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Biomedical subjects

A Brehm

Publications and source records attributed to A Brehm.

At least 19 recordsLinked to original sources
PubMed2006

Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans.

BACKGROUND: The mechanisms responsible for the progressive failure of hypoglycaemia counterregulation in long-standing type 1 diabetes are poorly understood. Increased brain glucose uptake during hypoglycaemia or alterations of brain energy metabolism could effect glucose sensing by the brain and thus contribute to hypoglycaemia-associated autonomic failure. MATERIALS AND METHODS: Type 1 diabetic patients (T1DM) and healthy volunteers (CON) were studied before, during and after a hypoglycaemic (50 mg dL(-1)) hyperinsulinaemic (1.5 mU kg(-1) min(-1)) clamp test. The (1)H magnetic resonance spectroscopy of the occipital lobe of the brain was performed employing the STEAM localization technique. The water signal was suppressed by the modified SWAMP method. All spectra were acquired on a 3 Tesla scanner (80 cm MEDSPEC-DBX, Bruker Medical, Ettlingen, Germany) using a 10-cm diameter surface coil. RESULTS: During hypoglycaemia, T1DM showed blunted endocrine counterregulation. At baseline the brain tissue glucose : creatine ratio was lower in CON than in T1DM (CON 0.13 +/- 0.05 vs. T1DM 0.19 0.11; P < 0.01). During hypoglycaemia glucose : creatine ratios decreased in both groups (CON 0.07 +/- 0.08, P < 0.05; T1DM 0.03 +/- 0.03, P < 0.001). A significant drop in the glutamate : creatine ratio could only be found in CON during hypoglycaemia (CON 1.36 +/- 0.08 vs. 1.26 +/- 0.11; P < 0.01; T1DM 1.32 +/- 0.13 vs. 1.28 +/- 0.15; P = NS). The ratios of glutamine, N-acetylaspartate, choline and myo-inositol : creatine were not different between both groups and did not change throughout the experiment. CONCLUSIONS: Only in CON does moderate hypoglycaemia reduce intracerebral glutamate concentrations, possibly owing to a slower substrate flux through the tricarboxylic acid cycle in neurones. The maintenance of normal energy metabolism in T1DM during hypoglycaemia might effect glucose sensing in the brain and contribute to hypoglycaemia-associated autonomic failure.

Adult↗
PubMed2005

Changes in hepatic glycogen cycling during a glucose load in healthy humans.

AIMS/HYPOTHESIS: Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen-->glucose 1-phosphate-->glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. MATERIALS AND METHODS: The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested (2)H(2)O (5 ml/kg body water) and were infused with [5-(3)H]glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of (2)H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the (3)H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. RESULTS: Glucose infusion rates increased (p<0.01) to approximately 50 mumol kg(-1) min(-1). Plasma insulin and the insulin : glucagon ratio rose approximately 3.6- and approximately 8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2-4 h, 54+/-6%; 4-6 h, 59+/-5%; 6-8 h, 63+/-4%) and indirect (32+/-3, 38+/-4, 36+/-3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14+/-4% (2-4 h) to 4+/-3% (4-6 h) and 1+/-3% (6-8 h). CONCLUSIONS/INTERPRETATION: This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.

Adult↗
PubMed2005

[HLA-B27 polymorphism and spondyloarthropathies].

The association of HLA-B27 with ankylosing spondylitis (AS), and other spondyloarthropathies (SpA), remains as one of the strongest between HLA molecules and human disease. Since it was reported, in 1973, it has been extensively studied in order to understand the underlying pathogenic mechanism. The objective of this article is to review the current knowledge on the structure and polymorphism of HLA-B27 molecule, as well as describe the main pathogenic hypotheses trying to explain its association with AS.

HLA-B27 Antigen↗
PubMed2005

HLA genes in Portugal inferred from sequence-based typing: in the crossroad between Europe and Africa.

