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Biomedical subjects

M Krieger

Publications and source records attributed to M Krieger.

At least 19 recordsLinked to original sources
PubMed2005

Degeneration of dopaminergic neurons triggers an expression of individual enzymes of dopamine synthesis in non-dopaminergic neurons of the arcuate nucleus in adult rats.

Non-dopaminergic neurons expressing individual complementary enzymes dopamine (DA) synthesis were shown to produce DA in cooperation [Ugrumov, M., Melnikova, V., Ershov, P., Balan, I., Calas A., 2002. Tyrosine hydroxylase- and/or aromatic L-amino acid decarboxylase-expressing neurons in the rat arcuate nucleus: ontogenesis and functional significance. Psychoneuroendocrinology 27, 533-548; Ugrumov, M.V., Melnikova, V.I., Lavrentyeva, A.V., Kudrin, V.S., Rayevsky, K.S., 2004. Dopamine synthesis by non-dopaminergic neurons expressing individual complementary enzymes of the dopamine synthetic pathway in the arcuate nucleus of fetal rats. Neuroscience 124, 629-635]. This study was aimed at testing our hypothesis that the cooperative synthesis of DA in non-dopaminergic neurons is an adaptive reaction under functional insufficiency of the dopaminergic system. Functional insufficiency of the tuberoinfundibular dopaminergic system was provoked by 6-OHDA-induced degeneration of dopaminergic neurons in the arcuate nucleus in adult rats. Bienzymatic (dopaminergic) neurons and monoenzymatic neurons expressing tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC) were detected with a double-immunofluorescent technique on cryostat sections. The 6-OHDA-induced degeneration of dopaminergic neurons was accompanied by a significant increase of the number of monoenzymatic TH neurons and AADC neurons that appears to support our hypothesis. The reaction of bienzymatic and monoenzymatic neuron populations to the 6-OHDA administration occurred to be region-specific. The former disappeared in the dorsomedial region of the arcuate nucleus while the latter increased in the ventrolateral region. Thus, degeneration of dopaminergic neurons in the arcuate nucleus of adult rats is accompanied by the expression of individual enzymes of DA synthesis in non-dopaminergic neurons that may be an adaptive reaction.

Adrenergic Agents↗
PubMed2001

Down-regulation of intestinal scavenger receptor class B, type I (SR-BI) expression in rodents under conditions of deficient bile delivery to the intestine.

Scavenger receptor class B, type I (SR-BI) is expressed in the intestines of rodents and has been suggested to be involved in the absorption of dietary cholesterol. The aim of this study was to determine whether intestinal SR-BI expression is affected in animal models with altered bile delivery to the intestine and impaired cholesterol absorption. SR-BI protein and mRNA levels were determined in proximal and distal small intestine from control, bile-duct-ligated and bile-diverted rats and from control and bile-duct-ligated mice. Two genetically altered mouse models were studied: multidrug resistance-2 P-glycoprotein-deficient [Mdr2((-/-))] mice that produce phospholipid/cholesterol-free bile, and cholesterol 7alpha-hydroxylase-deficient [Cyp7a((-/-))] mice, which exhibit qualitative and quantitative changes in the bile-salt pool. Cholesterol-absorption efficiency was quantified using a dual-isotope ratio method. SR-BI was present at the apical membrane of enterocytes in control rats and mice and was more abundant in proximal than in distal segments of the intestine. In bile-duct-ligated animals, levels of SR-BI protein were virtually absent and mRNA levels were decreased by approximately 50%. Bile-diverted rats, Mdr2((-/-)) mice and Cyp7a((-/-)) mice showed decreased levels of intestinal SR-BI protein while mRNA levels were unaffected. Cholesterol absorption was reduced by >90% in bile-duct-ligated and bile-diverted animals and in Cyp7a((-/-)) mice, whereas Mdr2((-/-)) mice showed an approximately 50% reduction. This study shows that SR-BI is expressed at the apical membrane of enterocytes of rats and mice, mainly in the upper intestine where cholesterol absorption is greatest, and indicates that bile components play a role in post-transcriptional regulation of SR-BI expression. Factors associated with cholestasis appear to be involved in transcriptional control of intestinal SR-BI expression. The role of SR-BI in the cholesterol-absorption process remains to be defined.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial.

