Nitric oxide synthase localized in a subpopulation of vestibular efferents with NADPH diaphorase histochemistry.
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Animals↗
Biomedical subjects
M Singer
Publications and source records attributed to M Singer.
Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing gastrointestinal resection.
OBJECTIVES: To assess whether immediate post-operative enteral feeding in patients who have undergone gastrointestinal resection is safe and effective. DESIGN: Randomised trial of immediate post-operative enteral feeding through a nasojejunal tube v conventional postoperative intravenous fluids until the reintroduction of normal diet. SETTING: Teaching hospitals in London. SUBJECTS: 30 patients under the care of the participating consultant surgeon who were undergoing elective laparotomies with a view to gastrointestinal resection for quiescent, chronic gastrointestinal disease. Two patients did not proceed to resection. MAIN OUTCOME MEASURES: Nutritional state, nutritional intake and nitrogen balance, gut mucosal permeability measured by lactulose-mannitol differential sugar absorption test, complications, and outcome. RESULTS: Successful immediate enteral feeding was established in all 14 patients with a mean (SD) daily intake of 6.78 (1.57)MJ (1622 (375) kcal before reintroduction of oral diet compared with 1.58 (0.14) MJ (377 (34) kcal) for those on intravenous fluids (P < 0.0001). Urinary nitrogen balance on the first postoperative day was negative in those on intravenous fluids but positive in all 14 enterally fed patients (mean (SD) - 13.2 (11.6) g v 5.3 (2.7) g; P < 0.005). There was no difference by day 5. There was no change in gut mucosal permeability in the enterally fed group but a significant increase from the test ratios seen before the operation in those on intravenous fluids (0.11(0.06) v 0.15 (0.12); P < 0.005). There were also fewer postoperative complications in the enterally fed group (P < 0.005). CONCLUSIONS: Immediate postoperative enteral feeding in patients undergoing intestinal resection seems to be safe, prevents an increase in gut mucosal permeability, and produces a positive nitrogen balance.
Enteral Nutrition↗
Fine-needle aspiration as the initial diagnostic modality in malignant lung disease.
Cytologic detection of lung cancer is accepted, accurate, and time-honored. Typically, cytologic workup of a radiologic abnormality proceeds sequentially from sputum to bronchoalveolar cytology, and, if necessary, to fine-needle aspiration biopsy (FNA). Initial use of FNA in lung cancer diagnosis is controversial, but increasingly popular. We therefore decided to objectively assess current practice in cytologic lung cancer diagnosis at our institution. All pulmonary cytologic diagnoses for 1993 and the first half of 1994 were retrieved. Positive diagnoses were then used to access all patient data. Patients were stratified according to the specimen from which the first positive diagnosis was obtained. Of 542 pulmonary cytology specimens, 15% were sputa, 65% were bronchoalveolar, and 20% were FNAs. One hundred sixty-one of 172 malignant diagnoses were first diagnoses. Three percent of first malignant diagnoses were made from sputa, 47% were from lavages, and 50% were from FNAs. Although FNAs comprised just 20% of all pulmonary cytologies, 50% of all new malignant cytologic diagnoses were made by FNA. Initial use of FNA is successful, has a high diagnostic yield and low complication rate, and offers the most direct approach to diagnosis.
Biopsy, Needle↗
Interleukin-10 inhibits cytokine generation from mast cells.
This report examines the effects of recombinant murine interleukin-10 (rmIL-10) on antigen-induced beta-hexosaminidase, leukotriene (LT)C4 and cytokine release from mouse bone marrow-derived mast cells (BMMC). BMMC sensitized to hapten-monoclonal IgE directed against dinitrophenol-bovine serum albumin (DNP-BSA) and challenged with 10 ng/ml DNP-BSA generated beta-hexosaminidase and LTC4-like material which was followed by tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression and protein release. Incubation of BMMC with 1-100 ng/ml rmIL-10 inhibited cytokine generation, without affecting beta-hexosaminidase and LTC4-like material release. TNF-alpha, but not GM-CSF mRNA expression, was also diminished in rmIL-10-treated BMMC, suggesting that down-regulation of cytokine production by rmIL-10 involves different mechanisms. These results identify a novel biological action of IL-10 as an inhibitor of cytokine production by stimulated mast cells.