The human leukocyte antigen-A (HLA-A), -B and -DRB1 polymorphism was examined in the Portuguese population, discriminating between North, Centre and South inhabitants. All data were obtained at high-resolution level, using sequence-based typing. The most frequent allele at each locus was A* 020101 (26%), B* 440301 and B* 510101 (12% each) and DRB1* 070101 (15%). The predominant three-locus haplotype was A*020101-B*440301-DRB1*070101 (3.1%), highly frequent in North Portugal (5.4%), lower in Centre (2%) and absent in the South. The present study demonstrates that the Portuguese population has been genetically influenced by Europeans and North Africans, via several historic immigrations. North Portugal seems to concentrate, probably due to the pressure of Arab expansion, an ancient genetic pool originated from several North Africans and Europeans, influences throughout millenniums. South Portugal shows a North African genetic influence, probably of recent origin by means of Berbers accompanying Arab expansion. We found that Centre Portugal is the distribution limit of some alleles and haplotypes that characterize the North or the South of the country. Despite North, Centre and South Portugal not being significantly different in allele frequencies, this study shows that HLA allele and haplotype frequencies are not homogeneous in the country. North and South Portugal show more similarity to North Africans in opposition to Centre which appears closer to Europeans.

Africa↗
PubMed2005

HLA class I and II polymorphisms in Azores show different settlements in Oriental and Central islands.

Human leucocyte antigen-A, -B, -Cw, -DRB1, -DQA1 and -DQB1 polymorphisms were examined in the Azorean population. The data were obtained at high-resolution level, using polymerase chain reaction (PCR) with sequence-specific primer, PCR-sequence-specific oligonucleotides and sequence-based typing. The most frequent allele in each locus was: A*0201 (24.5%), B*510101 (9.8%), Cw*0401 (14.8%), DRB1*070101 (18.3%), DQA1*0201 (17.4%) and DQB1*0301 (19.4%). The predominant extended haplotype was A*0202-B*1503-Cw*0202-DRB1*090102-DQA1*0303- DQB1*0202 (1.9%), which was found to be absent in the Portuguese mainland. The present study corroborates historical sources that say the Azores were populated not only by Portuguese but also by other Europeans, mostly Flemish people. Despite dendrogram analysis showing some remote Asian genetic affinities, the lack of specific alleles and haplotypes from those populations does not allow us to conclude for direct influence. Haplotype and allele frequencies in Azores show no homogeneous distribution between Oriental and Central islands of this archipelago. The Oriental islands harbour several haplotypes already found in mainland Portugal and identified as Mediterranean and European. The Central group of islands on the contrary clearly shows an influence of north Europeans (most probably derived from a well-documented Flemish settlement), with much less affinity to mainland Portugal.

Alleles↗
PubMed2004

Brain energy metabolism during hypoglycaemia in healthy and type 1 diabetic subjects.

AIMS/HYPOTHESIS: This study aimed to examine brain energy metabolism during moderate insulin-induced hypoglycaemia in Type 1 diabetic patients and healthy volunteers. METHODS: Type 1 diabetic patients (mean diabetes duration 13 +/- 2.5 years; HbA1c 6.8 +/- 0.3%) and matched controls were studied before, during (0-120 min) and after (120-240 min) hypoglycaemic (approximately 3.0 mmol/l) hyperinsulinaemic (1.5 mU x kg(-1) min(-1)) clamp tests. Brain energy metabolism was assessed by in vivo 31P nuclear magnetic resonance spectroscopy of the occipital lobe (3 Tesla, 10-cm surface coil). RESULTS: During hypoglycaemia, the diabetic patients showed blunted endocrine counter-regulation. Throughout the study, the phosphocreatine:gamma-ATP ratios were lower in the diabetic patients (baseline: controls 3.08 +/- 0.29 vs diabetic patients 2.65 +/- 0.43, p<0.01; hypoglycaemia: 2.97 +/- 0.38 vs 2.60 +/- 0.35, p<0.05; recovery: 3.01 +/- 0.28 vs 2.60 +/- 0.35, p<0.01). Intracellular pH increased in both groups, being higher in diabetic patients (7.096 +/- 0.010 vs. 7.107 +/- 0.015, p<0.04), whereas intracellular magnesium concentrations decreased in both groups (controls: 377 +/- 33 vs 321 +/- 39; diabetic patients: 388 +/- 47 vs 336 +/- 68 micromol/l; p<0.05). CONCLUSIONS/INTERPRETATION: Despite a lower cerebral phosphocreatine:gamma-ATP ratio in Type 1 diabetic patients at baseline, this ratio does not change in control or diabetic patients during modest hypoglycaemia. However, both groups exhibit subtle changes in intracellular pH and intracellular magnesium concentrations.