OBJECTIVE: To investigate the effectiveness of baclofen for the treatment of tics in children with Tourette syndrome (TS). BACKGROUND: Baclofen, which contains both gamma-aminobutyric acid (GABA) and phenylethylamine moieties, was suggested in an open-label protocol to be an effective treatment for TS. This is a double-blind, placebo-controlled study to investigate this medication in children with TS. METHODS: Subjects received, in a randomized sequence, 4-week medication cycles of baclofen (20 mg three times daily) and placebo with a 2-week intervening washout period between the cycles. Outcome measures included the Clinical Global Impression (CGI) scale, and the Yale Global Tic Severity Scale (YGTSS), the latter including subscales for total tics and overall impairment. Measures were assessed at baseline and on days 28, 42, and 70 of the study. RESULTS: Ten children (seven boys and three girls, aged 8 to 14) with TS participated. Nine subjects completed the protocol; one dropped out for psychosocial reasons. No major side effects were reported. The mean change in CGI score (-0.9) after 4 weeks of baclofen treatment as compared with placebo treatment showed a significant improvement (95% CI, -1.7 to -0.1; p = 0.04). All subjects showed some amelioration in total YGTSS score during baclofen treatment. The mean change in total YGTSS score (-14.7) approached significance (95% CI, -30.3 to 0.9; p = 0.06). Examination of differences between baclofen and placebo treatment groups expressed as a percent change from baseline showed that baclofen had a statistically significant effect on both outcome measures. Subscales of the YGTSS showed that the reduction in total tic scores was primarily due to a reduction in the impairment score rather than a decrease in tics. CONCLUSIONS: Children with TS may benefit from treatment with baclofen, although improvements may be related to factors other than tics. Larger studies directly comparing baclofen against other tic-suppressing agents are recommended.

Adolescent↗
PubMed2001

Drosophila scavenger receptor CI is a pattern recognition receptor for bacteria.

One hallmark of innate immunity apparently conserved from primitive life forms through to humans is the ability of the host to recognize pathogen-associated molecular patterns (PAMPs). Since macrophage pattern recognition receptors are not well defined in Drosophila, we set out to identify such receptors. Our findings reveal that Drosophila macrophages express multiple pattern recognition receptors and that the Drosophila scavenger receptor, dSR-CI, is one such receptor capable of recognizing both gram-negative and gram-positive bacteria, but not yeast. Our data indicate that scavenger receptor bacterial recognition is conserved from insects to humans and may represent one of the most primitive forms of microbial recognition.

Amino Acid Sequence↗
PubMed2001

Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice.

Mammalian female fertility depends on complex interactions between the ovary and the extraovarian environment (e.g., the hypothalamic-hypophyseal ovarian axis). The role of plasma lipoproteins in fertility was examined using HDL-receptor SR-BI knockout (KO) mice. SR-BI KO females have abnormal HDLs, ovulate dysfunctional oocytes, and are infertile. Fertility was restored when the structure and/or quantity of abnormal HDL was altered by inactivating the apoAI gene or administering the cholesterol-lowering drug probucol. This suggests that abnormal lipoprotein metabolism can cause murine infertility--implying a functional hepatic-ovarian axis--and may contribute to some forms of human female infertility.

Animals↗
PubMed2001

Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice.

