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Biomedical subjects

M Muller

Publications and source records attributed to M Muller.

At least 19 recordsLinked to original sources
PubMed2006

Modular changes of cis-regulatory elements from two functional Pit1 genes in the duplicated genome of Cyprinus carpio.

The pituitary-specific transcription factor Pit1 is involved in its own regulation and in a network of transcriptional regulation of hypothalamo-hypophyseal factors including prolactin (PRL) and growth hormone (GH). In the ectotherm teleost Cyprinus carpio, Pit1 plays an important role in regulation of the adaptive response to seasonal environmental changes. Two Pit1 genes exist in carp, a tetraploid vertebrate and transcripts of both genes were detected by RT-PCR analysis. Powerful comparative analyses of the 5'-flanking regions revealed copy specific changes comprising modular functional units in the naturally evolved promoters. These include the precise replacement of four nucleotides around the transcription start site embedded in completely conserved regions extending upstream of the TATA-box, an additional transcription factor binding site in the 5'-UTR of gene-I and, instead, duplication of a 9 bp element in gene-II. Binding of nuclear factors was assessed by electro mobility shift assays using extracts from rat pituitary cells and carp pituitary. Binding was confirmed at one conserved Pit1, one conserved CREB and one consensus MTF1. Interestingly, two functional Pit1 sites and one putative MTF1 binding site are unique to the Pit1 gene-I. In situ hybridization experiments revealed that the expression of gene-I in winter carp was significantly stronger than that of gene-II. Our data suggest that the specific control elements identified in the proximal regulatory region are physiologically relevant for the function of the duplicated Pit1 genes in carp and highlight modular changes in the architecture of two Pit1 genes that evolved for at least 12 MYA in the same organism.

Animals↗
PubMed2006

Bone micro-damage assessment using non-linear resonant ultrasound spectroscopy (NRUS) techniques: a feasibility study.

Non-linear resonant ultrasound spectroscopy (NRUS) is a technique exploiting the significant non-linear behavior of damaged materials, related to the presence of damage. This study shows for the first time the feasibility of this technique for damage assessment in bone. Two samples of bovine cortical bone were subjected to a progressive damage experiment. Damage accumulation was progressively induced in the samples by mechanical testing. For independent assessment of damage, X-ray CT imaging was performed at each damage step, but only helped in the detection of the prominent cracks. Synchrotron micro-CT imaging and histology using epifluorescence microscopy were performed in one of the two samples at the last damage step and allowed detection of micro-cracks for this step. As the quantity of damage accumulation increased, NRUS revealed a corresponding increase in the non-linear response. The measured change in non-linear response is much more sensitive than the change in elastic modulus. The results suggest that NRUS could be a potential tool for micro-damage assessment in bone. Further work has to be carried out for a better understanding of the physical nature of damaged bone, and for the ultimate goal of in vivo implementation of the technique where bone access will be a challenging problem.

Algorithms↗
PubMed2006

Oxcarbazepine versus phenytoin monotherapy for epilepsy.

