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Biomedical subjects

M Singer

Publications and source records attributed to M Singer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mitochondrial dysfunction in sepsis.

The current mainstream view of organ failure induced by sepsis revolves around inflammation and loss of vascular control. However, there has been a resurgence in interest in bioenergetic failure due to mitochondrial dysfunction. This concept is not new--studies date back 30 years; however, the data have been highly conflicting with findings of either decreased, increased or unchanged mitochondrial activity and/or nucleotide levels. These studies are virtually all based on non-human cells, isolated perfused organs or in vivo animal models that have received a variety of insults ranging from mild to severe, and monitored for different durations ranging from minutes to weeks. As a generalization, there does appear to be depression of mitochondrial function with longer-duration models of greater severity. This is confirmed by the scanty human data currently available. This chapter provides an overview, and attempts to relate the biochemical changes to the clinical condition. The potential roles of nitric oxide, intracellular calcium and reactive oxygen species are highlighted.

Adenosine Triphosphate↗
PubMed1999

Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.

Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.

Adolescent↗
PubMed1999

Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration.

BACKGROUND: Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration (CVVH). Despite adequate exogenous anticoagulation, the occlusion of CVVH circuits can occur within minutes to a few hours of use and is associated with evidence of thrombin generation. Having found no evidence of activation of the contact factor (intrinsic coagulation) pathway during CVVH, we sought to examine the effect of the first episode of CVVH on the tissue factor (extrinsic) pathway of coagulation and thrombin generation. METHODS: Twelve critically ill patients were studied prior to the commencement of hemofiltration and at regular intervals thereafter until the filter clotted. RESULTS: Prior to hemofiltration, most patients had increased levels of plasma tissue factor, thrombin-antithrombin (TAT) complexes, and tissue factor pathway inhibitor (TFPI); during hemofiltration, further generation of TAT complexes occurred. Initially, levels of activated factor VII (FVIIa) fell and TFPI increased, but during the course of hemofiltration, the levels of TFPI fell and FVIIa increased. Levels of tissue factor increased during CVVH in some patients, but this was not related to the generation of FVIIa. CONCLUSIONS: These data indicate that activation of FVII occurred during CVVH, which was related to levels of TFPI, but not tissue factor, and was coincidental to thrombin generation.

Adult↗
PubMed1999

Septic arthritis of the metacarpophalangeal and interphalangeal joints of the hand.

Septic arthritis of the small joints of the hand is not reported frequently. Twenty-eight patients were treated during a 15-month period, from November 1992 to January 1994. Prompt surgical drainage, antibiotics, and early postoperative mobilization (within 24 hours) were the cornerstones of management. Nineteen patients were available for a median follow-up of 10 months. Patients who presented after 10 days all had a poor result. Patients who presented earlier achieved a good result unless they defaulted from treatment or had sustained an associated severe traumatic joint injury. Ten of the 19 patients obtained a good result. Good functional results can be obtained with early postoperative mobilization.

Adolescent↗
PubMed1999

Prediction of postoperative cardiac surgical morbidity and organ failure within 4 hours of intensive care unit admission using esophageal Doppler ultrasonography.

OBJECTIVE: To compare esophageal Doppler ultrasonography with standard hemodynamic variables used in postoperative care for the prediction of postoperative complications after cardiac surgery. DESIGN: Prospective, observational pilot study. SETTING: University hospital, multidisciplinary intensive care unit PATIENTS: Postoperative cardiac surgical patients. INTERVENTIONS: Standard postoperative management as guided by routinely measured hemodynamic variables. MEASUREMENTS: An esophageal Doppler ultrasound probe was inserted for measurement of stroke volume (SV), cardiac output (CO), and other flow-related variables. Both these and routine hemodynamic variables (mean arterial pressure, central venous pressure, heart rate, arterial base deficit, urine output, core-toe temperature difference) were recorded at half-hourly intervals for the first 4 postoperative hrs. The incidence of systemic inflammatory response syndrome at 24 hrs, Acute Physiology and Chronic Health Evaluation II, and multiple organ failure scores, postoperative complications, and length of ICU and hospital stays were recorded. MAIN RESULTS: Twenty consecutively admitted patients were studied: eight after emergency bypass grafting and 12 after elective bypass grafts and/or valve replacement. Of the nine patients who developed postoperative complications, two died. At admission, significant differences were seen between patients with a complicated and those with an uncomplicated surgical procedure for SV, heart rate, and standard base excess, but not for cardiac output. By using receiver operator characteristic curves, SV was the best marker for predicting postoperative complications during the initial postoperative period. CONCLUSIONS: A low SV and a high heart rate, both at ICU admission and during the subsequent 4 hrs, were the best prognostic factors for development of complications after cardiac surgery. Cardiac output values were not useful. This pilot study suggests that the minimally invasive technique of esophageal Doppler ultrasonography may be a useful tool to assist early prognostication.

Analysis of Variance↗
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↗