Adenosine Triphosphate↗
PubMed2003

Direct and indirect effects of amino acids on hepatic glucose metabolism in humans.

AIM/HYPOTHESIS: The study was designed to examine the contribution of direct (substrate-mediated) and indirect (hormone-mediated) effects of amino acids on hepatic glucose metabolism in healthy men. METHODS: The protocols were: (i) CON+S (n=7): control conditions with somatostatin to inhibit endogenous hormone release resulting in fasting plasma concentrations of amino acids, insulin (approximately 28 pmol/l) and glucagon (approximately 65 ng/l), (ii) AA+S ( n=7): amino acid infusion-fasting insulinaemia-fasting glucagonaemia, (iii) GLUC+S ( n=6): fasting amino acids-fasting insulinaemia-hyperglucagonaemia (approximately 99 ng/l) and (iv) AA-S (n=5): amino acid infusion without somatostatin resulting in amino acid-induced hyperinsulinaemia (approximately 61 pmol/l)-hyperglucagonaemia (approximately 147 ng/l). Net glycogenolysis was calculated from liver glycogen concentrations using (13)C nuclear magnetic resonance spectroscopy. Total gluconeogenesis (GNG) was calculated by subtracting net glycogenolysis from endogenous glucose production (EGP) which was measured with [6,6-(2)H(2)]glucose. Net GNG was assessed with the (2)H(2)O method. RESULTS: During AA+S and GLUC+S, plasma glucose increased by about 50% (p<0.01) due to a comparable rise in EGP. This was associated with a 53-% (p<0.05) and a 65% increase (p<0.01) of total and net GNG during AA+S, whereas net glycogenolysis rose by 70% (p<0.001) during GLUC+S. During AA-S, plasma glucose remained unchanged despite nearly-doubled (p<0.01) total GNG. CONCLUSION/INTERPRETATION: Conditions of postprandial amino acid elevation stimulate secretion of insulin and glucagon without affecting glycaemia despite markedly increased gluconeogenesis. Impaired insulin secretion unmasks the direct gluconeogenic effect of amino acids and increases plasma glucose.

Adult↗
PubMed2003

Tumour suppressors--a fly's perspective.

For a century, the little fruitfly Drosophila melanogaster has taught generations of geneticists about how genes control the development of a multicellular organism. More recently, Drosophila has begun to contribute more directly towards our understanding of human disease [Bernards A, Hariharan IK. Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev 2001, 11, 274-278]. It is capable of doing this because it shares many disease-related genes with us. For example, the Drosophila genome sequencing project has revealed that two thirds of the genes implicated in human cancers have a counterpart in the fly genome [Adams MD, Celniker SE, Holt RA, et al. The genome sequence of Drosophila melanogaster. Science 2000, 287, 2185-2195, Fortini ME, Skupski MP, Boguski MS, Hariharan IK. A survey of human disease gene counterparts in the Drosophila genome. J Cell Biol 2000, 150, F23-30]. In particular, the fly has homologues of the Retinoblastoma protein (pRb) and of p53, two prototypical tumour suppressors which are inactivated in the majority of human tumours. Here, we will compare the fly's tumour suppressors with their human counterparts and we will review recent advances in our understanding of how these factors function in the fly.

Animals↗
PubMed2003

Phylogeography of the Madeiran endemic lizard Lacerta dugesii inferred from mtDNA sequences.

