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M Levin

Publications and source records attributed to M Levin.

At least 19 recordsLinked to original sources
PubMed1999

Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group.

BACKGROUND: The reasons why meningococcal disease develops in only a small proportion of individuals carrying the causative bacteria are unknown. Differences in host responses to bacterial colonisation are thought to be involved, since people with deficiencies in the terminal components of the complement pathway, or of properdin, are susceptible to meningococcal disease. We postulate that genetic variants of mannose-binding lectin (MBL), a plasma opsonin that initiates another pathway of complement activation, might similarly cause susceptibility to meningococcal disease. METHODS: The frequency of variants of the MBL gene was ascertained in children with meningococcal disease and controls from two independent studies; one hospital-based (194 patients and 272 controls [patients with non-infectious disorders]), and one community-based (72 patients and 110 controls [healthy individuals]), by means of PCR and restriction-enzyme digestion, with confirmation by DNA sequencing. FINDINGS: The proportion of people homozygous for MBL-variant alleles was higher in patients with meningococcal disease than in controls in the hospital study (15 [7.7%] vs four [1.5%]; odds ratio 6.5 [95% CI 2.0-27.2]) and in the community study (six [8.3%] vs three [2.7%]; 4.5 [0.9-29.1]). The population attributable fraction of cases attributable to MBL variants (homozygous and heterozygous) was 32%. INTERPRETATION: The MBL pathway is a critical determinant of meningococcal-disease susceptibility, and genetic variants of MBL might account for a third of all disease cases.

Adolescent↗
PubMed1999

Neutrophil response to Neisseria meningitidis: inhibition of adhesion molecule expression and phagocytosis by recombinant bactericidal/permeability-increasing protein (rBPI21).

Polymorphonuclear neutrophil (PMNL) activation enhances microbial clearance but also contributes to the vascular damage and multiorgan failure associated with severe meningococcal sepsis. By use of a whole blood model of meningococcal bacteremia, loss of PMNL L-selectin and up-regulation of CD11b was observed in response to Neisseria meningitidis serogroups B and C, which is followed by opsonophagocytosis. PMNL priming with either Escherichia coli lipopolysaccharide (LPS) or FMLP prior to meningococcal challenge resulted in enhancement of both PMNL L-selectin shedding (1.5- to 4-fold) and phagocytosis (2- to 3-fold). Blockade of meningococcal LPS lipid A with recombinant bactericidal/permeability-increasing protein (rBPI21) resulted in partial inhibition of the PMNL activation and phagocytosis response to N. meningitidis. The effect of rBPI21 was reversed by excess E. coli LPS or FMLP. It is proposed that PMNL priming by N. meningitidis results in an exaggerated activation and phagocytosis response to the organism.

Adult↗
PubMed1999

Evidence of hypoxic areas within the arterial wall in vivo.

The anoxemia theory of atherosclerosis states that an imbalance between the demand and supply of oxygen in the arterial wall is a key factor for the development of atherosclerotic lesions. Direct in vitro and in situ measurements have shown that PO2 is decreased in the more deeply situated parts of the media, but the degree of hypoxia in vivo or the distribution of hypoxia along the arterial tree is not known. For this reason, we have developed a method for the detection of hypoxia in the arterial wall in vivo by using a hypoxia marker, 7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline, that may be visualized by immunofluorescence. In the present study, we have used this method in rabbits with experimentally induced atherosclerosis. Our results indicate that zones of hypoxia occur at depth in the atherosclerotic plaque. The mechanism was probably an impaired oxygen diffusion capacity due to the thickness of the lesion, together with high oxygen consumption by the foam cells. Thus, we have for the first time demonstrated that hypoxia actually does exist in the arterial wall in vivo, lending support to the anoxemia theory of atherosclerosis.

Animals↗
PubMed1999

A bioluminescence method for the mapping of local ATP concentrations within the arterial wall, with potential to assess the in vivo situation.

