Sale and exchange of syringes.
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Connecticut↗
Biomedical subjects
M Singer
Publications and source records attributed to M Singer.
Ectopic production of guanosine penta- and tetraphosphate can initiate early developmental gene expression in Myxococcus xanthus.
Amino acid or carbon limitation is sufficient to initiate fruiting body development in Myxococcus xanthus. In both Escherichia coli and M. xanthus the levels of guanosine 3'-di-5'-(tri)di-phosphate nucleotides [(p)ppGpp] rise transiently when cells are starved for amino acids or carbon. Ectopic increase in the intracellular concentration of (p)ppGpp was achieved in M. xanthus by introducing a copy of the E. coli relA gene, whose product catalyzes pyrophosphate transfer from ATP- to GTP-forming pppGpp. The E. coli RelA protein was detected in these M. xanthus strains, and a rise in (p)ppGpp was observed chromatographically. This increase in the intracellular (p)ppGpp levels was sufficient to activate developmentally specific gene expression. Although (p)ppGpp is made from GTP, the intracellular GTP pool from these strains was not significantly decreased. Moreover, when the GTP pool was lowered by either of two specific inhibitors of GTP synthesis, mycophenolic acid or decoyinine, development was not induced. These results suggest that M. xanthus cells can assess their nutritional status by monitoring the internal availability of amino acids through (p)ppGpp levels.
Adenosine Triphosphate↗
A novel class of potent tetrahydrocannabinols (THCS): 2'-yne-delta 8- and delta 9-THCS.
A series of 3-alkyl-2'-yne (side chain) acetylenic analogs of delta 9-THC were synthesized and evaluated for in vitro and in vivo activity. Analogs were evaluated for receptor affinity in a [3H]CP-55,940 displacement assay and for in vivo pharmacological activity in a mouse procedure utilizing a tetrad of measures. These compounds represent a preliminary exploration of the consequences of restricting the flexibility of the side chain regarding cannabimimetic activity. All analogs proved to have receptor affinities (4-11 nM) that were five to ten times greater than that observed for delta 9-THC. However, the in vivo activities of these compounds varied greatly. All analogs proved to possess the greatest potency for production of antinociception, with activity similar to or less than that observed for the production of hypomotility, hypothermia, and catalepsy. The most potent analog 11b exhibited an ED50 of 0.031 mg/kg in the tail-flick procedure, with values in other measures being between 0.5 and 1.0 mg/kg. The least active compound (11c), though still possessing a KI of 11 nM, exhibited ED50 values of 3.1 and 9.3 mg/kg for tail-flick and temperature procedures, as well as 41 and 48 mg/kg for ring-immobility and spontaneous locomotor activity, respectively. This profile (high receptor affinity but low in vivo potency) would normally be suggestive of a compound with antagonist properties (at least for immobility and activity measures). It is unclear why these acetylenic analogs were so potent in vitro, while only one (11b) exhibited the degree of in vivo potency anticipated based upon comparison to values for delta 9-THC. It is possible these side chain modifications do not interfere with receptor recognition, but limit receptor activation or second messenger signal transduction. Regardless, it is clear these novel analogs provide a basis for the further exploration of the cannabinoid receptor pharmacophore.
Analgesics↗
Pharmacological and behavioral evaluation of alkylated anandamide analogs.
Anandamide (arachidonylethanolamide), isolated from porcine brain, has been shown to bind to the cannabinoid receptor and also to produce cannabimimetic activity in pharmacological assays. This study examined structure-activity relationships in alkylated anandamide analogs. The analogs were evaluated for their ability to displace [3H]CP-55,940 in a filtration binding assay using rat brain membranes in the presence and absence of the enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF). Behavioral activity was assessed by the ability of the analogs to produce hypomotility and antinociception. Methylations at carbons 2 and 1 produced compounds stable in the absence of PMSF with similar affinities and behavioral activity as anandamide. Addition of larger alkyl groups at these positions or nitrogen methylation reduced receptor affinity and behavioral potency. These results indicate that methylations at specific carbons of anandamide confer stability in vitro.
Alkylation↗
Recent evolution of genes encoding the prohormone-like protein SMR1 in the rat submandibular gland.
