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Biomedical subjects

D Miller

Publications and source records attributed to D Miller.

At least 19 recordsLinked to original sources
PubMed2007

The relationship between dosing of alosetron and discontinuation patterns reported by patients participating in a follow-up programme.

BACKGROUND: Alosetron was reintroduced for treatment of irritable bowel syndrome with a risk management programme in November 2002. Recommended starting dosage was 1 mg/day for 4 weeks. If symptoms remained uncontrolled, dosage could be changed to 2 mg/day. AIM: To describe alosetron dosages and associated patient characteristics from the Lotronex follow-up survey programme. METHODS: Patients reported dosages of alosetron at start and regular follow-up intervals. Analyses were limited to patients with the potential to have at least 1 year of follow-up (enrolled between 9 December 2002 and 31 December 2003). RESULTS: At baseline, 75% of 2817 respondents reported starting on 1 mg/day, 17% on 2 mg/day and 8% on other doses. Adherence to recommended starting dosage did not vary by status at end of follow-up, previous alosetron experience or age. At last reported dose, 50% of respondents were using 1 mg/day; 29% were using 2 mg/day. Discontinuation was not related to baseline doses. Longer times to discontinuation were associated with previous use, symptoms for more than 6 months and dose change throughout follow-up. CONCLUSIONS: High adherence to recommended dosing at baseline and follow-up suggests that the risk management programme is encouraging safe use of alosetron, including adherence to dosing recommendations.

Adult↗
PubMed2007

Antitumor activity of sorafenib in FLT3-driven leukemic cells.

Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.

Animals↗
PubMed2006

Spermatozoal RNA: Why is it there and what does it do?

The mammalian male gamete is transcriptionally silent as a consequence of the highly condensed architecture of its chromatin and there is also little or no cytoplasm capable of supporting translation; however, we now understand that these cells carry a full complement of mRNAs and that under certain conditions, spermatozoa can translate their mRNAs de novo. Moreover, there is now good evidence that spermatozoal RNA can potentially affect phenotypic traits in offspring. This epigenetic phenomenon may involve the transmission of extra-chromosomal episomal elements. These data indicate that the spermatozoon is well matched to its role of delivering the paternal genome, but that additional male-benefits may also be accrued by the delivery of spermatozoal RNA.

Animals↗
PubMed2006

A patient follow-up survey programme for alosetron: assessing compliance to and effectiveness of the risk management programme.

BACKGROUND: In November 2002, alosetron HCl (Lotronex, GlaxoSmithKline Research Triangle Park, NC, USA) was re-introduced to the US marketplace for women with severe diarrhoea-predominant irritable bowel syndrome. In support of the re-introduction, a risk management programme was implemented, which included a patient follow-up study in which all users of alosetron could participate. AIM: We report on the methods used and the effectiveness of key elements of the risk management programme. METHODS: Patients voluntarily enroled in the study and completed questionnaires at baseline, after 5 and 10 weeks, and quarterly thereafter. Questions focussed on patient eligibility, knowledge of risks and benefits, and adherence to the recommended programme elements for education, prescribing and dispensing. RESULTS: Between December 2002 and 2004, 4,803 patients enrolled in the study, and <3% were lost to follow-up. The average follow-up time was approximately 6 months, and the response rate for each assessment was >95%. A total of 90% of patients at baseline met the full clinical criteria recommended for the treatment. Patient adherence to the risk management programme was >87%. CONCLUSIONS: Using the Lotronex risk management programme, patients met clinical criteria, were knowledgeable about treatment risks and benefits, and were adherent to the process elements of the programme. These patients seemed to engage in active dialogue with their physicians about symptoms and use of alosetron.

Adolescent↗
PubMed2006

Image-guided ultrasonography for recurrent cystic gliomas.