According to the anoxemia theory of atherosclerosis, an imbalance between the demand for and supply of oxygen and nutrients in the arterial wall is a key factor in atherogenesis. However, the energy metabolic state of the arterial tissue in vivo is largely unknown. We applied a bioluminescence method, metabolic imaging, to study local ATP concentrations in cryosections of normal pig and atherosclerotic and normal rabbit aorta. Some vessels were subjected to energy metabolic restrictions by incubation at different oxygen and glucose concentrations and others were rapidly frozen in liquid nitrogen to reflect the in vivo situation. Local ATP concentrations and the ATP distribution at a microscale was dependent on oxygen as well as glucose concentrations during incubation. ATP depletion was seen in the mid media of pig aorta in all incubations, but only at low oxygen concentration without glucose in the media of the thinner rabbit aorta. ATP-depleted zones were seen deep in pig media (>750 microm from the lumen) and in rabbit plaques (>300 micrometer+ from the lumen) even at high oxygen (pig 75% O2 and rabbit 21% O2) and glucose concentrations (5.6 mmol/L glucose). This observation probably illustrates an insufficient diffusion of glucose, which highlights the importance of studying the conditions for diffusion not only of oxygen but also of other metabolites in the arterial wall. In rapidly frozen vessels the medial ATP concentration was shown to be 0.6 to 0.8 micromol/g wet weight (both pig and rabbit aorta) and in pig aorta a gradient could be seen indicating higher ATP concentrations at the lumenal side. We propose that metabolic imaging, as applied to snap-frozen tissue, may be used to assess the energy metabolic situation in the arterial wall in vivo. The spatial resolution allows the detection of local variations within the arterial tree. However, steep concentration gradients (eg, near the border of the tissue) will be underestimated. The method may be extended to include determinations of glucose and lactate concentrations and will be used in parallel with an established method to assess hypoxia in the arterial wall in vivo.

Adenosine Triphosphate↗
PubMed1998

Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children. National Institutes of Health-sponsored Pediatric AIDS Clinical Trials Group (ACTG-218).

Study objectives were to evaluate the safety and immunogenicity of three HIV recombinant glycoproteins in HIV-infected infants and children between 1 month and 18 years of age with asymptomatic (P-1) infection. Using Chiron rgp 120 (SF-2) 15 or 50 microg; MicroGeneSys rgp 160 (IIIB) 40 or 320 microg; Genentech rgp120 (MN) 75 or 300 microg; or adjuvant control (Alum or MF-59), children were randomized to a double-blind, placebo-controlled, dose-escalating study of vaccine administered intramuscularly at entry and 1, 2, 3, 4, and 6 months later. No adverse events were attributed to study vaccines. Between 30% and 56% of volunteers exhibited a lymphoproliferative response as defined in terms of stimulation index (SI) to vaccine antigens; 65% of vaccinees but none of placebo recipients exhibited moderate or strong responses after enzyme immunoassay to HIV specific antigens. CD4 cell counts and quantitative HIV culture did not differ significantly among vaccine and control groups, nor were differences found among groups in HIV disease progression. The rgp160 and gp120 subunit vaccines were safe and immunogenic in this population.

AIDS Vaccines↗
PubMed1998

Gap junctions are involved in the early generation of left-right asymmetry.

Invariant left-right asymmetry of the visceral organs is a fundamental feature of vertebrate embryogenesis. While a cascade of asymmetrically expressed genes has been described, the embryonic mechanism that orients the left-right axis relative to the dorsoventral and anteroposterior axes (a prerequisite for asymmetric gene expression) is unknown. We propose that this process involves dorsoventral differences in cell-cell communication through gap junctions composed of connexin proteins. Global modulation of gap junctional states in Xenopus embryos by pharmacological agents specifically induced heterotaxia involving mirror-image reversals of heart, gut, and gall bladder. Greatest sensitivity was observed between st. 5 and st. 12, well before the onset of organogenesis. Moreover, heterotaxia was also induced following microinjection of dominant negative and wild-type connexin mRNAs to modify the endogenous dorsoventral difference in junctional communication. Heterotaxia was induced by either blocking gap junction communication (GJC) dorsally or by introducing communication ventrally (but not the reverse). Both connexin misexpression and exposure to GJC-modifying drugs altered expression of the normally left-sided gene XNR-1, demonstrating that GJC functions upstream of XNR-1 in the pathway that patterns left-right asymmetry. Finally, lineage analysis to follow the progeny of microinjected cells indicated that they generally do not contribute the asymmetric organs. Together with the early sensitivity window, this suggests that GJC functions as part of a fundamental, early aspect of left-right patterning. In addition, we show that a potential regulatory mutation in Connexin43 is sufficient to cause heterotaxia. Despite uncertainty about the prevalence of the serine364 to proline substitution reported in human patients with laterality defects, the mutant protein is both a mild hypomorph and a potent antimorph as determined by the effect of its expression on left-right patterning. Taken together, our data suggest that endogenous dorsoventral differences in GJC within the early embryo are needed to consistently orient left-right asymmetry.