The Variable Coding Sequence (VCS) multigene family of Rattus norvegicus, is composed of at least 10 members, and shows extensive evolutionary divergence in the protein-coding region. Three members of the VCSA subclass, have been characterized: one of them, the VCSA1 gene mainly expressed in the submandibular gland (SMG) encodes the prohormone-like protein, SMR1-VA1. As VCSA-related genes have not been detected in Mus musculus, the VCSA genes subclass is presumed to have recently emerged. To study the evolution of this subclass, we have looked for VCSA genes in a closely related species, Rattus rattus. By Northern analysis, we demonstrate that VCS-related mRNAs are present in the SMG, and that the level of VCSA mRNA accumulation is approximately equal in both sexes. By contrast, in R. norvegicus, males accumulate about 3,000 times more VCSA1 mRNA than females. Using total SMG mRNA, an almost full-length cDNA, homologous to the cDNA of the R. norvegicus VCSA1 gene, was cloned by reverse transcriptase polymerase chain reaction (RT-PCR). The putative corresponding SMR1-VA1 protein is 146 amino acids long and presents the features characteristic of a secreted protein, with a potential signal peptide of 22 amino acids in the amino-terminal portion. The presence of potential processing multibasic sites suggests that small peptides could be generated (particularly a hexapeptide: Arg-Gln-His-Asn-Leu-Arg), as in the case of the SMR1-VA1 protein of R. norvegicus. From Southern blot analysis there appears that species-species modifications of VCSA gene copy number have occurred; R. rattus contains a greater VCSA1 copy number than R. norvegicus (two or three and one, respectively).
Amino Acid Sequence↗
Continuous measurement of cardiac output during aortic cross-clamping by the oesophageal Doppler monitor ODM 1.
We have compared the Doppler against the thermodilution technique for measurement of cardiac output in six patients during aortic surgery. The correlation coefficient between the two methods was between 0.76 and 0.84 during the different periods of the operation. Using the integral nomogram instead of direct calibration, the Doppler system underestimated cardiac output in atherosclerotic patients. However, the Doppler method did register accurately significant changes in cardiac output.
Aged↗
Bladder epithelial oxygen tension as a marker of organ perfusion.
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Acidosis↗
Immunotherapy in the management of sepsis.
The pathophysiological effects of severe sepsis, septic shock and related syndromes result from tissues damaged by the uncontrolled production of the mediators of inflammation. Early deaths are related primarily to the acute effects of the systemic inflammatory response. Later deaths are related more closely to the consequences of multiple organ dysfunction. Monoclonal antibodies and other immunotherapies have been developed against bacterial products, cytokines and other mediators involved in this systemic inflammatory response. Immunotherapies may improve outcome in the critically ill with sepsis if used early and as part of the therapeutic regimen of antimicrobial agents and intensive care support.
Animals↗
High dependency units in the UK: variable size, variable character, few in number.
An exploratory descriptive survey was conducted to determine the size and character of high dependency units (HDUs) in the UK. A telephone survey and subsequent postal questionnaire was sent to the 39 general HDUs in the UK determined by a recent survey from the Royal College of Anaesthetists; replies were received from 28. Most HDUs (82%, n = 23) were geographically distinct from the intensive care unit and varied in size from three to 13 beds, although only 64% (n = 18) reported that all beds were currently open. Nurse: patient ratios were at least 1:3. Fifty per cent of units had one or more designated consultants in charge, although only 11% (n = 3) had specifically designated consultant sessions. Junior medical cover was provided mainly by the on-call speciality term. Twenty units acted as a step-down facility for discharged intensive care unit patients and 21 offered a step-up facility for patients from general wards. Provision of facilities and levels of monitoring varied between these units. Few HDUs exist in the UK and they are variable in size and in the facilities and monitoring procedures which they provide. Future studies are urgently required to determine cost-effectiveness and outcome benefit of this intermediate care facility.
Health Facility Size↗
Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis.
The effect of endotoxin on tissue oxygen tension measured at the bladder epithelium was assessed in spontaneously breathing Sprague-Dawley rats anesthetized with halothane. Hyperdynamic (high cardiac output, group A, n = 6) and hypodynamic (low cardiac output, group B, n = 6) circulatory responses were achieved by intravenous administration of Escherichia coli lipopolysaccharide, 10 mg/kg over 30 min or 20 mg/kg over 1 min, respectively. Comparison was made against sham-operated control rats (group C, n = 6). Aortic and renal blood flows increased in group A and fell in group B (P < 0.001). However, in both groups, bladder epithelial oxygen tension rose significantly compared with control (P < 0.01), despite an increasing metabolic acidosis. This is in contradistinction to previous studies of nonseptic insults where bladder epithelial oxygen tension fell in line with an increasing arterial base deficit. If a raised tissue oxygen tension could be demonstrated in other organ beds, this would suggest that decreased utilization of oxygen rather than reduced tissue oxygen availability is responsible for the apparent anaerobic respiration seen in sepsis.
Animals↗
The effect of norepinephrine and dobutamine on bladder epithelial oxygen tension.
