longer tunnels along wood guidelines than they did along any of the plastic guidelines tested. However, tunnel length along the wood and the wood thermoplastic composites was not significantly different. The probability of two baits being discovered when they were connected by wood guidelines was significantly greater than when the baits were connected by plastic guidelines or left unconnected (no guideline). Pairs of baits connected by wood thermoplastic composites were also significantly more likely to be discovered than unconnected baits. Bait consumption was not enhanced by the presence of the guidelines. It is likely that guidelines made of wood competed with the baits as a termite food resource.

Animals↗
PubMed2004

Dead space and paediatric anaesthetic equipment: a physical lung model study.

Untested assumptions have been made with regard to functional dead space in facemasks, filters and breathing systems used in children for the administration of inhalation anaesthesia. Total functional dead space was measured in various combinations of this equipment applied to a spontaneous ventilation lung model with parameter settings appropriate for infants of 7-8 kg. We found that functional dead space was too large to allow for spontaneous ventilation of the lungs when a breathing filter was fitted. There was minimal relationship between size of the facemask and functional dead space; however, the provision of 22-mm female inlets to facemasks achieved proportionately less functional dead space than with 15-mm male inlets. Regardless of the apparatus used and the magnitude of the dead space, the leak induced when a poorly fitting facemask was used dramatically reduced the dead space of the breathing system - to near optimal conditions - by moving the alveolar gas elimination point to within the facemask itself.

Anesthesia, Inhalation↗
PubMed2004

Dynamic dead space in face masks used with noninvasive ventilators: a lung model study.

The aim of this study was to determine what the influence of different designs of face masks and different noninvasive ventilator modes would be upon total dynamic dead space. Using a spontaneous breathing model, total dynamic dead space was measured when using 19 commercially available face masks and a range of ventilators in various ventilation modes. Total dynamic dead space during spontaneous ventilation was increased above physiological dead space from 32% to 42% of tidal volume by using face masks. The use of noninvasive ventilation modes such as bilevel and continuous positive airway pressure, with continuous pressure throughout the expiratory phase, reduced total dynamic dead space to approach physiological dead space with most face masks. Pressure assist and pressure support ventilation decreased total dynamic dead space to a lesser degree, from 42% to 39% of tidal volume. Face masks with expiratory ports over the nasal bridge resulted in beneficial flow characteristics within the face mask and nasal cavity, so as to decrease total dynamic dead space to less than physiological dead space from 42% to 28.5% of tidal volume. Exhaust ports over the nasal bridge in face masks effect important decreases in dynamic dead space provided positive pressure throughout the expiratory phase is used.

Equipment Design↗
PubMed2003

Laboratory and clinical comparisons of the Streamlined Liner of the Pharynx Airway (SLIPA) with the laryngeal mask airway.

The Streamlined Liner of the Pharynx Airway (SLIPA) is a new inexpensive disposable supraglottic airway designed to seal without the use of an inflatable cuff. It comprises a hollow blow-moulded soft plastic airway shaped to form a seal in the pharynx. Being hollow, liquid entrapment is possible and this may provide effective protection against aspiration. A model silicone rubber pharynx with an 'oesophageal' tube for injecting volumes of regurgitant liquid was designed to evaluate the SLIPA and the standard and ProSeal laryngeal mask airways during positive-pressure ventilation. A linear relationship between the volume 'regurgitated' and the volume 'aspirated' was found with the laryngeal mask airway and the ProSeal laryngeal mask airway with the drainage tube clamped. Both the ProSeal laryngeal mask airway with an open drainage tube and the SLIPA, but not the standard laryngeal mask airway, provided effective protection against 'aspiration' during positive-pressure ventilation using the model. In a clinical study, 120 patients were randomly allocated to receive controlled ventilation of the lungs via the standard laryngeal mask airway or the SLIPA. Both devices were equally easy to insert and satisfactory for airway management.

Adolescent↗
PubMed2003

The effects of diminazene aceturate on systemic blood pressure in clinically healthy adult dogs.

Diminazene aceturate is a commonly used antibabesial agent. It has been postulated that diminazine may induce a decrease in blood pressure and exacerbate the hypotension presented in dogs with babesiosis. This study was undertaken to assess the effect of diminazine aceturate on the blood pressure of healthy dogs. Six healthy German shepherd dogs between 18 and 24 months of age with a mean weight of 30.4 +/- 2.75 kg were used. Blood pressure was directly measured at the following time intervals: -5, 0, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 90 and 120 minutes after treatment with diminazine aceturate (4.2 mg/kg) intramuscularly. No statistical difference (P > 0.05) was found in blood pressure between any of the time intervals. An increase in heart rate was seen 5 minutes after the administration of diminazine aceturate but no change in blood pressure was evident. This study concluded that diminazene aceturate in its current formulation with antipyrine does not alter blood pressure in healthy adult dogs.