Animals↗
Constructing and Validating Motive Bridging Inferences
Understanding Jane left early for the birthday party, She spent an hour shopping at the mall requires detecting that the first statement motivates the second. The validation model states that before accepting this bridging inference, the reader validates it with reference to relevant knowledge. In particular, a mediating idea is first derived from the text outcome and its candidate motive. If the mediating idea is supported by general knowledge, then the inference has been validated. In tests of this anaylsis, experimental subjects read motive or control sequences and then answered questions probing the knowledge hypothesized to validate the motive inferences, such as Do birthday parties involve presents? Five experiments confirmed that understanding motive sequences facilitates validating knowledge. A control procedure also refuted a priming counterexplanation of these effects (Experiment 1). Validation processing obtained for motive-outcome statements separated by two to four sentences in coherent sequences (Experiments 2 to 4). Inferred and explicit validating knowledge had a similar representational status (Experiment 3). Whereas proofreading abolished the validation effect, a reading strategy promoting causal processing did not enhance it (Experiment 4). A delayed priming procedure indicated that validating knowledge is integrated with the text representation (Experiment 5). The implications of these findings for the constructionist and minimal inference analyses were explored. The validation effects were simulated using construction-integration model.
Journal Article↗
Bladder epithelial oxygen tension--a new means of monitoring regional perfusion? Preliminary study in a model of exsanguination/fluid repletion.
OBJECTIVE: To assess whether monitoring of bladder epithelial oxygen tension (BEOT) would provide an indication of regional (renal) organ perfusion in an exsanguination/fluid repletion animal model. DESIGN: Prospective non-randomized laboratory study. SETTING: Research laboratory. INTERVENTIONS: Eight anaesthetised, spontaneously breathing Sprague-Dawley male rats weighing approximately 200 g were instrumented. They received 1-ml aliquots of fluid until no further haemodynamic improvement was seen, followed by removal of 1-ml aliquots of blood until renal blood flow fell by 50%. The animal was then resuscitated with repeated 1 to 2-ml aliquots of fluid until no further improvement was achieved and, finally, progressively exsanguinated to cardiovascular collapse. MEASUREMENTS AND RESULTS: A continuous Clark-type oxygen electrode lying in contact with the inside wall of the bladder measured changes in BEOT during these exsanguination and fluid repletion manoeuvres. Changes in BEOT closely mirrored both systemic (blood pressure and aortic blood flow) and regional (renal blood flow) haemodynamic changes. A direct correlation existed between percentage change in BEOT and base deficit, and an indirect correlation was seen with arterial oxygen tension. CONCLUSIONS: Measurement of BEOT may be a useful and relatively non-invasive means of monitoring regional organ perfusion. Further studies are warranted.
Animals↗
Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.
delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.
Animals↗
Botulinum toxin treatment of essential blepharospasm and hemifacial spasm.
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Adrenergic alpha-Agonists↗
Episodic evolution and rapid divergence of members of the rat multigene family encoding the salivary prohormone-like protein SMR1.