BACKGROUND: Worldwide, phenytoin is a commonly used antiepileptic drug. Oxcarbazepine is one of the newer antiepileptic drugs and has similar chemical properties to its parent compound carbamazepine. For the new drugs such as oxcarbazepine, it is important to know how they compare with standard treatments. OBJECTIVES: To review the best evidence comparing oxcarbazepine and phenytoin when used as monotherapy in patients with epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialized Register (December 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), and MEDLINE (1966 to November 2005). No language restrictions were imposed. We checked the reference lists of retrieved studies for additional reports of relevant studies. We also contacted pharmaceutical companies to try and identify any unpublished studies. SELECTION CRITERIA: Randomized controlled trials in children or adults with epilepsy. Trials must have included a comparison of oxcarbazepine monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Outcomes were (a) time on allocated treatment; (b) time to achieve 6, 12 and 24-month remission; (c) time to first seizure post randomization; (d) quality of life measures if available. Clinical heterogeneity was assessed by reviewing differences across trials in characteristics of randomized patients, dosing protocols and trial design. Data were analysed on an intention to treat basis. Stratified logrank tests were used to obtain study-specific and overall estimates of hazard ratios (with 95% confidence intervals), where a HR > 1 indicates that an event is more likely on phenytoin. MAIN RESULTS: Individual patient data were available for 480 patients from two trials, representing 100% of the patients recruited into the two trials that met our inclusion criteria. By convention, for the outcomes time to withdrawal of allocated treatment and time to first seizure a hazards ratio (HR) > 1 indicates a clinical advantage for oxcarbazepine and for time to 6 and 12-month remission a HR > 1 indicates a clinical advantage for phenytoin. The main overall results (HR, 95% confidence interval (CI)) were: (i) time to withdrawal of allocated treatment 1.64 (1.09 to 2.47), (ii) time to 6-month remission 0.89 (0.66 to 1.22), (iii) time to 12-month remission 0.92 (0.62 to 1.37), (iv) time to first seizure 1.07 (0.83 to 1.39). The overall results indicate that oxcarbazepine is significantly better than phenytoin for time to treatment withdrawal, but suggest no overall difference between oxcarbazepine and phenytoin for other outcomes. Results stratified by seizure type indicate no significant advantage for either drug for patients with generalized onset seizures, but a potentially important advantage in time to withdrawal for oxcarbazepine for patients with partial onset seizures: HR 1.92 (95% CI 1.17 to 3.16). The age distribution of adults classified as having generalized epilepsy suggests a significant number of patients may have had their epilepsy misclassified. AUTHORS' CONCLUSIONS: For patients with partial onset seizures oxcarbazepine is significantly less likely to be withdrawn, but current data do not allow a statement as to whether oxcarbazepine is equivalent, superior or inferior to phenytoin in terms of seizure control. Guidelines recommend carbamazepine as a first line treatment for patients with partial onset seizures and more evidence is needed regarding the comparative effects of oxcarbazepine and carbamazepine to further inform policy. For patients with generalized onset tonic-clonic seizures, valproate is considered the first line standard treatment and the results of this review do not inform current treatment policy. Misclassification of patients' epilepsy type may have confounded the results of this review.

Anticonvulsants↗
PubMed2006

Cloning of the prepro C-RFa gene and brain localization of the active peptide in Salmo salar.

In all vertebrates, the synthesis and release of prolactin (Prl) from pituitary lactotroph cells is tightly controlled by hypothalamic factors. We have cloned and characterized a hypothalamic cDNA from Atlantic salmon (Salmo salar) encoding C-RFa, a peptide structurally related to mammalian Prl-releasing peptide (PrRP). The deduced preprohormone precursor is composed of 155 amino acid residues presenting a 87.1% similarity to chum salmon C-RFa and a 100% similarity to all fish C-RFa in the bioactive precursor motifs. C-RFa-immunoreactive perikarya and fibres were located in the brain of S. salar, especially in the hypothalamus, olfactory tract, optic tectum and cerebellum. In contrast, immunolabelled fibres were not observed in the pituitary stalk or in the hypophysis. However, interestingly, we detected immunolabelled cells in the rostral pars distalis of the pituitary in the basolateral region in which Prl is synthesized. These results were confirmed by obtaining a strong signal by using reverse transcription/polymerase chain reaction (RT-PCR) on mRNA from both hypothalamus and pituitary. These data show, for the first time, by immunohistochemistry and RT-PCR, that C-RFa is produced in pituitary cells. Finally, based on these results, a possible function for C-RFa as a locally produced PrRP in this teleost is discussed.

Amino Acid Sequence↗
PubMed2006

Cardiovascular disease and cognitive performance in middle-aged and elderly men.