Animals↗
PubMed1998

Evolutionary conservation of mechanisms upstream of asymmetric Nodal expression: reconciling chick and Xenopus.

Recent experiments have suggested a pathway of genes that regulate left-right asymmetry in vertebrate embryogenesis. The most downstream member of this cascade is nodal (XNR-1 in frogs), which is expressed in the left-side lateral mesoderm. Previous work in the chick [Levin, 1998] suggests that an inductive interaction by Shh (Sonic hedgehog) present at the midline was needed for the left-sided expression of nodal, which by default would not be expressed. Interestingly, it has been reported [Lohr et al., 1997] that in Xenopus, right-side mesoderm that is explanted at st. 15 and allowed to develop in culture, goes on to express nodal, suggesting that lateral mesoderm expresses this gene by default and that a repression of nodal by the midline is needed to achieve asymmetry. Such a contradiction raises interesting questions about the degree of conservation of the mechanisms upstream of nodal asymmetry and, in general, about the differences in the LR pathway among species. Thus we examined this issue directly. We show that in the chick, as in the frog, explanted mesoderm from both sides does, indeed, go on to express nodal, including both the medial and lateral expression domains. Ectopic nodal expression in the medial domain on the right side is not sufficient to induce an ectopic lateral domain. We also show that explanted lateral tissue regenerates node/notochord structures exhibiting Shh expression. Furthermore, we show that Xenopus explants done at st. 15 also regenerate notochord by the stage at which XNR-1 would be expressed. Thus explants are not isolated from the influence of the midline. In contrast to the midline repressor model previously suggested [Lohr et al., 1997] to explain the presence of nodal expression in explants, we propose that the expression is due to induction by signals secreted by regenerating node and notochord tissue (Shh in the chick). Thus our results are consistent with Shh being necessary for nodal induction in both species, and we provide an explanation for both sets of data in terms of a single conserved mechanism upstream of nodal expression.

Animals↗
PubMed1998

Left-right asymmetry and the chick embryo.

Left-right (LR) asymmetry provides a fascinating example of the patterning of a major body axis during embryonic development. The chick embryo was the first system in which a molecular basis for left-right patterning was characterized, revealing that molecules known to play a role in other aspects of embryogenesis likewise are involved in the establishment of left-right asymmetry. The chick has been instrumental in the identification of a pathway of genes which regulate the sidedness of major body organs, as well as providing a basis for understanding laterality disturbances in twins. This review summarizes the advances in LR asymmetry which have been made in the chick system within the context of laterality research in general.

Animals↗
PubMed1998

Blood pressure and diurnal variation in sodium, potassium, and water excretion.

The objective of this study was to examine associations of blood pressure (BP) with ratios of overnight to 24-h urinary excretion of sodium, potassium, and water. Each of 125 men 27-64 years of age, not taking diuretics, had BP measured during the day on a Monday. Beginning Monday evening, each participant provided three carefully timed 24-h urine collections, divided into daytime and overnight (bedtime to awakening) specimens. Proportion of total 24-h excretion of sodium, potassium, and water in the overnight specimen, standardised for creatinine excretion, was determined for each 24-h period. Associations of systolic and diastolic BP (SBP/DBP) with these proportions were examined with control for age, body mass index, alcohol intake, and heart rate. Mean BP was 116/71 mm Hg; 15 men were on non-diuretic anti-hypertensive therapy. Mean 24-h urinary excretion was 168 mmol for sodium, 68 mmol for potassium, and 16 mmol for creatinine. Mean overnight to 24-h proportions averaged over the 3 days were 30.7% for sodium, 22.0% for potassium, 32.1% for urinary volume, and 33.2% for creatinine. Partial correlations of SBP and DBP with the 3-day averages were 0.257 (P < 0.01) and 0.210 (P < 0.05) for sodium; 0.223 (P < 0.05) and 0.222 (P < 0.05) for potassium; 0.127 and 0.091 for urinary volume; and -0.033 and 0.014 for creatinine. Correlations for sodium proportions were larger for the first 24-h period, compared to the second or third 24-h period. These results indicate that higher BP was associated with a relatively greater proportion of sodium and potassium excretion at night. Further work is needed to clarify temporal sequence, ie, whether a relatively greater sodium and potassium excretion at night is a risk factor for higher BP (eg, via renal mechanisms), or whether higher BP results in relatively greater sodium and potassium excretion at night, or both.