The scavenger receptor class B type I (SR-BI), which is expressed in the liver and intestine, plays a critical role in cholesterol metabolism in rodents. While hepatic SR-BI expression controls high density lipoprotein (HDL) cholesterol metabolism, intestinal SR-BI has been proposed to facilitate cholesterol absorption. To evaluate further the relevance of SR-BI in the enterohepatic circulation of cholesterol and bile salts, we studied biliary lipid secretion, hepatic sterol content and synthesis, bile acid metabolism, fecal neutral sterol excretion, and intestinal cholesterol absorption in SR-BI knockout mice. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. Hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis was not significantly changed. Bile acid pool size and composition, as well as fecal bile acid excretion, were not altered in SR-BI knockout mice. Intestinal cholesterol absorption was somewhat increased and fecal sterol excretion was slightly decreased in SR-BI knockout mice relative to controls. These findings establish the critical role of hepatic SR-BI expression in selectively controlling the utilization of HDL cholesterol for biliary secretion. In contrast, SR-BI expression is not essential for intestinal cholesterol absorption.

Animals↗
PubMed2000

Scavenger receptor class B, type I-mediated [3H]cholesterol efflux to high and low density lipoproteins is dependent on lipoprotein binding to the receptor.

The murine scavenger receptor class B, type I (mSR-BI) is a receptor for high density lipoprotein (HDL), low density lipoprotein (LDL), and acetylated LDL (AcLDL). It mediates selective uptake of lipoprotein lipid and stimulates efflux of [(3)H]cholesterol to lipoproteins. SR-BI-mediated [(3)H]cholesterol efflux was proposed to be independent of ligand binding. In this study, using anti-mSR-BI antibody KKB-1 and two mSR-BI mutants with altered ligand binding properties, we demonstrated that SR-BI-mediated [(3)H]cholesterol efflux to lipoproteins was correlated with ligand binding and lipid uptake activities of the receptor. The KKB-1 antibody, which blocked lipoprotein binding without substantially altering the cholesterol oxidase-accessible cellular [(3)H]cholesterol, also blocked [(3)H]cholesterol efflux to HDL and LDL. One of the SR-BI mutants, which has a double substitution of arginines for glutamines at positions 402 and 418 (Q402R/Q418R), exhibited a high level of LDL binding and lipid uptake from LDL, but lost most of the corresponding HDL receptor activity. This mutant could mediate efficient [(3)H]cholesterol efflux to LDL, but not to HDL. Another mutant, M158R, with an arginine in place of methionine at position 158, exhibited reduced HDL and LDL receptor activities, but apparently normal AcLDL receptor activity. This mutant could mediate efficient [(3)H]cholesterol efflux to AcLDL, but not to HDL or LDL. These results suggest that SR-BI-stimulated [(3)H]cholesterol efflux to lipoproteins critically depends on ligand binding to this receptor and raise the possibility that the mechanisms of selective lipid uptake and [(3)H]cholesterol efflux may be intimately related.

Antibody Specificity↗
PubMed2000

Tyrosine hydroxylase-expressing and/or aromatic L-amino acid decarboxylase-expressing neurons in the mediobasal hypothalamus of perinatal rats: differentiation and sexual dimorphism.