BACKGROUND: Decline of cognitive function with age may be due, in part, to atherosclerotic changes. The aim of the present study was to determine the relative contribution of cardiovascular disease (CVD) to cognitive functioning in middle-aged and elderly men. METHODS: In a cross-sectional study, cognitive tests were administered to 400 independently living men aged 40-80 years. Compound scores were calculated for memory function, processing capacity/speed, and executive function. The MMSE was used as a measure of global cognitive function. Carotid intima-media thickness, pulse wave velocity and ankle brachial blood pressure index were assessed as measures of sub-clinical CVD. The adjusted association of sub-clinical and prevalent CVD with neuropsychological test scores in the total group and in subgroups was assessed by linear regression analysis. RESULTS: Increased IMT was associated with lower scores on memory performance, and increased PWV was associated with lower scores on processing capacity and executive functioning. Compared with subjects with no CVD, both sub-clinical and prevalent cardiovascular diseases were related to a lower memory performance, beta's (95% CI) were -0.45 (-0.83, -0.07) and -0.45 (-0.84, 0.01), respectively. These associations were present in both middle-aged and elderly men. Furthermore, we observed that for subjects who had sub-clinical or prevalent cardiovascular disease the distribution of MMSE-scores was shifted toward lower values; the distributions were statistically different (p=0.003). CONCLUSIONS: The results of this study support a relation of sub-clinical CVD with cognitive functioning in middle-aged and elderly men. These results suggest that actions to prevent cognitive decline by preventing atherosclerosis should be taken before middle age.

Adult↗
PubMed2005

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

Animals↗
PubMed2005

Expression and functional properties of four slow skeletal troponin T isoforms in rat muscles.

We investigated the expression and functional properties of slow skeletal troponin T (sTnT) isoforms in rat skeletal muscles. Four sTnT cDNAs were cloned from the slow soleus muscle. Three isoforms were found to be similar to sTnT1, sTnT2, and sTnT3 isoforms described in mouse muscles. A new rat isoform, with a molecular weight slightly higher than that of sTnT3, was discovered. This fourth isoform had never been detected previously in any skeletal muscle and was therefore called sTnTx. From both expression pattern and functional measurements, it appears that sTnT isoforms can be separated into two classes, high-molecular-weight (sTnT1, sTnT2) and low-molecular-weight (sTnTx, sTnT3) isoforms. By comparison to the apparent migration pattern of the four recombinant sTnT isoforms, the newly described low-molecular-weight sTnTx isoform appeared predominantly and typically expressed in fast skeletal muscles, whereas the higher-molecular-weight isoforms were more abundant in slow soleus muscle. The relative proportion of the sTnT isoforms in the soleus was not modified after exposure to hindlimb unloading (HU), known to induce a functional atrophy and a slow-to-fast isoform transition of several myofibrillar proteins. Functional data gathered from replacement of endogenous troponin complexes in skinned muscle fibers showed that the sTnT isoforms modified the Ca(2+) activation characteristics of single skeletal muscle fibers, with sTnT2 and sTnT1 conferring a similar increase in Ca(2+) affinity higher than that caused by low-molecular-weight isoforms sTnTx and sTnT3. Thus we show for the first time the presence of sTnT in fast muscle fibers, and our data show that the changes in neuromuscular activity on HU are insufficient to alter the sTnT expression pattern.

Amino Acid Sequence↗
PubMed2005

Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level?

OBJECTIVE: To determine whether endogenous sex hormone levels are associated with cognitive functioning in men. METHODS: Cognitive performance was assessed in 400 independently living men between ages 40 and 80 in a population-based cross-sectional study. Compound scores were calculated for memory function, processing capacity/speed, and executive function. The Mini-Mental State Examination was used as a measure of global cognitive function. The adjusted association of testosterone (T) and estradiol (E2) (total, bioavailable) with neuropsychological test scores in the total group and in subgroups was assessed by linear and logistic regression analysis. RESULTS: Curvilinear associations were observed between T and memory performance and processing capacity/speed, suggesting optimal sex hormone levels. No association between E2 and cognitive functioning was found. After the population was subdivided into four age decades, a linear association of T with cognitive functioning in the oldest age category remained. No association was found in the other age decades. Lower bioavailable T levels were associated with lower scores on processing capacity/speed and executive function; beta (95% CI) values were 0.36 (0.07 to 0.66) and 0.17 (-0.01 to 0.35). Similar results were observed for total T. CONCLUSIONS: Higher testosterone (T) levels are associated with better cognitive performance in the oldest age category. Apparent curvilinear associations between T and certain cognitive functions in men suggest an optimal hormone level for particular cognitive tasks and are explained by linear associations in the oldest age category.

