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Thomas Lang

Publications and source records attributed to Thomas Lang.

At least 19 recordsLinked to original sources
PubMed2007

Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy.

UNLABELLED: Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486+5G>A resulting in a 54 bp (3465-3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a LOD score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median gamma-glutamyl transpeptidase (gamma-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P = 0.00341). CONCLUSION: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2007

TENS relieves acute posttraumatic hip pain during emergency transport.

BACKGROUND: In Central Europe, ambulances for patients suffering from pain caused by nonlife-threatening trauma, such as hip fractures are staffed by medical personnel (medics) without physicians. Thus, there is an urgent need for nonpharmacological interventions that can be applied during the transport by basic life-support (BLS) medical personnel. METHODS: In all, 101 patients were screened for participation in this randomized placebo-controlled double-blind study, and randomly assigned to two groups (verum and sham transcutaneous electrical nerve stimulation [TENS]). First, medic A recorded all baseline parameters and measurements, then medic B performed TENS in absence of medic A. At the end of transportation, medic A performed data collection. Each patient was asked to grade his/her pain and anxiety level on visual analog scales (VAS, 0 to 100 mm). RESULTS: From 101 screened patients fulfilling the entry criteria, 29 declined consent and 9 had to be excluded from the analysis because of their final diagnosis. Therefore, the data from 30 patients (group 1, verum TENS) as well as from 33 patients (group 2 [control], sham TENS) were analyzed. No significant differences in potentially influencing factors were found before treatment. Pain scores upon arrival at the hospital differed significantly between group 1 and group 2 (p < 0.01). In group 1, pain reduction was observed between departure from the site of emergency and arrival at the hospital (VAS: 89 +/- 9 to 59 +/- 6 mm), whereas pain scores remained nearly unchanged in group 2 (VAS: 86 +/- 12 to 79 +/- 11 mm). CONCLUSION: Our findings show that TENS is a valuable and fast-acting pain treatment under the difficult circumstances of "out-of-hospital rescue". Because of its lack of side effects, it could also be a valuable tool in the hospital.

Aged↗
PubMed2006

Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).

Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.

5' Flanking Region↗
PubMed2006

Cross-cultural adaptation of the JPF-Questionnaire for German-speaking patients with functional temporomandibular joint disorders.

OBJECTIVES: Clinical research related to the management of the syndrome of temporomandibular joint pain and dysfunction would be facilitated enormously between researchers in different locations around the world if a small number of patient-oriented questionnaires were to achieve wide acceptance. It would make comparison of therapeutic results possible. For this reason, a cross-cultural version of the Jaw Pain and Function (JPF)-Questionnaire was developed and validated for use in German-speaking patients with functional temporomandibular disorders. MATERIAL AND METHODS: The scale was translated from the English into the German language and translated back into English again, pretested and reviewed by a committee. The German version of the JPF-Questionnaire was tested on 137 patients with temporomandibular disorders. Reliability and concurrent construct validity were assessed using Pearson's correlation coefficients. RESULTS: The concurrent validity was assessed by evaluating the relation of the questionnaire's summary score (the internal criterion) to data on maximum interincisal distance (the external criterion). Spearman's and correlation coefficients were statistically significant for the comparison of the summary score with maximal mouth opening (r=-0.213; p=0.036). Test-retest reliability for the JPF-Questionnaire was also assessed by Spearman's correlation coefficients: at first admission at the clinic (time a, mean=20.23+/-16.42, median=16), then at the time of administration 1 day later at home (time b, mean=17.98+/-16.29, median=13), and 7 days later at home (time c, mean=17.90+/-15.77, median=13). They were r=0.91 (p=0.0001) for the initial administration with the repetition 1 day later, r=0.90 (p=0.0001) for the initial administration with the repetition 1 week later, and r=0.93 (p=0.0001) for the correlation between the two repetitions. Test - retest reliability measured by mean-against-difference graphs was not satisfactory for time (a) versus time (b) and time (a) versus time (c) but there was a good test-retest reliability for time (b) versus time (c). CONCLUSION: The use of this instrument can be recommended in future clinical trials, as the German version of the JPF-Questionnaire seems to be valid and--under the same test-retest conditions--reliable for the assessment of temporomandibular joint disorders.

Adolescent↗
PubMed2006

Biomarker responses in flounder (Platichthys flesus) and mussel (Mytilus edulis) in the Klaipeda-Būtinge area (Baltic Sea).

