Central patient registration and the computer.
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Centralized Hospital Services↗
Biomedical subjects
M Manning
Publications and source records attributed to M Manning.
Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. The role of gastric colonization.
Gram-negative nosocomial pneumonia may result from retrograde colonization of the pharynx from the stomach, and this may be more likely when the gastric pH is relatively high. We studied the rate of nosocomial pneumonia among 130 patients given mechanical ventilation in an intensive care unit who were receiving as prophylaxis for stress ulcer either sucralfate (n = 61), which does not raise gastric pH, or conventional treatment with antacids, histamine type 2 (H2) blockers, or both (n = 69). At the time of randomization to treatment, the two groups were similar in age, underlying diseases, and severity of acute illness. Patients in the sucralfate group had a higher proportion of gastric aspirates with a pH less than or equal to 4 (P less than 0.001) and significantly lower concentrations of gram-negative bacilli (P less than 0.05) in gastric aspirates, pharyngeal swabs, and tracheal aspirates than did patients in the antacid-H2-blocker group. The rate of pneumonia was twice as high in the antacid-H2 group as in the sucralfate group (95 percent confidence interval, 0.89 to 4.58; P = 0.11). Gram-negative bacilli were isolated more frequently from the tracheal aspirates of patients with pneumonia who were receiving antacids or H2 blockers. Mortality rates were 1.6 times higher in the antacid-H2 group than in the sucralfate group (95 percent confidence interval, 0.99 to 2.50; P = 0.07). Although our results fell just short of statistical significance when they were analyzed according to intention to treat, they suggest that agents that elevate gastric pH increase the risk of nosocomial pneumonia in patients receiving ventilation by favoring gastric colonization with gram-negative bacilli. We conclude that in patients receiving mechanical ventilation, the use of a prophylactic agent against stress-ulcer bleeding that preserves the natural gastric acid barrier against bacterial overgrowth may be preferable to antacids and H2 blockers.
Antacids↗
Bacterial colonization in humidifying cascade reservoirs after 24 and 48 hours of continuous mechanical ventilation.
We evaluated levels of bacterial colonization in the humidifying cascade reservoirs of 466 mechanical ventilators; 326 reservoirs were cultured after 24 hours and 140 were cultured after 48 hours of continuous mechanical ventilation. Bacterial colonization was absent in 284 (87.1%) of the humidifier reservoirs sampled at 24 hours and 125 (89.3%) of the reservoirs cultured at 48 hours. Levels of bacterial colonization in the remaining humidifiers were low (less than 100 organisms/mL). The median temperature recorded in the reservoir fluid of 30 different ventilators was 50 degrees C (range 40 degrees to 60 degrees C). In vitro seeding of reservoir fluid at 50 degrees C with 10(6) organisms/mL of four different species of nosocomial gram-negative bacilli and Staphylococcus aureus demonstrated rapid killing of all five strains over a 6-hour incubation period, and no significant bacterial aerosols were detected. Rates and levels of bacteria in heated humidifier reservoirs are low and nosocomial pathogens survive poorly at the median reservoir temperature of 50 degrees C. We conclude that the heated humidifier reservoir on a mechanical ventilator is an unlikely source of colonization or bacterial aerosols, and therefore it can be changed every 48 hours with the ventilator tubing.
Bacteria↗
C-terminal deletions in agonistic and antagonistic analogues of vasopressin that improve their specificities for antidiuretic (V2) and vasopressor (V1) receptors.
We report the solid-phase synthesis of 12 desGly and 12 desGly(NH2) analogues of arginine-vasopressin (AVP), two highly selective antidiuretic (V2) agonists, four vasopressor (V1) antagonists, and five V2/V1 antagonists. The parent AVP agonists are (1) AVP, (2) 1-deamino[8-D-arginine]vasopressin (dDAVP), and (3) its 4-valine analogue, dVDAVP. The parent V1 antagonists are (4) [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid)] arginine-vasopressin (d(CH2)5AVP), (5) d(CH2)5VDAVP, (6) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP), and (7) d(CH2)5[Tyr(Me)]AVP. The parent V2/V1 antagonists are (8) d(CH2)5[D-Phe2,Ile4]AVP, (9) d(CH2)5[D-Phe2]VAVP, (10) d(CH2)5[D-Tyr(Et)2]VAVP, (11) d(CH2)5[Tyr(Et2]VAVP, and (12) d(CH2)5[D-Ile2,Ile4]AVP. All 24 analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor and rat antidiuretic assays. The desGly and desGly(NH2) analogues of 1-3 are either weak partial agonists or weak antagonists of the V1 responses to AVP. Except for desGly(NH2)AVP, which is a weak V2 agonist, the remaining desGly and desGly(NH2) analogues of 1-3 exhibit substantial V2 agonism and are thus highly selective V2 agonists. With antidiuretic activity of 321 units/mg, a resynthesized desGly(NH2)dVDAVP is equipotent with AVP as a V2 agonist. Thus our previously stated conclusion about the need for C-terminal CONH2 for V2 agonism is no longer valid. The four pairs of desGly/desGly(NH2) analogues of the V1 antagonists (4-7) all retained varying degrees of V1 antagonism and some exhibited striking enhancements in anti-V1/V2 selectivity. Thus the desGly/desGly(NH2) analogues of d(CH2)5Tyr(Me)AVP are highly potent V1 antagonists/weak V2 antagonists with anti-V1/V2 selectivities of 200 and 1200, respectively. The four pairs of desGly/desGly(NH2) analogues of the V2/V1 antagonists (8-11) exhibited enhancements, full retention, or slight diminishment of both V1 and V2 antagonism, with the desGly analogue being usually the more potent of each pair. The desGly and desGly(NH2) analogues of d(CH2)5[D-Ile2,Ile4]AVP (12) exhibited anti-V2/V1 selectivities of 46 and about 440, respectively. These are the most selective V2 antagonists reported to date. Many of these analogues could serve as useful pharmacological tools in studies on the roles of AVP in normal and pathophysiological circumstances.
