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Biomedical subjects

M Singer

Publications and source records attributed to M Singer.

At least 73 records · Page 4Linked to original sources
PubMed1999

Increased interleukin-1 (IL-1) and imbalance between IL-1 and IL-1 receptor antagonist during acute inflammation in experimental Shigellosis.

Infection by the enteric bacterial pathogen Shigella results in intense mucosal inflammation and destruction of the colonic and rectal epithelium in infected humans. Initial bacterial translocation occurs through the follicle-associated epithelium. Previous experiments suggest that interleukin-1 (IL-1) is crucial to trigger inflammation, particularly in the follicular zones. During the first 4 hours of infection in a rabbit ligated-loop model of intestinal invasion, there are two salient characteristics: (i) a high concentration of IL-1alpha and IL-1beta, both in infected Peyer's patch tissue and in the corresponding efferent mesenteric blood, and (ii) a very low level of expression of IL-1 receptor antagonist (IL-1ra). These may reflect a combination of regulation of expression and secretion of IL-1alpha, IL-1beta, and IL-1ra by both resident and recruited phagocytes and the induction of mononuclear phagocyte apoptosis by Shigella. This low IL-1ra/IL-1 ratio likely accounts for the rapid, uncontrolled inflammation characteristic of shigellosis.

Acute Disease↗
PubMed1999

Oedipal dynamics in panic disorder.

Both research and clinical work have revealed factors that can lead to the onset and persistence of panic disorder. Preoedipal conflicts intensify the danger of oedipal longings for panic patients. Competition with the same-sex parent is linked with angry preoedipal fantasies and associated fears of disruption in attachments. Fantasies or actual successes can thus trigger panic episodes. Regression to a helpless, dependent state such as panic defends against the danger of aggressive, competitive fantasies and actual achievements. However, the regressive state can also be experienced as dangerous, and can be linked with frightening homosexual fantasies. A reactive aggressive oedipal stance can sometimes result, triggering escalating turmoil. The panic episode serves a series of compromise formations in dealing with these conflicted wishes.

Adult↗
PubMed1999

The oxygen trail: tissue oxygenation.

Aerobic cellular respiration depends on the efficient supply of oxygen and substrate to the mitochondria. There is an oxygen cascade from the environment to the subcellular environment. Efficient oxygen delivery depends on the coordinated interaction between the respiratory and circulatory systems. The circulation at both macro- and microvascular levels is under the control of humoral and neural factors. There is local autoregulation of flow at the tissue level by metabolic factors which reflect the energy state of the tissues. The response to hypoxia involves the activation of cytokines and genetically controlled factors which maximise capillary perfusion and haemoglobin concentration, and regulate cell metabolism. The formation of reactive oxygen species under such conditions has a detrimental effect on the mitochondria with respiratory chain dysfunction, increased permeability transition, and cell death. This review aims to explore the mechanisms by which the body attempts to maintain tissue oxygen levels at conditions optimal for cell survival.

Humans↗
PubMed1998

Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol.

The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.

Animals↗
PubMed1998

Systemic administration of endotoxin induces bronchopulmonary hyperreactivity dissociated from TNF-alpha formation and neutrophil sequestration into the murine lungs.

Bronchopulmonary hyperreactivity (BHR), an increased responsiveness to nonspecific bronchoconstrictor agents, is a well-known characteristic of bronchial asthma. It has been recently suggested that the severity of this disease is related to the endotoxin content of house dust. In the present report, it is shown that the i.p. administration of bacterial LPS to mice is followed by a marked early dose-dependent BHR in response to methacholine. The microscopic examination showed no ultrastructural lesions of the lungs or of the airways, but a marked neutrophil accumulation in the capillaries, as confirmed by an increase of the lung content in the neutrophil enzyme marker myeloperoxidase. In parallel, high levels of TNF-alpha were found in plasma as well as its transcripts in the lung tissues. Using immunologic (anti-TNF-alpha and anti-granulocyte Abs), and pharmacologic (dexamethasone and vinblastine) tools, it is demonstrated that BHR is apparently neither related to the presence of neutrophils in the pulmonary microvasculature nor to the synthesis of TNF-alpha.

Aerosols↗
PubMed1998

The guanosine nucleotide (p)ppGpp initiates development and A-factor production in myxococcus xanthus.