During the EU project BEEP a battery of biomarkers was applied in flounder (Platichthys flesus) and the blue mussel (Mytilus edulis) collected at three locations off the Lithuanian coast (Baltic Sea) in June and September 2001 and 2002. The elevated biomarker responses in specimens sampled in September 2001 were apparently related to the extensive dredging activities in the Klaipeda port area and subsequent dumping of contaminated sediments. High concentrations of organic pollutants (organochlorines and PBDEs) were also measured in the tissues of both indicator species. In addition, response levels of genotoxicity, cytotoxicity, immunotoxicity as well as concentrations of PAH metabolites in the bile of flounder showed elevations in 2002 after an oil spill in the Būtinge oil terminal in November 2001. In flounder, biomarker measurements 10 months after the spill indicated recovery processes but in mussels a high level of genotoxicity could still be observed 22 months later. The present study illustrates the usefulness of the multi-biomarker approach in the detection of biological effects of pollution in this region of the Baltic Sea.

Acetylcholinesterase↗
PubMed2006

The BEEP project in the Baltic Sea: overview of results and outline for a regional biological effects monitoring strategy.

Field studies in the framework of the EU funded BEEP project (Biological Effects of Environmental Pollution in Marine Coastal Ecosystems, 2001-2004) aimed at validating and intercalibrating a battery of biomarkers of contaminant exposure and effects in selected indicator species in the Mediterranean, the North Atlantic and the Baltic Seas. Major strategic goals of the BEEP project were the development of a sensitive and cost-efficient biological effects monitoring approach, delivery of information and advice to end-user groups, and the implementation of a network of biomarker researchers around Europe. Based on the main results obtained in the Baltic Sea component of the BEEP the present paper summarises and assesses the applicability of biomarkers for different regions and species in this sea area. Moreover, a general strategy and some practical considerations for the monitoring of biological effects in the Baltic Sea are outlined.

Acetylcholinesterase↗
PubMed2006

Liver histopathology in Baltic flounder (Platichthys flesus) as indicator of biological effects of contaminants.

Results are presented of a study on liver histopathology in Baltic flounder (Platichthys flesus) carried out in 2001 and 2002 in four coastal sampling areas of the Baltic Sea: Kvädöfjärden (Swedish east coast, reference area), Klaipeda-Butinge (Lithuanian coast), Gulf of Gdansk (Polish coast), and Wismar Bay (German coast) within the framework of the EU-funded BEEP project. Liver lesions were diagnosed and categorised using standardised methodologies and, for a spatial and temporal assessment of the prevalence and types of lesions detected, a scoring system was applied, involving the calculation of mean histopathology lesion scores. 83.0% of the 436 female flounder examined (size range: 20-43 cm total length, age range: 2-8 years) were affected by liver lesions, out of which 74.3% were assigned to the category of non-specific, 3.4% to the category of early toxicopathic non-neoplastic, 4.6% to the category of pre-neoplastic and 0.7% to the category of neoplastic lesions. Mean lesions scores were highest in the areas at the Lithuanian and Swedish coast and there is indication of an impact of the age structure of the flounder populations studied, the sampling season as well as of contaminant effects.

Age Factors↗
PubMed2006

May organic pollutants affect fish populations in the North Sea?

The North Sea is a highly productive area with large fish populations that have been extensively harvested over the past century. North Sea fisheries remain important to the surrounding countries despite declining fish stocks over the past decades. The main reason for declining fish stocks is nearly certainly overfishing, but other environmental pressures also affect fish populations, such as eutrophication, climate change, and exposure to metals and organic pollutants, including polyaromatic hydrocarbons (PAHs), alkylphenols, and organochlorine compounds. There are three main sources of organic pollutants in the North Sea: atmospheric, land-based sources, and inputs from offshore gas and oil installations. All three sources contribute to elevated concentrations of organic pollutants in the North Sea compared to the Norwegian Sea. There is evidence that chlorinated organic contaminants were present in sufficiently high concentrations in the southern North Sea two decades ago, to alter embryonal development in fish. The results from extensive, long-term monitoring programs show that some diseases decreased whereas other increased in the southern North Sea and that, among other factors, contaminants may play a role in the temporal changes recorded in disease prevalence. Recent studies demonstrated that components in offshore effluents may affect fish reproduction and that tissues of fish near oil rigs are structurally different to tissues of fish from reference areas. Data on effluents from offshore activities have recently become available through an international workshop (BECPELAG) and follow-up studies.

Animals↗
PubMed2006

Transcutaneous electrical nerve stimulation: an effective treatment for pain caused by renal colic in emergency care.