Adult↗
PubMed2005

Management of high voltage electrical injury in children.

High voltage electrical injuries in children are rare. They produce severe internal damage to limbs resulting in a high incidence of amputation. Early, aggressive serial debridement ensures adequate removal of dead tissue. Flap coverage to defects is necessary. Secondary surgery is common, and delayed sequelae such as tendon rupture should be expected.

Abdomen↗
PubMed2005

Comparison of three ultrasonic axial transmission methods for bone assessment.

This study compared three approaches to bone assessment using ultrasonic axial transmission. In 41 fresh human radii, velocity of the first arriving signal was measured with a commercial device (Sunlight Omnisense) operating at 1.25 MHz, a prototype based on 1-MHz bidirectional axial transmission and a low-frequency (200 kHz) prototype, also measuring the velocity of a slower wave. Cortical and trabecular bone mineral density, cortical thickness and cross-sectional area were determined by peripheral quantitative computed tomography. Significant but modest correlation between velocities reflects differences in the nature of the propagating waves and methodological differences. Of the higher frequency devices, bidirectional measurements provided stronger correlations with bone properties than did conventional measurements. High-frequency devices were less sensitive to cortical thickness than was the low-frequency device, because higher frequency waves interrogate thinner cortical layers. The results suggest that different axial transmission approaches reflect different bone properties. Therefore, a multifrequency technique might be useful in probing different bone properties.

Aged↗
PubMed2005

HIV and male circumcision--a systematic review with assessment of the quality of studies.

This Cochrane systematic review assesses the evidence for an interventional effect of male circumcision in preventing acquisition of HIV-1 and HIV-2 by men through heterosexual intercourse. The review includes a comprehensive assessment of the quality of all 37 included observational studies. Studies in high-risk populations consisted of four cohort studies, 12 cross-sectional studies, and three case-control studies; general population studies consisted of one cohort study, 16 cross-sectional studies, and one case-control study. There is evidence of methodological heterogeneity between studies, and statistical heterogeneity was highly significant for both general population cross-sectional studies (chi(2)=132.34; degrees of freedom [df]=15; p<0.00001) and high-risk cross-sectional studies (chi(2)=29.70; df=10; p=0.001). Study quality was very variable and no studies measured the same set of potential confounding variables. Therefore, conducting a meta-analysis was inappropriate. Detailed quality assessment of observational studies can provide a useful visual aid to interpreting findings. Although most studies show an association between male circumcision and prevention of HIV, these results may be limited by confounding, which is unlikely to be adjusted for.

Africa South of the Sahara↗
PubMed2005

Single lateral locked screw plating of bicondylar tibial plateau fractures.

We prospectively followed a case series of 68 patients with 69 AO/ASIF 41-C-type fractures treated with the Less Invasive Stabilization System for the proximal lateral tibia. We assessed malreduction, secondary loss of reduction, and infection rates in patients with a locked screw plate for unilateral fixation of bicondylar fractures. Sixty-two (91%) patients returned for final followup (range, 11-13 months). Malreduction and malalignment were defined as an intraarticular step-off of 2 mm or greater, or as a malalignment in the frontal or sagittal plane greater than 5 degrees . Fourteen fractures were open. Primary bone grafting was done in 13 patients. Significant malreduction was seen in 16 patients. There were four superficial infections and one deep infection. One fracture did not heal, and nine patients had substantial loss of reduction. Unilateral locked screw plating is a good alternative for treatment of problematic fractures of the tibial plateau that are associated with soft tissue damage and metaphyseal comminution. The reduction technique for exact alignment is demanding.

Adolescent↗
PubMed2005

Alcohol and arterial wave reflections in middle aged and elderly men.