Adult↗
PubMed1998

Functionally active cardiac antibodies in chronic Chagas' disease are specifically blocked by Trypanosoma cruzi antigens.

Antibodies of chronic chagasic patients have been shown to interfere with electric and mechanical activities of cardiac embryonic myocytes in culture and with whole mammalian hearts. A mechanism proposed for this effect involves interaction of the antibodies with G-protein-linked membrane receptors, thus leading to activation of beta adrenergic and muscarinic receptors; more specifically, IgG of chagasic patients would interact with the negatively charged regions of the second extracellular loop of these receptors. We performed competition experiments to test this hypothesis. We evaluated the effect of sera/IgG from patients previously known to depress electrogenesis and/or atrioventricular conduction in isolated rabbit hearts after incubation with live and lysed parasites, the peptide corresponding to the second extracellular loop (O2) of the M2 receptor, and different peptides derived from two ribosomal proteins of T. cruzi: P0 and P2beta. Our results indicate that 1) the antigenic factor inducing the functionally active IgGs in the chagasic patients is probably an intracellular T. cruzi antigen; 2) IgG/serum is interacting with the O2 region of the M2 receptor in the rabbit heart; and 3) the negative charges present in the ribosomal proteins of T. cruzi are important in mediating the interaction between the patients' serum/IgG and the receptor.

Amino Acid Sequence↗
PubMed1998

Kawasaki disease thirty years on.

This year marks the 30th anniversary of the first description of Kawasaki disease. The disease has emerged as an important cause of acquired heart disease in children. The cause of Kawasaki disease remains unknown and this presents many problems in the diagnosis and management of the disease. This paper reviews recent publications on the pathogenesis, diagnosis, and the short- and long-term management of Kawasaki disease.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Avoidable deficiencies in the delivery of health care to children with meningococcal disease.

OBJECTIVES: It is apparent that delays and inadequate or inappropriate management occur frequently and may contribute to the continued high mortality seen in meningococcal disease. An attempt has been made to define the major sources of delay or inappropriate treatment. METHODS: A prospective, descriptive study of children with meningococcal disease referred to a tertiary centre paediatric intensive care and infectious disease unit. Definitions of optimal care were established at three stages: parental; general practitioner (GP)/accident and emergency (A&E) department; and hospital. Duration of symptoms and management were recorded from direct questioning of parents and carers, and from hospital records. RESULTS: 54 consecutive children with meningococcal disease were recruited to the study. Delayed parental recognition occurred in 16 children. GPs correctly diagnosed 19 of 35 children. Delay of 2.5-21 hours occurred in those who were incorrectly diagnosed. Two of 15 children who presented to the A&E department with specific features were incorrectly diagnosed. Hospital treatment was suboptimal in 71%. Shock was not recognised or treated in 50%, 20% of children had unnecessary lumbar punctures. Time from illness onset to treatment was longer in fatal disease (median 18.3, range 8-24 hours), compared with survivors (median 12, range 2-48 hours; p < 0.01, Mann-Whitney U test). CONCLUSION: Suboptimal treatment in meningococcal disease is due to failure of parents, GPs, and hospital doctors to recognise specific features of the illness. Improvement by public education and better training of clinicians in recognition, resuscitation, and stabilisation of seriously ill children.

Adolescent↗
PubMed1998

Acute oliguric renal failure associated with unilateral renal embolism: a successful treatment with iloprost.

A 66-year-old woman presented with acute-onset rapid atrial fibrillation and right upper quadrant pain which had appeared 24 h prior to admission. The patient also manifested acute oliguric renal failure (serum creatinine 6.9 mg/dl). Selective renal angiography revealed total occlusion of the right renal artery with normal visualization of the left kidney vasculature. The patient was treated with intra-arterial urokinase and intravenous heparin, with no response. Intravenous administration of the prostacyclin analogue, iloprost, resulted in rapid resolution (within hours) of the oliguric acute renal failure, in spite of the continuing presence of a nonfunctioning right kidney. We conclude that the etiology of the acute renal insult in this patient is probably related to unilateral renal arterial embolization accompanied by arterial spasm of the unaffected kidney. The contralateral vasospasm can be reversed by iloprost, which then leads to a rapid recovery from acute renal failure. We are unaware of prior reports documenting the beneficial effect of iloprost in a clinical setting as described here.

Acute Kidney Injury↗