STUDY OBJECTIVES: To assess the effects of two contrasting vasoactive agents (dobutamine [DOB] and norepinephrine [NE]) on (1) global and regional cardiorespiratory variables, (2) acid base status, and (3) bladder epithelial oxygen tension (BEOT), a putative marker of organ perfusion. DESIGN: Measurement of aortic blood flow (ABF) and renal blood flow (RBF), mean arterial blood pressure, arterial blood gases, and BEOT were made during infusion of placebo and varying doses of DOB and NE. SETTING: Medical school laboratory. SUBJECTS: Eighteen anesthetized, spontaneously breathing, male Sprague-Dawley rats divided into three groups. INTERVENTIONS: Two groups were allocated to receive escalating doses of DOB (to 40 micrograms/kg/min) or NE (to achieve a 50% change in any hemodynamic variable). The drug therapy was then discontinued for 15 min and restarted at the previous maximum dose. A third group received 0.9% saline solution at the same infusion rate (16 mL/kg/h). MEASUREMENTS AND RESULTS: There was a dose-related increase in mean blood pressure with NE and fall with DOB. Compared with control values, NE had no effect on ABF but decreased RBF significantly whereas DOB significantly increased ABF but had no effect on RBF. Base excess and BEOT decreased significantly and in parallel with both agents, more so with NE. CONCLUSIONS: Despite their different macrocirculatory effects, DOB and NE both produced a significant but reversible fall in BEOT and a metabolic acidosis. BEOT shows potential as a monitor of the effectiveness of organ perfusion.
Animals↗
Beyond the Ivory Tower: critical praxis in medical anthropology.
Recent discussion in critical medical anthropology has turned to the issue of application beyond the academy. Building on Gorz's notion of "non-reformist reform," that is, applied work that unmasks rather than mystifies the sources of social inequality and ill health, this article argues for the possibility of an applied critical medical anthropology, suggests concrete opportunities for such work in health settings, and identifies problems and social conditions that affect the development of a critical health praxis. These points are illustrated by reviewing case studies of anthropological work with the Farm Labor Organizing Committee in Indiana, the United Farm Workers Union in California, and the Hispanic Health Council in Connecticut. The article concludes with an examination of the skills and resources critical medical anthropology has to offer system-challenging movements in health care.
Anthropology↗
AIDS prevention for African-American and Latina women: building culturally and gender-appropriate intervention.
African-American and Latino women are at high risk of HIV infection through heterosexual transmission, reflected in the significant increases in reported AIDS cases of women thus infected. Few AIDS-prevention programs have addressed this risk for women by directly, separately and, in appropriate ways, focusing on specific women's issues of gender roles, sexuality, and differential power relationships with men, in the context of racial and class relations, as these affect HIV transmission. This article discusses the contributions of a community-based AIDS-prevention program to the development of culturally and gender-appropriate intervention for African-American and Latina women at high risk. Further such programs are needed which build on the use of ethnic cultural concepts, racial and other social relations, and acknowledge issues specific to minority women in order to prevent their infection with HIV.
Acquired Immunodeficiency Syndrome↗
Current nursing practices in fever management.
Data regarding fever management were obtained through a retrospective or concurrent review of the medical records of 150 patients. For 41% of the patients studied, nurses notified physicians of the fever episode. The decision to treat fever was significantly influenced by fever intensity and the drawing of blood cultures, but not by age, length of hospital stay, or the duration of the fever episode. Despite recent evidence of the protective value of fever, the majority of fever episodes were treated. Acetaminophen alone, and acetaminophen in combination with physical cooling methods, were effective in lowering fever.
Adult↗
Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs.
Recent evidence implicates anandamide as the endogenous ligand for the cannabinoid receptor. One purpose of this study was to determine the structural requirements for anandamide's receptor interaction and the influence of phenylmethylsulfonyl fluoride (PMSF), an enzyme inhibitor, on receptor affinity. A second objective was evaluation of the correlation between affinities of the analogs and in vivo pharmacological activities. The ability of anandamide and analogs to displace [3H]CP-55,940 ([3](-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3- hydroxylpropyl]cyclohexan-1-ol) was determined by a filtration assay. Displacement curves for anandamide in the presence of PMSF produced a Ki of 89 +/- 10 nM; without PMSF the Ki increased to 5400 +/- 1600 nM. Anandamide analogs were evaluated for their ability to produce antinociception and hypomotility. The levels of saturation of the anandamide structure were critical to receptor affinity and in vivo potency, with complete saturation and hydroxyl substitution with a fluorine moiety resulting in a compound with increased potency in the spontaneous activity and antinociception assays. Substitution of the hydroxyl with a fluorine atom increased affinity only in the presence of PMSF and reduced potency in the antinociception assay. Ethanolamide substitution with bromobenzenesulfonamide produced an inactive compound in all assays. Increasing the length of the N-substituent by one or two carbons decreased receptor binding affinity and potency in the tail-flick assay only. Certain structural modifications, such as methylations, allowed the analogs to retain affinity without the addition of PMSF. Linear correlation between the behavioral and binding assays were performed, and the greatest correlation was obtained with compounds that were either very potent or inactive.
Animals↗
Ethnography and the evaluation of needle exchange in the prevention of HIV transmission.
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Connecticut↗
Synthesis and 5-lipoxygenase inhibitory activities of some novel 2-substituted 5-benzofuran hydroxamic acids.
A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.
Animals↗
Bacterial sporulation. An ATP/ADP switch.
Regulatory factors that initiate forespore-specific transcription during Bacillus subtilis sporulation respond to adenosine nucleotide ratios.
Adenosine Diphosphate↗