Guanosine 3'-di-5'-(tri)di-phosphate nucleotides [(p)ppGpp], synthesized in response to amino acid limitation, induce early gene expression leading to multicellular fruiting body formation in Myxococcus xanthus. A mutant (DK527) that fails to accumulate (p)ppGpp in response to starvation was found to be blocked in development prior to aggregation. By use of a series of developmentally regulated Tn5lac transcriptional fusion reporters, the time of developmental arrest in DK527 was narrowed to within the few hours of development, the period of starvation recognition. The mutant is also defective in the production of A-factor, an early extracellular cell-density signal. The relA gene from Escherichia coli, which encodes a ribosome-dependent (p)ppGpp synthetase, rescues this mutant. We also demonstrate that inactivation of the M. xanthus relA homolog blocks development and the accumulation of (p)ppGpp. Moreover, the wild-type allele of Myxococcus relA rescues DK527. These observations support a model in which accumulation of (p)ppGpp, in response to starvation, initiates the program of fruiting body development, including the production of A-factor.

4-Butyrolactone↗
PubMed1998

A comparison of the nutritional status and food security of drug-using and non-drug-using Hispanic women in Hartford, Connecticut.

This study compared food insecurity, nutritional status (as measured through anthropometry and dietary intake), and food preparation patterns of low-income Puerto Rican female out-of-treatment drug users with that of low-income Puerto Rican women who reported no drug use. A convenience sample of 41 drug users was compared with 41 age-matched non-drug-users from inner-city Hartford, Connecticut. A culturally appropriate food frequency questionnaire was administered and anthropometric measurements were taken. The findings suggest a high degree of poverty among all study participants, but in particular among drug users. Drug users were more likely than the controls to be food insecure (P < 0.05) and to be exposed to increasingly severe food sufficiency problems. The daily frequency of consumption of vegetables was lower (P = 0.03) for drug users than non-drug-users. Conversely, the frequency of consumption for sweets/desserts was significantly higher for drug users than the controls (P = 0.0001). Drug users, who were classified as food insecure were less likely to consume vegetables (P = 0.004) and fish (P = 0.03) than were controls who were food insecure. When comparing drug users with controls, the former group reported consuming fewer meals during a usual week than the latter group (P < 0.0001). Drug users were more likely to fry foods (P = 0.02) while the controls were more likely to bake (P = 0.005), boil (P = 0.02), and steam (P = 0.002) foods. All anthropometric measurements, except for height, were significantly lower for drug users. The results show that drug users generally maintain poorer nutritional status than non-drug-users. Nutrition interventions as part of drug treatment are needed.

Adolescent↗
PubMed1998

IL-4 mRNA transcription is induced in mouse bone marrow-derived mast cells through an MHC class II-dependent signaling pathway.

We have previously shown that mouse bone marrow-derived mast cells (BMMC) can process and present immunogenic peptides to CD4 T cells. Here, we report on a T cell-dependent MHC class II-mediated mast cell activation resulting in IL-4 transcription and protein release. Presentation of optimal doses of ovalbumin peptide 323-339 resulted in IL-2 production by a specific T cell hybridoma and increase in IL-4 mRNA transcription in mast cells. IL-4 mRNA transcription increased by 200-fold in mast cells treated in IL-3/IL-4/granulocyte-macrophage colony-stimulating factor (high presenters) whereas only a tenfold increase or no increase were obtained with IL-3/IL-4/IFN-gamma- or IL-3-treated mast cells (low presenters), respectively. Induction of IL-4 mRNA transcription in purified mast cells by direct ligation of MHC class II molecules, using anti-I-A and anti-I-E-coated beads, indicates that MHC class II molecules are critical in this signaling pathway. However, when compared to T cells, anti-MHC class II-coated beads were less efficient, indicating a potential role of accessory molecules in this mast cell activation process. IgE-independent IL-4 production by mast cells as a result of cognate interaction with CD4 T cells could be critical for the development of type 2 responses. This novel mechanism may contribute to the induction and/or amplification of specific IgE-mediated allergic responses.

Animals↗
PubMed1998

Cardiorespiratory, tissue oxygen and hepatic NADH responses to graded hypoxia.