BACKGROUND: Long-term survival of patients with recurrent gliomas depends on the extent of resection. Thus, the desirability of an intra-operative imaging modality that can augment the resection extension without affecting vital surrounding structures is more than obvious. It was the aim of the present study to evaluate a possible benefit of image-guided intra-operative ultrasonography for the surgery of recurrent gliomas. METHOD: The authors performed ultrasonography-assisted image-guided resection of recurrent gliomas in 16 patients. An ultrasound device (IGSonic) was integrated into the VectorVision2 navigation system (BrainLAB, Heimstetten, Germany). The IGSonic Probe 10V5 was connected to the VectorVision Navigation station via an IGSonic Device Box. Following patient registration, MRI based neuronavigation was used to determine the skin incision and the bone flap. Before opening the dura, the underlying structures were explored by ultrasound combined with the corresponding MR images. The navigated ultrasound displayed the sonographic image of the intracranial anatomy on the navigation screen in a composed overlay fashion. FINDINGS: The integration of intra-operative ultrasound into neuronavigation system offered quick and helpful intra-operative images in all 16 procedures. Due to the specific ultrasonic characteristics of the solid and the cystic parts, our technique created highly useful images in 10 patients with cystic recurrences. In these, user friendly images were obtained that were easy to understand even for neurosurgeons without major experience in intra-operative ultrasound. CONCLUSIONS: Neurosonography is a time- and cost-effective technology offering intra-operative imaging. The improved orientation and visualization of tumour remnants, adjacent ventricles, and the enhanced intra- and peri-tumoural vasculature is one of the main advantages of ultrasonography-assisted image-guided surgery, which is most obvious during surgery for cystic gliomas.

Brain Neoplasms↗
PubMed2006

Qualitative assessment of patient experiences related to extended pelvic resection for rectal cancer.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) represent a complex management challenge. While there is potential for cure in a subset of patients, the cost in terms of morbidity can be high. Few descriptions of the physical, psychological, social, and emotional experiences of these patients exist. METHODS: Face-to-face interviews were completed with ten LARC and LRRC patients treated with multimodal therapy that included surgery. Patient opinions and experiences were explored in depth until information redundancy and common themes were delineated using qualitative research methods. Clinical information was obtained from the database. RESULTS: Nine of the ten patients were male, seven had LARC, and the median age was 71. Six themes were identified from the patient interviews. Themes reflected patients' highly focused desire to seek wellness and cure, but also revealed misunderstanding of their disease biology, probability of cure, therapeutic options, and treatment morbidity. CONCLUSIONS: Patient experiences confirm that this is challenging treatment to complete, and that patient understanding of pre-operative information is incomplete. Our findings underscore the need for a multidisciplinary approach when managing this patient population, with emphasis on both supportive care needs and the technically skilled delivery of surgery, chemotherapy, and radiotherapy.

Adult↗
PubMed2005

The effect of grazing forage containing condensed tannins on gastro-intestinal parasite infection and milk composition in Angora does.