BACKGROUND: Augmentation index (AIx) is a measure of arterial wave reflection, providing information on the workload of the heart. and is a possible marker for cardiovascular disease risk. The relation of alcohol consumption with cardiovascular disease (CVD) risk is U-shaped with a protective effect of moderate alcohol consumption. The relation of alcohol consumption level with AIx has not been widely investigated, which prompted this study of the relation of alcohol consumption with AIx in a population-based cohort of men aged 40-80 years. METHODS: Three hundred and seventy-four men (mean age 60.5 years) participated in this cross-sectional study. Alcohol consumption and smoking habits were determined through a validated questionnaire. Fasting blood samples were drawn and analyzed for glucose and lipid levels and AIx was estimated by radial applanation tonometry using the SphygmoCor Device. The resultant data were analyzed using linear regression models. RESULTS: Age, height, heart rate, blood pressure, packyears, current smoking, presence of CVD and hypertension were independently related to AIx. The relation of alcohol consumption with AIx was U-shaped, with a significantly lower AIx in the group drinking 4-8 glasses/week (difference = -2.91%, 95% CI [-5.65; -0.18]) relative to those drinking 0-3 glasses/week. Additional adjustment for current smoking did not change this relationship, but adjustment for pulse wave velocity attenuated the relation. CONCLUSIONS: In a population-based cohort of men aged 40-80 years the relation of alcohol consumption level with AIx was U-shaped, further expanding the evidence for vascular protective effects of moderate alcohol intake.

Adult↗
PubMed2004

[Impaired cognitive functioning in low-grade glioma patients: relationship to tumor localisation, radiotherapy and the use of anticonvulsants].

OBJECTIVE: To determine the effects of radiotherapy and other medical interventions on cognitive functioning in patients with a low-grade glioma (LGG). DESIGN: Cross-sectional study. METHOD: A total of 195 LGG patients, of whom 104 had received radiotherapy 1-22 years previously, were compared to 100 patients with a low-grade haematological malignancy and 195 healthy controls. The analysis was aimed at differentiating between the effects of the tumour (disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, use of anticonvulsants) on cognitive function and the relative risk of cognitive disability. RESULTS: LGG patients had lower performance levels in all cognitive domains than haematological patients and performed even worse when they were compared to healthy controls. Radiotherapy was associated with poorer cognitive functioning; however, cognitive disability was found only in patients receiving fractional doses exceeding 2 Gy. The use of anticonvulsants was strongly associated with disorders in the area of attention and planning functions. CONCLUSION: In this study, the tumour itself was the most damaging factor with respect to cognitive function and radiotherapy was associated with cognitive disability only if elevated fractional doses were used. Epilepsy or the use of anticonvulsants was also associated with diminished cognitive functioning.

Anticonvulsants↗
PubMed2004

Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma.

PURPOSE: The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice. METHODS: Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment. RESULTS: As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib (P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups. CONCLUSION: Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.

Animals↗
PubMed2004

Hydrofluoric acid burns.

OBJECTIVE: The purpose of this article is to report our experience with hydrofluoric acid (HF) burns and to present our management guidelines for these burns, which include a novel way of delivering calcium combined with dimethyl sulphoxide (DMSO) for cutaneous burns. METHOD: We reviewed our institutional experience from 1977 to 1999 for patients presenting with burns caused by hydrofluoric acid and collected data on age, sex, burn size, anatomical site, method of contact, surgical procedure, and outcome. RESULTS: Of a total of 2310 admissions, 42 HF burns patients were identified during the study period. The average age was 34 years. There were 35 males and 7 females. Seventy-four percent of cases received burns to the upper limb. Median burn size was 1% of the total body surface area. Seventeen percent of patients required a surgical procedure. In 24% of cases, the method of contact was work related and 40% were injured using cleaning products at home or on boats. No deaths were recorded. CONCLUSION: HF injury is uncommon but problematic burns often requiring surgery. RECOMMENDED MANAGEMENT: In cases of cutaneous exposure, treatment should commence immediately with 30 min lavage followed by application dimethyl sulphoxide 50% + calcium gluconate 10% in surgical jelly. If hand or forearm is affected, regional intravenous calcium 'Bier's block' using 40 ml 10% calcium gluconate with 5000 U heparin in total final volume of 40 ml may be indicated. Subcutaneous infiltration may be indicated for elsewhere at 0.5 ml/cm(2) burn of 10% calcium gluconate. Persisting pain may require nail removal or arterial calcium infusion.

Administration, Topical↗