OBJECTIVE: To assess cardiorespiratory, tissue oxygen and hepatic nicotine adenine dinucleotide hydride (NADH) responses to graded hypoxia. DESIGN: Prospective, controlled, randomized study. SETTING: University laboratory. ANIMALS AND INTERVENTIONS: 18 anaesthetised Sprague-Dawley rats spontaneously breathing either 21% (controls), 12.5% or 10% inspired oxygen concentrations (6 rats per group). MEASUREMENTS AND RESULTS: All animals in the 21 and 12.5% O2 groups survived the 3-h study period, compared to only 1 in the 10% O2 group. In this latter group, mean arterial pressure and renal blood flow fell immediately with hypoxaemia, whereas aortic blood flow was maintained until the preterminal stages. Critical cellular hypoxia was suggested by an increasingly severe base deficit, an initial rise then a preterminal fall in hepatic NADH intensity and premature death in all but 1 animal. Hepatic NADH fluorescence intensity was unchanged in control animals but showed a progressive rise in the 12.5% O2 group, accompanied by a small though static increase in arterial base deficit. No significant differences were seen in arterial and tissue partial pressure of oxygen between the 12.5 and 10% O2 groups. CONCLUSIONS: This study demonstrates major differences in cardiorespiratory, hepatic NADH and outcome responses to small variations in the degree of hypoxic hypoxia. The fall in NADH fluorescence intensity presages impending death and is likely to reflect failure of cellular metabolic processes.

Animals↗
PubMed1998

Endothelial dysfunction in critically ill patients: the effect of haemofiltration.

OBJECTIVES: To examine the effect of a single episode of continuous venovenous haemofiltration (CVVH) on indicators of endothelial injury and the protein C/S system in critically ill patients. DESIGN: Observational study. SETTING: University teaching hospital intensive care unit. PATIENTS: 12 critically ill patients with acute renal failure receiving their first episode of CVVH. INTERVENTIONS: Blood samples were collected prior to starting CVVH and at 15 min and 1, 3-4, 8-12, and 24 h, and at 24-h intervals thereafter until the filter clotted. MEASUREMENTS AND RESULTS: Soluble tissue factor, soluble thrombomodulin, E-selectin and endothelin-1 were measured as indicators of endothelial injury. Changes in the protein C/S system were assessed by measurement of protein C (PC) and both free and total protein S (PS). Levels of PC and both free and total PS were subnormal in 6 and 11 patients, respectively, prior to CVVH, but there were no further changes during CVVH. Levels of tissue factor, thrombomodulin, E-selectin, and endothelin-1 were raised prior to haemofiltration in 9, 10, 9 and 9 patients, respectively. There were further increases during CVVH in at least one, but not all, of the markers of endothelial injury in most patients. There was no consistency between the changes in different markers of endothelial injury during haemofiltration in individual patients. CONCLUSIONS: The PC/PS system and endothelial integrity is compromised in critically ill patients prior to haemofiltration, but a single episode of CVVH has little effect on the PC/PS system. The increase in markers of endothelial dysfunction seen during CVVH is more likely to be related to the underlying condition of the patient rather than any specific consequence arising from the technique itself.

Acute Kidney Injury↗
PubMed1998

Effects of rolipram on cyclic AMP levels in alveolar macrophages and lipopolysaccharide-induced inflammation in mouse lung.

1. Our previous work demonstrated that bacterial lipopolysaccharide (LPS), administered by aerosol, induced tumour necrosis factor (TNF-alpha) synthesis leading to the infiltration of neutrophils into mice lungs. The treatment of animals with prostaglandin E2 or dibutyryl cyclic AMP impaired both processes. In this study, the target cell for LPS and the modulation by cyclic AMP of TNF-alpha production and neutrophil recruitment were investigated. 2. One hour after inhalation of 2 ml of 0.3 mg ml(-1) LPS, TNF-alpha levels measured by an ELISA method increased in the bronchoalveolar lavage fluid (BALF) of BALB/c mice, reaching a maximal level 3 h after inhalation. The immunocytochemistry assay demonstrated that 1 h after inhalation, 21.2% of alveolar macrophages collected in the BALF were immunopositive for TNF-alpha. 3. When mice were pretreated, i.p., with 20 mg kg(-1) rolipram, a selective inhibitor of phosphodiesterase type 4, TNF-alpha levels in the BALF were significantly reduced and only 7.3% of alveolar macrophages were immunopositive for TNF-alpha. 4. Alveolar macrophages from rolipram-treated mice collected 30 min after inhalation of LPS had a significant increase in the intracellular concentrations of cyclic AMP. This was accompanied by a marked reduction of TNF-alpha levels in the BALF that were associated with a suppression of TNF-alpha mRNA expression. 5. Systemic treatment with 20 mg kg(-1) rolipram almost completely inhibited the LPS-induced neutrophil recruitment, whereas it did not significantly reduce the recruitment induced by rmTNF-alpha. 6. Our results indicate that alveolar macrophages may be the target cells for both the induction and control of the lung inflammatory response to LPS. They also suggest that systemic treatment with cyclic AMP-elevating agents may be useful to control local inflammation resulting from inhalation of bacterial endotoxin.