PURPOSE: Acute renal colic is one of the most anguishing forms of pain in humans. We hypothesized that TENS is an effective pain treatment in patients with acute renal colic. MATERIALS AND METHODS: A total of 100 patients with acute flank pain and suspected renal colic consented to participate in our study. Paramedic 1 recorded baseline parameters at the emergency site and at the end of transportation. Paramedic 2 performed TENS in patients randomly assigned to G1 with actual TENS or to G2 with sham TENS. Pain and anxiety were measured using paper based visual analog scales on a scale of 0 to 100 mm. RESULTS: Of 100 screened patients 73 had renal colic, including 39 in G1 and 34 in G2. There was no significant difference with regard to potentially influencing factors, such as patient age, sex, weight, height, blood pressure and heart rate, pain, nausea and anxiety between the groups before treatment. G1 showed a significant mean pain decrease +/- SD of more than 50% (85.7 +/- 10.5 to 33.3 +/- 16.0 mm, p <0.01). G2 showed no variation in mean pain scores (85.8 +/- 18.0 to 82.6 +/- 14.3 mm). G1 showed changes in the mean anxiety score (69.0 +/- 8.4 to 37.7 +/- 15.1 mm, p <0.01), nausea score (90.7 +/- 9.2 to 44.9 +/- 22.0 mm) and heart rate (92 +/- 10 to 64 +/- 8 bpm), while G2 showed nonsignificant changes. CONCLUSIONS: This trial shows that local TENS is a rapid and effective treatment for renal colic pain. We found TENS to be a good nondrug therapy under the difficult circumstances of out of hospital rescue.

Adult↗
PubMed2006

Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics.

OBJECTIVE: Our aim was to investigate possible effects of sequence variations in ABCC2, encoding the multidrug resistance-associated protein 2 (MRP2), on the pharmacokinetics of the MRP2 substrate pravastatin. METHODS: Deoxyribonucleic acid samples of 41 healthy volunteers, in whom SLCO1B1 single nucleotide polymorphisms (SNPs) and haplotypes had previously been found to be associated with increased plasma pravastatin concentrations, were investigated. Each study participant had ingested a single 40-mg dose of pravastatin followed by blood sampling for pharmacokinetic characterization in standardized conditions. The exons, exon-intron boundaries, promoter region and 3'-untranslated region of the ABCC2 gene of six individuals with the highest and six individuals with the lowest pravastatin area under the plasma concentration-time curve (AUC) values were sequenced. RESULTS: Of the 26 sequence variations found, the synonymous c.1446C>G SNP was observed heterozygously in three (50%) of the six individuals with a low pravastatin AUC and in none (0%) of the six individuals with a high AUC (P=0.06 for allele frequency). The remaining 29 participants were then also genotyped for c.1446C>G, but none of them carried the SNP. In addition, the effect of c.1446C>G on MRP2 mRNA expression was investigated in 93 human liver samples. A multiple linear regression analysis in the 41 participants with pravastatin pharmacokinetic data indicated that the ABCC2 c.1446C>G SNP and the previously identified SLCO1B1 haplotype *17 were independent predictors of the AUC0-12 and Cmax of pravastatin (r=32 and 29%, respectively) (P<0.01). In the participants heterozygous for the ABCC2 c.1446C>G SNP (n=3), who were not carriers of the SLCO1B1*17 haplotype, the AUC0-12 and Cmax of pravastatin were 67 and 68% lower than in those carrying neither the SLCO1B1*17 haplotype nor the ABCC2 c.1446C>G SNP (n=35) (P<0.05). MRP2 mRNA expression was 95% higher in livers with the c.1446CG genotype (n=7) than in those with the c.1446CC genotype (n=86) (P<0.05). CONCLUSIONS: These results support the idea that the ABCC2 c.1446C>G SNP is associated with reduced systemic exposure to pravastatin as a consequence of increased MRP2 expression. The underlying mechanism may involve either a modulating effect of the SNP on mRNA stability or linkage to other polymorphism(s) acting at the transcriptional level.

Cells, Cultured↗
PubMed2006

Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpreting nitric oxide measures.