The objective of this study was to evaluate effects of the condensed tannin (CT)-containing forage sericea lespedeza (sericea lespedeza (SL); Lespedeza cuneata; 15.2% CT), on fecal egg count (FEC), larval development (larvae/10 g of feces), worm burden and immune response compared with a crabgrass (Digitaria ischaemum)/Kentucky 31 tall fescue (Festuca arundinacea; control forage (CTF)) forage low in CT (0.32% CT) in grazing Angora does and their kids. Fifty worm-free mixed-age does were randomly allocated to three treatments. One treatment (10 does; initial liveweight (LW) = 45+/-1.5 kg) entailed grazing of SL forage from April 25 to July 15, 2002 with a second treatment of CTF (20 does; initial LW = 43+/-1.4 kg) grazing during the same period. Does of the third treatment (20 does; initial LW = 44+/-1.4 kg) grazed a sward of SL for 2 weeks and then one of CTF for 2 weeks followed by alternating between the two pastures every 2-week rotational grazing (ROT). To gauge levels of infective larvae on pasture, three worm-free Angora kids (initial LW = 3.6+/-0.2 kg) were randomly selected as tracers. Tracers grazed for final 60 days and were euthanized for determination of worm burden. The immune response of does was measured by skin thickness reaction after the intradermal injection of 250 microg phytohemagglutinin (PHA). Mean FEC for SL and ROT were substantially lower (P < 0.01) than for CTF does (145, 329 and 894 eggs/g, respectively). The FEC for kids was lower (P < 0.05) for SL than for ROT and CTF (550, 2757 and 3600 eggs/g, respectively). Total fecal egg output (3.3, 6.0 and 26.9 x 10(5) eggs/day, respectively) and larval development (242, 263 and 792 larvae/10 g, respectively) were lower (P < 0.05) for SL and ROT than for CTF. Tracers grazing on SL had lower total worm burdens than ROT and CTF (P < 0.01). The immune response was higher (P < 0.01) for SL (4.9 mm) and ROT (6.0 mm) than for CTF (3.0 mm) at 12 h after injection of PHA. The packed cell volume (PCV) in does was higher (P < 0.01) for SL and ROT than for CTF (27, 26 and 23%, respectively). Does that grazed CT-containing forage had considerably lower milk somatic cell counts (SCC) than does grazing non-CT-containing forage. In summary, grazing CT forages reduced FEC, larval development and worm burden, and also appeared to enhance immune response. The CT-containing forage SL reduced gastro-intestinal parasite infections of Angora does and kids.

Animal Feed↗
PubMed2005

Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis.

OBJECTIVE: To evaluate concurrent and predictive validity for low-contrast letter acuity (L-CLA) testing as a candidate visual component for the Multiple Sclerosis Functional Composite (MSFC). METHODS: L-CLA testing was conducted in two MS patient cohorts. In the MSFC Validation Study, 137 participants from a Phase III trial of inteferon beta-1a (Avonex) for relapsing-remitting MS were followed. A second cohort included 65 patients with secondary progressive MS who participated in a substudy of the International MS Secondary Progressive Avonex Controlled Trial (IMPACT). The total number of letters read correctly at four contrast levels (100, 5, 1.25, and 0.6%) was correlated with Expanded Disability Status Scale (EDSS), MSFC, Sickness Impact Profile, Multiple Sclerosis Quality of Life Inventory, and brain parenchymal fraction (BPF), as determined by MRI. RESULTS: Low- and high-contrast letter acuity scores correlated with BPF at follow-up in the MSFC Validation Study (5%: r = 0.40, p < 0.0001; 100%: r = 0.31, p = 0.0002). L-CLA also correlated with EDSS (5%: r = -0.35, p < 0.0001; 1.25%: r = -0.26, p = 0.0003) and MSFC (5%: r = 0.47, p < 0.0001; 1.25%: r = 0.45, p < 0.0001). In the IMPACT Substudy, change in L-CLA scores from baseline to year 1 predicted subsequent change in the EDSS from year 1 to 2 at the 5% (p = 0.0142) and the 1.25% (p = 0.0038) contrast levels, after adjusting for change in MSFC scores from baseline to year 1. CONCLUSIONS: Low-contrast letter acuity (L-CLA) scores demonstrate concurrent and predictive validity in patients with relapsing-remitting and secondary progressive multiple sclerosis (MS). L-CLA testing provides additional information relevant to the MS disease process that is not entirely captured by the Multiple Sclerosis Functional Composite.

Adult↗
PubMed2005

Prenatal screening for congenital heart disease using real-time three-dimensional echocardiography and a novel 'sweep volume' acquisition technique.