Animals↗
PubMed1998

Management of multiple organ failure: guidelines but no hard-and-fast rules.

Multiple organ failure is the commonest cause of death in the intensive care unit setting. There are numerous precipitating factors including sepsis, trauma and pancreatitis. The resulting tissue hypoxia, exaggerated inflammatory response and generation of free oxygen radicals leads to tissue damage and organ dysfunction. No definitive treatment exists despite considerable efforts to find a 'magic bullet'. Management still revolves around support of organ function and prevention of iatrogenic complications until recovery occurs. An increasing emphasis is being placed on prevention of organ dysfunction, including maintenance of tissue oxygenation, nutrition and infection control.

Anti-Bacterial Agents↗
PubMed1998

SdeK is required for early fruiting body development in Myxococcus xanthus.

Myxococcus xanthus cells carrying the Omega4408 Tn5lac insertion at the sde locus show defects in fruiting body development and sporulation. Our analysis of sde expression patterns showed that this locus is induced early in the developmental program (0 to 2 h) and that expression increases approximately fivefold after 12 h of development. Further studies showed that expression of sde is induced as growing cells enter stationary phase, suggesting that activation of the sde locus is not limited to the developmental process. Because the peak levels of sde expression in both an sde+ and an sde mutant background were similar, we conclude that the sde locus is not autoregulated. Characterization of the sde locus by DNA sequence analysis indicated that the Omega4408 insertion occurred within the sdeK gene. Primer extension analyses localized the 5' end of sde transcript to a guanine nucleotide 307 bp upstream of the proposed start for the SdeK coding sequence. The DNA sequence in the -12 and -24 regions upstream of the sde transcriptional start site shows similarity to the sigma54 family of promoters. The results of complementation studies suggest that the defects in development and sporulation caused by the Omega4408 insertion are due to an inactivation of sdeK. The predicted amino acid sequence of SdeK was found to have similarity to the sequences of the histidine protein kinases of two-component regulatory systems. Based on our results, we propose that SdeK may be part of a signal transduction pathway required for the activation and propagation of the early developmental program.

Amino Acid Sequence↗
PubMed1998

Identification and characterization of the Myxococcus xanthus argE gene.

The chromosomal acetylornithine deacetylase (argE) gene of Myxococcus xanthus was identified via homology to acetylornithine deacetylases from other bacterial species. A mutant carrying a disruption in argE was unable to grow on minimal media lacking supplemental arginine and formed fruiting bodies and spores in response to arginine starvation at high cell density.

Amidohydrolases↗
PubMed1998

Aftereffects and sense of presence in virtual environments: formulation of a research and development agenda.

This report represents a committee summary of the current state of knowledge regarding aftereffects and sense of presence in virtual environments (VEs). The work presented in this article, and the proposed research agenda, are the result of a special session that was set up in the framework of the Seventh International Conference on Human Computer Interaction. Recommendations were made by the committee regarding research needs in aftereffects and sense of presence, and, where possible, priorities were suggested. The research needs were structured in terms of the short, medium, and long term and, if followed, should lead toward the effective use of VE technology. The 2 most critical research issues identified were (a) standardization and use of measurement approaches for aftereffects and (b) identification and prioritization of sensorimotor discordances that drive aftereffects. Identification of aftereffects countermeasures (i.e., techniques to assist users in readily transitioning between the real and virtual worlds), reduction of system response latencies, and improvements in tracking technology were also thought to be of critical importance.

Adaptation, Physiological↗