In this quantitative and semiquantitative immunocytochemical study, the authors evaluated the differentiation of neurons expressing tyrosine hydroxylase (TH) and/or aromatic L-amino acid decarboxylase (AADC) in the mediobasal hypothalamus (MBH) of male and female rats on embryonic day 18 (E18), E20, and postnatal day 9 (P9). Four neuronal populations were distinguished according to either enzyme expression or neuron location. The earliest and most prominent first population was represented by TH-immunoreactive (IR)/AADC-immunonegative (IN) neurons that were detected initially at E18 and always were located in the ventrolateral region of the MBH. The second population of TH-IN/AADC-IR neurons was observed first at E20 and, after that time, was distributed dorsomedially. The third minor population of TH-IR/AADC-IR neurons initially was detected at E20 and was located dorsomedially. The fourth population was represented by TH-IR/AADC-IN neurons that were distributed in the dorsomedial region at any studied age. The numbers of TH-IR and AADC-IR neurons increased from their initial detection at E18 and E20 until P9. The area of TH-IR and AADC-IR neurons also increased from E18 to E20 and from E20 to P9, respectively. Both TH-IR and AADC-IR neurons showed sex differences in the neuron number, size, and optic density (OD). The numbers of TH-IR neurons in males exceeded those of females at E20 and at P9, although, at P9, sexual dimorphism was a characteristic only of the ventrolateral population. The area and OD of TH-IR neurons from females exceeded those from males in the entire mediobasal hypothalamus (MBH) at E18 and E20 but only in its dorsomedial region at P9. Sexual dimorphism also was an attribute of AADC-IR neurons at E20 and P9. Their number, size, and OD were significantly higher in females than in males. Thus, the MBH of perinatal rats contained two major populations of TH-IR/AADC-IN or TH-IN-AADC-IR neurons and a minor population of TH-IR/AADC-IR neurons. The differentiating neurons expressing either enzyme showed sexual dimorphism.

Age Factors↗
PubMed2000

Binding of high density lipoprotein (HDL) and discoidal reconstituted HDL to the HDL receptor scavenger receptor class B type I. Effect of lipid association and APOA-I mutations on receptor binding.

The binding of apoA-I-containing ligands to the HDL receptor scavenger receptor class B type I (SR-BI) was characterized using two different assays. The first employed conventional binding or competition assays with (125)I-labeled ligands. The second is a new nonradioactive ligand binding assay, in which the receptor-associated ligand is detected by quantitative immunoblotting ("immunoreceptor assay"). Using both methods, we observed that the K(d) value for spherical HDL (density = 1.1-1.13 g/ml) was approximately 16 microgram of protein/ml, while the values for discoidal reconstituted HDL (rHDL) containing proapoA-I or plasma apoA-I were substantially lower (approximately 0.4-5 microgram of protein/ml). We also observed reduced affinity and/or competition for spherical (125)I-HDL cell association by higher relative to lower density HDL and very poor competition by lipid-free apoA-I and pre-beta-1 HDL. Deletion of either 58 carboxyl-terminal or 59 amino-terminal residues from apoA-I, relative to full-length control apoA-I, resulted in little or no change in the affinity of corresponding rHDL particles. However, rHDL particles containing a double mutant lacking both terminal domains competed poorly with spherical (125)I-HDL for binding to SR-BI. These findings suggest an important role for apoA-I and its conformation/organization within particles in mediating HDL binding to SR-BI and indicate that the NH(2) and COOH termini of apoA-I directly or indirectly contribute independently to binding to SR-BI.

Animals↗
PubMed2000

Dissociation of the high density lipoprotein and low density lipoprotein binding activities of murine scavenger receptor class B type I (mSR-BI) using retrovirus library-based activity dissection.

The murine class B, type I scavenger receptor (mSR-BI) is a receptor for both high density lipoprotein (HDL) and low density lipoprotein (LDL) and mediates selective, rather than endocytic, uptake of lipoprotein lipid. We have developed a "retrovirus library-based activity dissection" method to generate mSR-BI mutants in which some, but not all, of the activities of this multifunctional protein have been disrupted. This method employs three techniques: 1) efficient in vitro cDNA mutagenesis (here error-prone PCR was used), 2) efficient retroviral delivery and high expression of single mutant cDNAs into individual cells, and 3) isolation of infected cells expressing the desired mutant phenotype using high sensitivity positive/negative screening by two-color fluorescence-activated cell sorting. A set of mutants, all having arginine substitutions at two common sites (positions 402 or 401 and position 418), were isolated and characterized. Mutation at either site alone did not generate as strong a mutant phenotype (loss of DiI uptake from DiI-HDL) as did the double mutations. "Activity-dissected" double mutants were as effective as wild-type mSR-BI in functioning as LDL receptors, mediating high affinity LDL binding and uptake of metabolically active cholesterol from LDL, but they lost most of their corresponding HDL receptor activity. Thus, these mutants provide support for the proposal that the interaction of SR-BI with HDL differs from that with LDL. Examination of the in vivo function of such mutants may provide insights into the differential roles of the LDL and HDL receptor activities of SR-BI in normal lipoprotein metabolism and in SR-BI's ability to protect against atherosclerosis.