OBJECTIVES: Conventional prenatal screening for congenital heart disease (CHD) involves a time-consuming and highly operator-dependent acquisition of the four-chamber view and outflow tracts. By acquiring the entire fetal heart instantaneously as a single volume, real-time three-dimensional echocardiography (RT3DE) may facilitate fetal cardiac screening. METHODS: Four reviewers, each experienced with fetal cardiac imaging, blindly and independently evaluated a single cardiac volume from each of 18 fetuses (11 normal, seven with CHD). Two-dimensional echocardiography served as the gold standard. Three-dimensional evaluation of each fetus included a series of volume acquisitions lasting 2-6 s each. A 'sweep volume' technique was developed to fit larger hearts into a single non-gated volume. RESULTS: RT3DE had a high sensitivity for detecting CHD (93%), with only a single case being missed by two observers. Specificity for CHD was low (45%), with a high rate of 'cannot determine' responses and false positive artifacts. CONCLUSIONS: These preliminary results suggest that RT3DE has the potential to function as a screening tool for fetal heart disease. However, artifacts must be recognized and minimized, resolution must improve, and substantial training will be necessary prior to widespread clinical use.

Artifacts↗
PubMed2005

Soluble vascular cell adhesion molecule (VCAM) is associated with treatment effects of interferon beta-1b in patients with secondary progressive multiple sclerosis.

BACKGROUND: Subcutaneous IFNbeta-1b (Betaferon) is an established immunomodulatory treatment for relapsing remitting MS and active secondary progressive multiple sclerosis (SPMS). It modulates cytokine and adhesion molecule expression but long term in vivo effects of IFNbeta-1b on the immune system are not known in multiple sclerosis. OBJECTIVE: To address the effects of IFNbeta-1b on serum levels for soluble adhesion molecules and cytokine receptors from MS patients. METHODS: Serial blood samples were obtained from 40 patients of the frequent MRI subgroup (20 patients each from the placebo and the IFNbeta-1b treatment group), participating in the European multi-center clinical trial with IFNbeta-1b for secondary progressive MS, at regular intervals for up to 36 months. Soluble adhesion molecules (sVCAM, sICAM-1, sL-Selectin) as well as TNF-receptor I and II were analysed in the serum of patients by enzyme linked immunosorbent assays (ELISAs). Monthly brain MRI was performed in 34 of these patients (16 patients from the placebo and 18 from the IFNbeta-1b group) during months 1-6 and 19-24 to monitor disease activity as assessed by newly occurring gadolinium (Gd) enhancing lesions. RESULTS: An early and significant increase in sVCAM and sTNF-RII serum levels was detected in 16 out of 20 patients (80 %) treated with subcutaneous IFNbeta-1b already at month 1 but was absent in all but one patient during placebo treatment (p < 0.01). Raised sVCAM and TNF RII serum levels during months 1-6 inversely correlated with less MRI activity in the 19-24 months treatment interval in the IFNa-1b treatment group ( p = 0.0093 for TNF-RII; p = 0.047 for VCAM). CONCLUSIONS: sVCAM and sTNF RII levels in the serum of SPMS patients are increased during IFNbeta-1b therapy and may at least in part explain some of the treatment effects, like reduced immune cell transmigration.

Adult↗
PubMed2005

Conservative management, percutaneous or open repair of acute Achilles tendon rupture: a retrospective study.

BACKGROUND AND AIMS: To ascertain the differences in patients' perceived outcomes between conservative, percutaneous or open repair of Achilles tendon ruptures. METHODS: We studied 111 patients who had been managed for a unilateral closed Achilles tendon rupture. We excluded patients with open Achilles tendon lesions, patients whose tear had occurred more than seven days from operation, patients with diabetes, inflammatory disease, systemic corticosteroids or fluoroquinolones. Patients were contacted by telephone and asked to answer a questionnaire. RESULTS: There was no difference in effects on working life, patient satisfaction, sports performance, muscle strength, swelling and fear of re-rupture. Pain on weight bearing and cramps were signficantly more frequent in the patients managed conservatively. Re-rupture and complication rates were comparable to published rates. CONCLUSION: Treatment should be individualised according to the demands and health of the patient.

Achilles Tendon↗
PubMed2005

Expression of Polycomb-group genes in human ovarian follicles, oocytes and preimplantation embryos.