Partial sequences from two mitochondrial DNA genes, cytochrome b and 12S rRNA, were used to assess the phylogenetic relationships of populations of Lacerta dugesii from the volcanic Atlantic islands of Madeira, the Desertas, Porto Santo, and the Selvagens. All four-island groups are genetically distinguishable and populations within each contain similar degrees of genetic diversity. Molecular clock estimates suggest that the islands were colonized much later after their emergence compared to other Atlantic islands, possibly due to their greater geographical isolation. Mismatch analysis of all populations is consistent with exponential growth, as expected after colonization of empty niches. The Selvagens contain genetic substructuring between the islets.

Animals↗
PubMed2003

Genetic differentiation of the Cabo Verde archipelago population analysed by STR polymorphisms.

Allele frequencies for 17 STR loci were analyzed in a sample of unrelated males from the Cabo Verde Archipelago. The samples were gathered in such a way that the origin of the subjects was perfectly identified, and they could be included in one of the leeward or windward groups of islands. This study reveals that there are significant differences between both groups of islands, and between Cabo Verdeans and other populations from sub-Sahara Africa including the Guineans, the most probable source population for Cabo Verdeans. This study confirms mtDNA data and, together with HLA and Y chromosome data already published, shows that the Cabo Verde population is sub-structured and atypical, diverging substantially from mainland sub-Saharan populations. Overall these differences are most probably due to admixture between sub-Saharan slaves brought into the islands and other settlers of European origin. In the absence of a clear indication of a different ethnic composition of the first sub-Saharan settlers of Cabo Verde, the differentiation exhibited in both groups of islands can be most probably be attributed to genetic drift.

Africa, Western↗
PubMed2002

Mitochondrial portrait of the Cabo Verde archipelago: the Senegambian outpost of Atlantic slave trade.

In order to study the matrilineal genetic composition in Cabo Verde (Republic of Cape Verde), an archipelago that used to serve as a Portuguese entrepôt of the Atlantic slave trade, we have analysed a total of 292 mtDNAs sampled from the seven inhabited islands for the hypervariable segment I (HVS-I) and some characteristic RFLPs of the coding regions. The different settlement history of the northwestern group of the islands is well reflected in the mtDNA pool. The total Cabo Verde sample clearly displays the characteristic mitochondrial features of the Atlantic fringe of western Africa and testifies to almost no mitochondrial input from the Portuguese colonizers.

Amino Acid Sequence↗
PubMed2002

Distribution of HLA alleles in Portugal and Cabo Verde. Relationships with the slave trade route.

HLA-A, -B, and -DR frequencies were analysed in populations from Portugal and the Madeira and Cabo Verde Archipelagos, aiming to characterize their genetic composition. Portuguese settlers colonized both Archipelagos in the 15th and 16th centuries. Madeira received many sub-Saharan slaves to work in the sugar plantations, and Cabo Verde served as a pivotal market in the Atlantic slave trade and was populated by individuals coming from the Senegambia region of the West African coast. The population of Madeira shows the highest genetic diversity and the presence of alleles and haplotypes usually linked to sub-Saharan populations, the haplotypes accounting for 3.5% of the total. Cabo Verde presents typical markers acknowledged to be of European or Ibero-Mediterranean origin, thus revealing the admixture of European settlers with Sub-Saharan slaves. Altogether the number of European haplotypes reaches 15% of the total. The Portuguese population shows a perceivable and significant heterogeneity both in allele and haplotype frequencies, unveiling a differential input of peoples from different origins. A PCA of the populations studied, plus other relevant ones, clearly shows gene heterogeneity in mainland Portugal as well as the differences and relationships between these populations and Madeira and Cabo Verde.

Africa, Western↗
PubMed2002

Insertion polymorphism of retrotransposable elements in populations of the insular, endemic species Drosophila madeirensis.