Animals↗
PubMed2002

Peritoneal implantation of squamous cell carcinoma following rupture of a dermoid cyst during laparoscopic removal.

BACKGROUND: In recent years, there has been a move toward using laparoscopy in the management of presumed benign ovarian masses. This paper discusses the use of laparoscopy for ovarian masses (particularly dermoid cysts). The focus is on the implications for unexpected malignancies. CASE: We report here a case involving a dermoid cyst that was removed at laparoscopy and was subsequently found to contain a squamous cell carcinoma. Spillage of the cyst's contents occurred at the time of removal. At staging laparotomy, peritoneal implants of the tumor were found, upgrading the tumor from FIGO stage Ia to IIc. CONCLUSION: Spillage rates of dermoid cyst content with laparoscopic removal are inevitably higher than with excision at laparotomy. It remains controversial whether upstaging from FIGO stage Ia to IIc affects prognosis; however, in this case it led to aggressive adjuvant therapy which imposed significant additional morbidity, including loss of fertility, on the patient. One should be aware of the possibility of unexpected malignancy when the decision to manage an ovarian mass laparoscopically is made.

Adult↗
PubMed2002

Human cytomegalovirus inhibition of major histocompatibility complex transcription and interferon signal transduction.

Pathogens have evolved diverse mechanisms for escaping host innate and adaptive immunity. Viruses that maintain a persistent infection are particularly effective at disabling key arms of the host immune response. For example, the herpesviruses establish a persistent infection in human and animal hosts, in part through critical immunoevasive strategies. Cytomegalovirus, a beta-herpesvirus, impairs major histocompatibility complex (MHC) class I and class II antigen presentation by decreasing MHC expression on the surface of the infected cell, thus enabling infected cells to escape CD8+ and CD4+ T lymphocyte immunosurveillance. Moreover, cytomegalovirus blocks the interferon signal transduction pathway, thereby limiting the direct and indirect antiviral effects of the interferons. In this review, we focus on an emerging paradigm in which the effectiveness of viruses, particularly human cytomegalovirus, to escape antiviral immune responses is significantly enhanced by their ability to inhibit MHC transcription and interferon (IFN)-stimulated (JAK/STAT) signal transduction.

Antigen Presentation↗
PubMed2001

Unique function for carboxyl-terminal domain of Oct-2 in Ig-secreting cells.

The activity of Ig gene promoters and enhancers is regulated by two related transcription factors, Oct-1 (ubiquitous) and Oct-2 (B lineage specific), which bind the octamer motif (ATTTGCAT) present in these elements. As Ig promoter-binding factors, Oct-1 and Oct-2 each work together with a B lymphocyte-specific cofactor OCA-B/OBF-1/Bob-1 that interacts with them through their POU (DNA-binding) domains. Because both can mediate Ig promoter activity in B cells, there has been some question as to whether these two octamer-binding factors serve distinct functions in lymphocytes. We have shown previously that the silencing of B lymphocyte-specific genes in plasmacytoma x T lymphoma hybrids can be prevented by preserving Oct-2 expression. The pronounced effect of this transcription factor on the phenotype of plasmacytoma x T lymphoma hybrids established a critical role for Oct-2 not only in maintaining Ig gene expression, but in maintaining the overall genetic program of Ig-secreting cells. In the present study, we have explored the functional differences between Oct-1 and Oct-2 using chimeric Oct-1/Oct-2 proteins in cell fusion assays. Our results provide further evidence for an essential role for Oct-2 in Ig-secreting cells and identify the C-terminal domain of Oct-2 as responsible for its unique function in these cells.

Antibody-Producing Cells↗
PubMed2001

Psoralen-modified clamp-forming antisense oligonucleotides reduce cellular c-Myc protein expression and B16-F0 proliferation.

The c-myc protooncogene plays an important role in the abnormal growth pattern of melanoma cells. In an attempt to inhibit c-Myc expression and the growth of an established murine melanoma cell line, we targeted homopurine sequences within the mouse myc mRNA with modified antisense oligonucleotides (AS ODNs). Psoralen was conjugated to the 5'-end of these clamp-forming oligonucleotides (clamp ODNs). Gel mobility shift analysis demonstrated a sequence-specific interaction between the active clamp ODNs (Myc-E2C and Myc-E3C) and the 1.4 kb c-myc mRNA, but no interaction with the control clamp ODN (SCR**). This association was further confirmed by thermal denaturation studies. In vitro translation assays demonstrated that both Myc-E2C and Myc-E3C at 5 microM inhibited c-Myc expression >99% after UV activation at 366 nm. Immunostaining of B16-F0 cells with a c-Myc monoclonal antibody revealed a significant reduction in c-Myc after clamp ODN treatment compared with the untreated or SCR** control-treated cells. This result was corroborated by western blot analysis. Utilizing the MTT assay to determine the effects of ODN-mediated c-Myc reduction on B16-F0 growth, we observed 60 and 64% reductions in growth after treatment with 5 microM Myc-E3C and Myc-E2C, respectively. We attribute the enhanced effectiveness of the clamp ODNs to psoralen activation. Our preliminary data suggest that inhibiting c-Myc overexpression results in a significant reduction in abnormal proliferation of B16-F0 melanoma cells and that the increased efficiency of clamp ODNs may provide an important advantage for their use in antisense therapies.