Mammalian oocytes possess unique properties with respect to their ability to regulate and reprogram chromatin structure and epigenetic information. Proteins containing the conserved chromodomain motif that is common to the Polycomb-group (Pc-G) proteins and the heterochromatin-associated protein HP1, play essential roles in these processes and more specifically, in X-chromosome inactivation in female zygotes and extra-embryonic tissues and in the regulation of genomic imprinting. To characterize the potential role of these proteins in the regulation of epigenetic events during early human development, we utilized a degenerate PCR priming assay to assess the expression of mRNAs of chromodomain proteins in cDNA samples derived from the human female germline and preimplantation embryos. Expression of mRNAs of HP1 genes was observed in ovarian follicles, (HP1 (HSalpha), HP1 (HSbeta), HP1 (HSgamma)), mature oocytes (HP1 (HSalpha), HP1 (HSbeta)), cleavage stage preimplantation embryos (HP1 (HSalpha), HP1 (HSbeta), HP1 (HSgamma)) and blastocysts (HP1 (HSalpha), HP1 (HSgamma)). Transcripts for three Pc-G genes, which are essential for early mammalian development (Yin Yang 1 (YY1), Enhancer of Zeste-2 (EZH2) and Embryonic Ectoderm Development (EED)) and that are essential for the regulation of X-inactivation and certain imprinted genes (EED) were revealed by gene-specific-PCR expression analysis of human ovarian follicles, oocytes and preimplantation embryos. YY1 and EZH2 transcripts were additionally detected in metaphase II oocytes.

Base Sequence↗
PubMed2004

[A psychosocial training program for elderly patients with age-related macular degeneration: findings of a pilot evaluation study].

The purpose of this work was to develop and evaluate a psychosocial intervention aimed to improve quality of life of AMD patients. A total of 22 outpatients (age 62 to 80 years) treated in the University Eye Clinic in Heidelberg were divided into an intervention group (n=14) and a comparison group without intervention (n=8). The intervention program was based on six modules carried out in five weekly group sessions. These modules included: (1) progressive muscle relaxation, (2) exchange of disease-related experiences, (3) connection between thought, emotion, and behavior, (4) activation of available resources, (5) general problem solving skills and (6) information exchange. Pre-post assessment addressed a set of standardized emotional and behavioral outcome measures. Findings revealed that the intervention group showed improvement or prevention of additional loss in emotional as well as in behavioral outcomes, while the comparison group did not. Results are interpreted as initial evidence that the developed program is able to improve the quality of life in patients suffering from AMD.

Age Factors↗
PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗
PubMed2004

Familial hyperinsulinaemia associated with epilepsy and mental retardation--a syndrome of familial insulin resistance.

BACKGROUND: Variants of type A insulin resistance, characterized by female hyperandrogenism and 'acromegaloid' features, have been ascribed to genetic defects of the insulin receptor or post-receptor pathways via autosomal dominant or recessive inheritance patterns. Whilst a variety of congenital syndromes of insulin resistance are identified by their characteristic clinical phenotypes, an association with epilepsy and mental retardation has not previously been reported. CASE REPORT: We describe three female siblings (aged 12, 19 and 21) with fasting hyperinsulinaemia (116-443 pmol/l; normal range < 80 pmol/l) and mental retardation. Two siblings also have epilepsy. The eldest has features of severe insulin resistance with dyslipidaemia, acanthosis nigricans, 'acromegaloid features' and diabetes requiring high dose insulin therapy in combination with a glitazone. Their mother has fasting hyperinsulinaemia (113 pmol/l), mental retardation and epilepsy. None had clinical or biochemical features of hyperandrogenism or evidence of pigmentory retinopathy, deafness or renal insufficiency. Autoantibody screens were negative. Interestingly, there is no evidence of mental retardation or epilepsy among males in the family. CONCLUSION: This family suggests the presence of a yet-undefined syndrome of familial insulin resistance affecting female kindred. Further studies are being undertaken to clarify the genetic defects and mode of inheritance.

Adult↗