Nitric oxide (NO) may play important roles in rheumatoid arthritis (RA). RA is an inflammatory disease involving joints and other systems including salivary glands. To assess NO production in RA patients, we compared levels of serum, urine, and salivary nitrite and nitrate (NOx) in patients with RA and normal subjects, and we examined the relationships of these measures to disease activity. Serum, urine, and NOx levels as well as renal creatinine, NOx clearance and fractional excretion rates were compared in 25 RA patients and 20 age- and gender-matched healthy controls. Subjects were hospitalized for 3 days and placed on a NOx restricted diet. NOx was assayed using nitrate reductase and the Griess reagent. RA activity was assessed using standard clinical and laboratory measures. While consuming a restricted diet for 3 days to eliminate the effects of oral intake of NOx, 24 hour urinary NOx excretion decreased in both RA patients and healthy controls. Urine NOx levels at all time points were not significantly different between RA patients and normal subjects. Serum NOx levels also decreased during the 3 days of NOx restriction, but RA patients had higher serum NOx levels at all time points compared with the control group. Likewise, serum NOx/creatinine ratios were higher in RA patients than in controls. Although basal salivary flow rate and tear flow were lower in RA patients, salivary NOx levels did not differ between normal and RA subjects. While renal creatinine clearance was not different between the two groups, we found that RA patients had lower renal NOx clearance and lower renal NOx fractional excretion. After correction of p values for multiple comparisons, there were no significant relationships for the RA group between measures of disease activity and the urinary NOx, serum NOx, or urinary NOx clearance. Despite interest in the use of NO as a marker of disease activity, alterations in renal NOx clearance and fractional excretion in RA make it difficult to assess in vivo NO production even with strict dietary restriction of NOx intake.

Arthritis, Rheumatoid↗
PubMed2006

Effects of testosterone, 17beta-estradiol, and downstream estrogens on cytokine secretion from human leukocytes in the presence and absence of cortisol.

Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol.

Adult↗
PubMed2005

Alpha-1-antitrypsin deficiency in children: liver disease is not reflected by low serum levels of alpha-1-antitrypsin - a study on 48 pediatric patients.

BACKGROUND: Alpha-1-antitrypsin (alpha1-AT) is an important protease inhibitor. The phenotypes are characterized by a low total serum alpha1-AT or by an abnormal protein accumulating in the hepatocytes. The aim of our study was to examine a correlation of total serum alpha1-AT, phenotype, and liver involvement in pediatric patients. METHODS: 48 patients, deficient for alpha1-AT were included. The phenotypes for alpha1-AT were determined by isoelectric focusing. Liver disease was defined either as elevated transaminases or/and as elevated conjugated bilirubin and gammaGT. Patients were reexamined after a mean interval of 2 years. RESULTS: Homozygous alpha1-AD was found in 12 patients, heterozygous in 24 patients. In 12 children rare variants of alpha1-AD were diagnosed. Serum alpha1-AT levels less than 60% of normal were found in all patients with homozygous, in 37% of patients with heterozygous alpha1-antitrypsin deficiency (alpha1-AD), and in patients with the homozygous variant PiM(palermo). Liver disease was found in 8/12 patients with the phenotype PiZZ and in 15/24 patients with heterozygous alpha1-AD. Three of 4 patients with the phenotype PiMQ0 had severe liver disease despite normal serum levels for alpha1-AT. In 11 patients with heterozygous alpha1-AD liver disease was apparent despite normal serum alpha1-AT levels. In two patients with the variant type Mpalermo serum levels were as low as 11% of normal without any signs of liver disease. CONCLUSIONS: Our data clearly show that in the diagnostic workup of neonatal cholestasis measurement of total serum alpha1-AT does not exclude liver disease due to abnormal alpha1-AT variants. We suggest analysis of alpha1-AT-phenotype by isoelectric focussing in patients with unknown liver disease. Heterozygous or rare variant types might remain undiagnosed by measuring total alpha1-AT only.

Adolescent↗
PubMed2005

Prevalence and clinical role of GBV-C infection after cardiac surgery in childhood: a study on 414 patients.

OBJECTIVES: GB-virus C (GBV-C) and hepatitis C virus (HCV) share similar modes of transmission. We, therefore, examined the prevalence and clinical role of GBV-C and HCV in patients after cardiac surgery in childhood. METHODS: We analysed blood samples of 414 patients and compared them to 487 controls. Evidence of liver disease and risk factors for infection was analysed. RESULTS: Overall prevalence of GBV-C infection was 22.5% in the patients, compared to 6.2% in the controls (HCV infection 11.3 vs. 0.7%). GBV-C RNA was detected in 8.2% of the patients vs. 3.7% in the controls (HCV RNA in 6 and 0%, respectively). Eleven patients had detectable RNA of GBV-C and HCV. 63.4% of patients infected with GBV-C and 46.8% of patients infected with HCV cleared the virus from circulation. GBV-C infection was not associated with hepatitis. Liver disease was not more frequent in patients co-infected with HCV and GBV-C. CONCLUSIONS: before 1991 have a substantial risk for HCV and GBV-C infection. However, GBV-C infection seems not to be associated with a liver disease. Co-infection with GBV-C and HCV has no influence on long-term clinical outcome or viral clearance of HCV infection.