In rodents, the variable coding sequence (VCS) multigene family displays extensive evolutionary divergence in the protein-coding region. While certain VCS genes coding for proline-rich proteins (hPR-PB, mMSG1, rPR-VB1) are conserved in primates and rodents, others seem to be specific to certain genera. This appears to be the case for the Rattus genes forming the A-subclass. This subclass is composed of three genes in R. norvegicus and probably five genes in R. rattus. The first described VCSA gene (Rn. VCSA1) was found to encode a prohormone-like protein named SMR1 (-VA1), expressed mainly in the submandibular glands (SMG) of male rats. To further understand the evolution of this variable multigene family, we have cloned the two additional genes (Rn. VCSA2 and Rn. VCSA3) forming the R. norvegicus A-subclass and three VCSA genes (Rr. VCSA1a, b and Rr. VCSA2) of R. rattus. The putative SMR1 proteins encoded by all these genes display the same prohormone-like structure as Rn. SMR1-VA1. However, we observe a polymorphism in some internal cleavage sites which suggests that multiple processing of the SMR1 proteins could result in the liberation of peptides differing in structure and length. The phylogenetic analysis of the sequences reveals that the duplication events giving rise to the VCSA1, -A2, and -A3 progenitors were anterior to the R. norvegicus and R. rattus split, and that a VCSA1 duplication event likely occurred specifically in R. rattus. A striking observation is that the coding sequences of the VCSA genes have rapidly diverged from their ancestors. Along all branches of the phylogeny, the nonsynonymous divergence rate is identical or superior to the synonymous divergence rate. We suggest that frequent changes in functional requirements are mainly responsible for the episodic evolution and the rapid divergence of the VCSA genes.
Amino Acid Sequence↗
Cardiorespiratory and tissue oxygen dose response to rat endotoxemia.
The dose response to endotoxin (Escherichia coli serotype 127:B8) was assessed in a spontaneously breathing, halothane-anesthetized, Sprague-Dawley rat model monitoring blood pressure, aortic and renal blood flows, blood gases, and bladder epithelial PO2, a marker of organ perfusion. The animals received either saline or endotoxin at doses of 1, 10 and 100 mg/kg body wt. Blood pressure changed significantly in all three endotoxin groups, though only the 100 mg/kg group showed significant changes in arterial PCO2, arterial PO2, and body temperature compared with controls. Whereas aortic and renal blood flow rose significantly in the two lower-dose groups, an approximate one-third fall occurred in the 100 mg/kg group (P < 0.001). Notwithstanding these macrocirculatory hemodynamic changes, both bladder epithelial PO2 and arterial base deficit rose significantly in all groups, though only the base deficit showed a progressive dose response. This model illustrates that responses to endotoxin are dose dependent but with changing patterns for different variables. The consistent finding of an elevated tissue PO2 in endotoxemia, regardless of dose, is suggestive of defective cellular oxygen metabolism.
Animals↗
Farewell to adaptationism: unnatural selection and the politics of biology.
This article argues that human adaptation has lost its utility as a conceptual tool for either biological or medical anthropology, despite the recent efforts of practitioners in these subdisciplines to rescue it by considering the influences of power, history, and global social processes. It draws on cases from diverse fields, including evolutionary studies, ethology, genetics, and epidemiology, to suggest new ways of conceptualizing the relationship between humans and their physical and biotic environments; environments that they, and to a lesser degree other species, are not so much "adapting to" as transforming, while being transformed themselves in the process. Central to this reconceptualization is an understanding of human behavior and environmental relationships in political-economic context.
Adaptation, Psychological↗
The role of working memory capacity and knowledge access in text inference processing.
Individual differences in drawing bridging inferences during text comprehension were examined. We measured reader differences in working memory capacity, using the reading span task, and in access to relevant knowledge, using Potts and Peterson's (1985) integration task. The dependent measure of greatest concern was answer time about facts posited to validate the bridging inference. Reading span and access were negligibly correlated, an outcome that supports their independence. Answer times were lower both for high reading span and high-access readers. In addition, readers who were either high on both reader traits or low on both traits exhibited qualitatively different inference effects from the typical pattern. It is proposed that knowledge access during comprehension is facilitated by the extraction of integrated situation models from text and that it is individuals with efficient reading processes who can construct these models.
Analysis of Variance↗
Structural impediments to operational syringe-exchange programs.
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Connecticut↗
Routine immunization in HIV: helpful or harmful?
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Bacterial Vaccines↗
Sale and exchange of syringes.
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Connecticut↗
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↗