Amino Acid Sequence↗
PubMed2000

Identification and characterization of naturally occurring variants of the macrophage scavenger receptor (SR-A).

The scavenger receptor (SR) family comprises a group of cell surface proteins functionally defined by their ability to bind chemically modified lipoproteins. In macrophages, the class A Type I and Type II SRs (SR-AI/II) are thought to play a key role in adherence to and phagocytosis of infectious agents. Immunoprecipitation studies show that the rat anti-SR-AI/II monoclonal antibody 2F8 detects the mature, trimeric form of the receptor expressed in peritoneal macrophages from A/J, but not from C57Bl/6J (B6) mice. Subsequent sequencing of cDNA and genomic clones indicates that SR-AI and AII of A/J and B6 mice differ in sequence at nine positions, two in the cytoplasmic domain and seven in the extracellular spacer and alpha-helical coiled coil domains. These sequence polymorphisms are non-conservative and produce distinct receptor molecules that differ by four charged residues and alter recognition of the receptor by the monoclonal 2F8 antibody. The B6 SR-AI/II haplotype appears unique, since most inbred strains analyzed show the A/J-type haplotype. Interestingly, several of the B6 polymorphic variant residues are conserved in human and bovine receptors, suggesting a recent divergence of the A/J haplotype. Initial studies in CHO-derived cells expressing individual receptor isoforms indicate that the A/J and B6 receptors are stable and can mature into oligomers expressed in the membrane fractions of these cells. In these transfectants, no major functional differences were detected between receptors of the two haplotypes with respect to internalization and degradation of (125)I-labeled acetylated LDL. However, since SR-AI/II recognizes a large number of structurally unrelated anionic molecules, the possibility that different haplotypes may affect either binding and release of other ligands, or receptor recycling, cannot be excluded.

Animals↗
PubMed2000

Decrease of vigilance assessed by EEG-mapping in type I diabetic patients with history of recurrent severe hypoglycaemia.

In Type I diabetic patients with history of recurrent severe hypoglycaemia, a more rapid decrease in vigilance (slowing of brain function) during hypoglycaemia in comparison to patients without history of such events was found. Our aims were: (1) to study EEG parameters of vigilance in non-hypoglycaemic state in representative groups of Type I diabetic patients with and without previous recurrent severe hypoglycaemia; and (2) to compare them with non-diabetic controls. A vigilance-controlled EEG mapping (10-20 system, significance probability maps) was performed in a non-hypoglycaemic state (blood glucose 4.0-10.0 mmol/l) in a group of 13 Type I diabetic patients with a history of recurrent severe hypoglycaemia and compared to that of 14 Type I diabetic patients without history of severe hypoglycaemia, matched for HbA1c, age and gender, and to age- and gender-matched non-diabetic controls. When compared to non-diabetic controls, hypoglycaemia patients demonstrated a reduction in absolute power in beta band (13-35 Hz) and slowing of centroid frequencies of beta and total frequency bands (1.3-35 Hz) (up to P < 0.01), whereas patients without history of severe hypoglycaemia showed only a borderline reduction of absolute power in delta (1.3-3.5 Hz) band. Deceleration in hypoglycaemia patients versus those without recurrent hypoglycaemia was most remarkable (P < .01) in centroid frequency of total frequency band. Patients with history of recurrent severe hypoglycaemia demonstrated in non-hypoglycaemic state significantly reduced vigilance when compared to the group without hypoglycaemia history and to the controls, as well. Lower vigilance may be at least in part responsible for impaired hypoglycaemia perception in these patients, but, as it resembles EEG patterns seen in pathologic ageing, it might also represent a consequence of recurrent episodes of severe hypoglycaemia.