Adolescent↗
PubMed2005

Automated registration of hip and spine for longitudinal QCT studies: integration with 3D densitometric and structural analysis.

To eliminate user interaction in longitudinal quantitative computed tomography (QCT) measurements of bone mineral density (BMD) and geometry, we have developed and optimized an automated registration algorithm for QCT images of the hip and spine and integrated it with a previously developed 3D densitometric and structural analysis program. With registration, the follow-up images are automatically aligned with respect to the baseline scans, and the bone quantification of the aligned follow-up scan is initiated based on the bone morphometric features defined on the baseline scan. To validate the algorithm, we analyzed 20 pairs of repeat QCT images (10 hip pairs and 10 spine pairs) acquired on a modern multi-slice CT scanner, with repositioning between each scan pair to simulate repeat visits. Bone measurements obtained with automatic registration achieved comparable or improved precision errors compared to those obtained by careful manual analysis of the follow-up scans. The algorithm we have developed was based on the mutual information approach, with simplex optimization under a multi-resolution scheme. The average registration time was 2.3 min for a hip pair and 1.1 min for a vertebra pair using a standard desktop computer. Based on the reduced user interaction, high degree of precision, and short execution time, this is a promising technique for monitoring therapy in patients and clinical trials.

Absorptiometry, Photon↗
PubMed2005

A natural CYP2B6 TATA box polymorphism (-82T--> C) leading to enhanced transcription and relocation of the transcriptional start site.

We investigated the impact of promoter polymorphisms on transcription of the human CYP2B6 gene. In total, 98 DNA samples from white persons from a previously characterized liver bank were sequenced throughout 2.3 kilobases of upstream sequence and haplotype structures were determined using additional coding sequence information. HepG2 cells and primary rat and human hepatocytes were transfected with luciferase reporter gene constructs driven by 2033 base pairs (bp) of the most frequent promoter variants. The novel haplotype *22 (-1848C--> A, -801G--> T, -750T--> C, and -82T--> C) showed 3- to 9-fold enhanced transcriptional activity in all transfected cells. Constructs containing single mutations surprisingly revealed -82T--> C, predicted to disrupt a putative TATA box, to be alone responsible for this effect. In silico analysis and electrophoretic mobility shift assay demonstrated conversion of the putative TATA box into a functional CCAAT/enhancer-binding protein binding site. Analysis of transcriptional start sites showed the mutant promoter to be transcribed from a start site located approximately 30 bp downstream of the wild-type start site, consistent with the use of a noncanonical TATA box at -55 bp. Median CYP2B6 mRNA expression and bupropion hydroxylase activity as a selective marker of CYP2B6 catalytic activity were approximately 2-fold higher in livers genotyped -82TC as in those genotyped -82TT (20.4 versus 9.8 arbitrary units, p = 0.007, and 201.8 versus 106.7 pmol/mg/min, p = 0.042, respectively). This promoter polymorphism thus contributes to CYP2B6 functional variability and represents a novel mechanism by which mutations can enhance transcription. Furthermore, a detailed interspecies comparison of CYP2B promoters and transcriptional start sites provided novel insights into evolutionary relationships.

Animals↗
PubMed2005

Components of behavioral pathology in dementia.

OBJECTIVE: The purpose of this study was to examine the occurence of the noncognitive behavioral and psychological symptoms and signs of dementia in a geriatric chronic-care hospital and to separate agitated and affective components of behavioral pathology using factor analysis. METHODS: The frequency and severity of Alzheimer's disease, vascular dementia, mixed dementia and Lewy Body dementia was assessed in 145 consecutive residents of a chronic-care hospital. The presence of noncognitive behavioral symptoms was evaluated with the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Cohen-Mansfield Agitation Inventory (CMAI). A Factor analysis on the BEHAVE-AD subscores was performed to create symptom clusters. Analysis of covariance and post hoc tests were used to compare means of factor variables between different types of dementia. RESULTS: Statistical analysis showed a significant correlation between severity of dementia and BEHAVE-AD total score and between severity of dementia and CMAI total score. Factor analysis with Varimax rotation revealed the presence of three behavioral subsyndromes: agitation, affectivity and day/night disturbances. CONCLUSIONS: The finding of three factors of behavioral pathology in demented patients reflects the possibility that different etiological mechanisms could explain the expression of the symptoms and signs of psychosis in demented patients.

Affective Symptoms↗