The insertion site numbers of the retrotransposable elements (TE) 412, gypsy and bilbo were determined in individuals of five distinct natural populations of the endemic species Drosophila madeirensis from the island of Madeira. The TE distributions were compared to those of the paleartic, widespread and phylogenetically closely related species, D. subobscura. In situ hybridization and Southern blots showed that in D. madeirensis the number of insertion sites ranged between 10 and 15, three and six, and 35 and 42 for elements 412, gypsy and bilbo, respectively. The corresponding values for D. subobscura were similar. Two of these elements, 412 and gypsy, had very few insertions in the heterochromatin, unlike bilbo, which displayed a high heterochromatic insertion number. The Southern band polymorphism was very high, leading to within-population variation of 97.2%, whatever the population and the TE concerned. Using the polymorphic TE insertion sites as markers to analyse population structure by AMOVA, adapted for RAPD (Randomly Amplified Polymorphic DNA) data, we found small but significant genetic differences between the populations on Madeira. This slight differentiation, coupled with similar copy numbers for each TE between populations, suggests that the D. madeirensis species consists of a single, only slightly subdivided population. These data also show that insular populations and endemic species of Drosophila can have as many copies of TEs as more widespread species.

Animals↗
PubMed2001

Tramtrack69 interacts with the dMi-2 subunit of the Drosophila NuRD chromatin remodelling complex.

dMi-2, the ATPase subunit of the Drosophila nucleosome remodelling and histone deacetylation (dNuRD) complex, was identified in a two-hybrid screen as an interacting partner of the transcriptional repressor, Tramtrack69 (Ttk69). A short region of Ttk69 is sufficient to mediate this interaction. Ttk69, but not the Ttk88 isoform, co-purifies with the dNuRD complex isolated from embryo extracts. dMi-2 and Ttk69 co-immunoprecipitate from embryonic extracts, indicating that they can associate in vivo. Both dMi-2 and Ttk69 co-localize at a number of discrete sites on polytene chromosomes, showing that they bind common target loci. We also demonstrate that dMi-2 and Ttk interact genetically, indicating a functional interaction in vivo. We propose that Ttk69 represses some target genes by remodelling chromatin structure through the recruitment of the dNuRD complex.

Adenosine Triphosphatases↗
PubMed2001

Physical and functional association of SU(VAR)3-9 and HDAC1 in Drosophila.

Modification of histones can have a dramatic impact on chromatin structure and function. Acetylation of lysines within the N-terminal tail of the histone octamer marks transcriptionally active regions of the genome whereas deacetylation seems to play a role in transcriptional silencing. Recently, the methylation of the histone tails has also been shown to be important for transcriptional regulation and chromosome structure. Here we show by immunoaffinity purification that two activities important for chromatin-mediated gene silencing, the histone methyltransferase SU(VAR)3-9 and the histone deacetylase HDAC1, associate in vivo. The two activities cooperate to methylate pre-acetylated histones. Both enzymes are modifiers of position effect variegation and interact genetically in flies. We suggest a model in which the concerted histone deacetylation and methylation by a SU(VAR)3-9/HDAC1-containing complex leads to a permanent silencing of transcription in particular areas of the genome.

Animals↗
PubMed2001

Relationships of scincid lizards (Mabuya spp; Reptilia: Scincidae) from the Cape Verde islands based on mitochondrial and nuclear DNA sequences.

Partial DNA sequences from two mitochondrial (mt) and one nuclear gene (cytochrome b, 12S rRNA, and C-mos) were used to estimate the phylogenetic relationships among the six extant species of skinks endemic to the Cape Verde Archipelago. The species form a monophyletic unit, indicating a single colonization of the islands, probably from West Africa. Mabuya vaillanti and M. delalandii are sister taxa, as indicated by morphological characters. Mabuya fogoensis and M. stangeri are closely related, but the former is probably paraphyletic. Mabuya spinalis and M. salensis are also probably paraphyletic. Within species, samples from separate islands always form monophyletic groups. Some colonization events can be hypothesized, which are in line with the age of the islands. C-mos variation is concordant with the topology derived from mtDNA.

Animals↗