Adult↗
PubMed2000

CD34+ selection of hematopoietic blood cell collections and autotransplantation in lymphoma: overnight storage of cells at 4 degrees C does not affect outcome.

The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34+ selection may delay platelet count recovery after high-dose chemotherapy and CD34+-enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m2 i.v. and G-CSF 10 microg/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34+ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4 degrees C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34+ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34+ selection and cryopreservation. Median yield of CD34+ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P = 0.339). Neutrophil recovery >500 x 10(9)/l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P = 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P = 0.933). We conclude that storage of PBPC overnight at 4 degrees C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34+-selected progenitor cells. Bone Marrow Transplantation(2000) 25, 559-566.

Adolescent↗
PubMed2000

The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism.

The HDL receptor scavenger receptor class B type I (SR-BI), which mediates selective HDL cholesterol uptake, plays a role in murine HDL metabolism, reverse cholesterol transport and whole-body cholesterol homeostasis. SR-BI is found in the liver, where its expression is regulated by estrogen, dietary cholesterol and fat, and controls murine plasma HDL cholesterol levels and bile cholesterol secretion. SR-BI is also highly expressed in rodent steroidogenic cells, where it facilitates cholesterol uptake for storage or steroid hormone synthesis and where its expression is regulated by trophic hormones. The detailed mechanism(s) underlying SR-BI-mediated selective cholesterol uptake have not yet been elucidated. Further analysis of the molecular and cellular bases of SR-BI regulation and function should provide new insights into the physiology and pathophysiology of cholesterol metabolism.

Animals↗
PubMed2000

Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse.

HDL cholesterol levels in humans are inversely correlated with the risk of atherosclerosis. The class B scavenger receptor type I (SR-BI) is the first molecularly well-defined HDL receptor, and hepatic overexpression of SR-BI in normal mice has been shown to result in decreased plasma HDL cholesterol levels. To determine whether SR-BI overexpression is proatherogenic or is protective against atherosclerosis, LDL receptor-deficient mice were placed on a high-fat/high-cholesterol diet for 2 or 12 weeks to induce atherosclerotic lesions of different stages and then were injected with a recombinant adenovirus encoding murine SR-BI. Transient hepatic overexpression of SR-BI in mice with both early and advanced lesions significantly decreased atherosclerosis. SR-BI expression was associated with markedly decreased HDL cholesterol and either unchanged or only modestly reduced non-HDL cholesterol levels; in all experiments, the mean HDL cholesterol levels were significantly correlated with atherosclerotic lesion size. These data suggest that interventions that promote HDL cholesterol transport and lower plasma HDL cholesterol levels can suppress atherosclerosis, even when initiated after significant lesion development. Thus, stimulation of hepatic SR-BI activity may provide a novel target for therapeutic intervention in atherosclerotic cardiovascular disease.

Adenoviridae↗
PubMed2000

BRCA1 and BRCA2 mutation carriers as potential candidates for chemoprevention trials.

The identification of cancer susceptibility genes offers new avenues for selecting high-risk individuals as subjects for chemoprevention trials. Because carriers of predisposing mutations are at high risk, they are more likely to enroll and comply with chemoprevention trials, and meaningful results can be achieved with smaller numbers of participants and shorter periods of follow-up. Such studies have immediate benefits for carriers themselves, but they are also likely to result in effective chemopreventive strategies for the general population. In this review, we discuss BRCA1 and BRCA2 carriers as potential candidates for breast and ovarian cancer chemoprevention trials. The existence of a large population with a high frequency of easily identifiable BRCA1/2 mutations can provide ample opportunity for such studies. However, the possibility that tumor characteristics and hormonal profile of BRCA1/BRCA2 related cancers are not completely equivalent to cancers in the general population should be borne in mind.

Anticarcinogenic Agents↗