Animals↗
PubMed2001

Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides.

The discovery of G-rich oligonucleotides (GROs) that have non-antisense antiproliferative activity against a number of cancer cell lines has been recently described. This biological activity of GROs was found to be associated with their ability to form stable G-quartet-containing structures and their binding to a specific cellular protein, most likely nucleolin (Bates, P. J., Kahlon, J. B., Thomas, S. D., Trent, J. O., and Miller, D. M. (1999) J. Biol. Chem. 274, 26369-26377). In this report, we further investigate the novel mechanism of GRO activity by examining their effects on cell cycle progression and on nucleic acid and protein biosynthesis. Cell cycle analysis of several tumor cell lines showed that cells accumulate in S phase in response to treatment with an active GRO. Analysis of 5-bromodeoxyuridine incorporation by these cells indicated the absence of de novo DNA synthesis, suggesting an arrest of the cell cycle predominantly in S phase. At the same time point, RNA and protein synthesis were found to be ongoing, indicating that arrest of DNA replication is a primary event in GRO-mediated inhibition of proliferation. This specific blockade of DNA replication eventually resulted in altered cell morphology and induction of apoptosis. To characterize further GRO-mediated inhibition of DNA replication, we used an in vitro assay based on replication of SV40 DNA. GROs were found to be capable of inhibiting DNA replication in the in vitro assay, and this activity was correlated to their antiproliferative effects. Furthermore, the effect of GROs on DNA replication in this assay was related to their inhibition of SV40 large T antigen helicase activity. The data presented suggest that the antiproliferative activity of GROs is a direct result of their inhibition of DNA replication, which may result from modulation of a replicative helicase activity.

Apoptosis↗
PubMed2001

Regulation of neurotransmitter vesicles by the homeodomain protein UNC-4 and its transcriptional corepressor UNC-37/groucho in Caenorhabditis elegans cholinergic motor neurons.

Motor neuron function depends on neurotransmitter release from synaptic vesicles (SVs). Here we show that the UNC-4 homeoprotein and its transcriptional corepressor protein UNC-37 regulate SV protein levels in specific Caenorhabditis elegans motor neurons. UNC-4 is expressed in four classes (DA, VA, VC, and SAB) of cholinergic motor neurons. Antibody staining reveals that five different vesicular proteins (UNC-17, choline acetyltransferase, Synaptotagmin, Synaptobrevin, and RAB-3) are substantially reduced in unc-4 and unc-37 mutants in these cells; nonvesicular neuronal proteins (Syntaxin, UNC-18, and UNC-11) are not affected, however. Ultrastructural analysis of VA motor neurons in the mutant unc-4(e120) confirms that SV number in the presynaptic zone is reduced ( approximately 40%) whereas axonal diameter and synaptic morphology are not visibly altered. Because the UNC-4-UNC-37 complex has been shown to mediate transcriptional repression, we propose that these effects are performed via an intermediate gene. Our results are consistent with a model in which this unc-4 target gene ("gene-x") functions at a post-transcriptional level as a negative regulator of SV biogenesis or stability. Experiments with a temperature-sensitive unc-4 mutant show that the adult level of SV proteins strictly depends on unc-4 function during a critical period of motor neuron differentiation. unc-4 activity during this sensitive larval stage is also required for the creation of proper synaptic inputs to VA motor neurons. The temporal correlation of these events may mean that a common unc-4-dependent mechanism controls both the specificity of synaptic inputs as well as the strength of synaptic outputs for these motor neurons.

Animals↗
PubMed2001

Expression of a CIC chloride channel in Caenorhabditis elegans gamma-aminobutyric acid-ergic neurons.

In this study, we report the complete cDNA sequence, genomic organization and expression pattern of the Caenorhabditis elegans ClC chloride channel gene, clh-6. Two different types of reporter gene fusions suggest that clh-6 expression is restricted to two gamma-aminobutyric acid-ergic RME neurons. These results are in striking contrast with the wide tissue distribution of messenger RNA for the related mammalian isoforms, CIC-6 and CIC-7. The restricted expression pattern of clh-6 provides a unique opportunity to study the biological function of a neuronal CIC chloride channel.

Amino Acid Sequence↗