Animals↗
Iodination of vasopressin analogues with agonistic and antagonistic properties: effects on biological properties and affinity for vascular and renal vasopressin receptors.
Twelve L- and D-tyrosine-containing vasopressin analogues were prepared in their mono- and diiodinated forms. These include six arginine vasopressin (AVP) vascular (V1) type antagonists/antidiuretic (V2) agonists, four V1/V2 antagonists, and two V1/V2 agonists, one of which is AVP itself. Ten peptides were iodinated on the tyrosyl residue in position 2; two were iodinated on a tyrosyl amide residue replacing the glycyl amide residue at position 9. All peptides were tested both for their biological activities in vivo (rat vasopressor and antidiuretic tests) and for their ability to bind to vasopressin receptors of the V1 (vascular) and V2 (renal) types from rat liver and rat kidney membranes, respectively. It is shown that monoiodination of the tyrosyl residue in the vasopressin analogues that were tested either preserves or reduces to a highly variable extent the in vivo and in vitro biological activities of these analogues. In most cases diiodonitation resulted in a marked decrease in biological activity. The effects of iodination on the affinity of vasopressin analogues for hepatic V1 receptors and renal V2 receptors were more related to the affinity of the noniodinated peptide for these receptors than to the biological properties (antagonist versus agonist) of the tested analogues, the nature (L versus D) of the iodinated tyrosyl residue, or the position (2 versus 9) at which this residue was introduced. The loss of affinity due to iodination was usually more pronounced for peptides exhibiting high affinity for vasopressin receptors. However, we show that among the monoiodinated peptides some (especially monoiodinated [2-D-Tyrosine]-AVP) retained enough affinity for vasopressin binding sites to suggest that their radioiodinated conterparts would be promising labeled ligands for use in studies in vasopressin receptors.
Animals↗
Canada Health Act: unpalatable carrot, unconstitutional stick.
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Canada↗
Multiple unusual manifestations of Wegener's granulomatosis: breast mass, microangiopathic hemolytic anemia, consumptive coagulopathy, and low erythrocyte sedimentation rate.
We describe a patient who presented with multiple unusual manifestations of Wegener's granulomatosis, including a breast mass, microangiopathic hemolytic anemia, and consumptive coagulopathy. Erythrocyte sedimentation rate (Westergren), usually elevated in the course of this disease, persistently remained low in this patient. We found that C-reactive protein levels were, in this case, a more sensitive gauge of disease activity.
Anemia, Hemolytic↗
Synthesis and receptor specificities of vasopressin antagonists.
We present some highlights of our findings on the design and synthesis of antagonists of the vascular (V1) and renal tubular (V2) responses to arginine vasopressin. The most potent of our original V1 antagonists, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid) 2-O-methyltyrosine] arginine vasopressin [d(CH2)5Tyr(Me)AVP], and the most potent of our original V2/V1 antagonists, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin [d(CH2)5Tyr(Et)VAVP], have been modified at positions 1, 2, 4, and 8 and at positions 2, 4, 7, 8, and 9, respectively. A number of highly potent and highly selective arginine vasopressin (AVP) V1 and AVP V2/V1 antagonists have resulted from these studies. The in vivo antioxytocic properties of many of those antagonists are also given here, a number for the first time. We also present preliminary data on some orally active antagonists. A number of these antagonists have become valuable pharmacological tools in studies on the physiological and pathophysiological roles of AVP. In addition, the AVP V2 antagonists may be of therapeutic value for the treatment of hyponatremia resulting from the excessive secretion of AVP.
Animals↗
Vasopressin antagonists allow demonstration of a novel type of vasopressin receptor in the rat adenohypophysis.
The ligand specificity of rat adenohypophyseal vasopressin receptors was directly compared to that of peripheral receptors of the V1 and V2 types. For this purpose a series of 15 recently designed vasopressin antagonists was used. The affinities of these antagonists for rat adenohypophyseal membranes were deduced from the determination of the concentration-dependent inhibition of [3H]vasopressin binding. In parallel experiments the corticotropin (or anti-corticotropin)-releasing activities of the tested peptides were determined on freshly dispersed rat adenohypophyseal cells. All peptides tested which were found to be antagonists of the vasopressor and antidiuretic responses to vasopressin in vivo behaved as antagonists of vasopressin-induced corticotropin release. There was a close correlation between the relative affinities of the analogues tested for binding to adenohypophyseal membranes and their relative potencies in inhibiting vasopressin-induced corticotropin release, indicating that the detected vasopressin-binding sites are the receptors involved in the vasopressin effect on corticotropin secretion. No correlation could be demonstrated between anti-corticotropin-releasing activities and either anti-antidiuretic or antivasopressor potencies of the antagonists tested. A direct comparison of the ligand specificities of adenohypophyseal receptors on the one hand, and V1 (hepatic) and V2 (renal) receptors on the other hand, showed that most of the antagonists discriminated very efficiently between adenohypophyseal and either hepatic or renal receptors. The selectivity index reaches values as high as 260,000 for desGly(NH2)9 [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-D-O-ethyl-tyrosine, 4-valine] arginine vasopressin. It is concluded that adenohypophyseal receptors represent a novel type of vasopressin receptors. Based on the observation that adenohypophyseal receptors, like hepatic or vascular V1 receptors, do not appear to be coupled to adenylate cyclase, we propose that adenohypophyseal receptors could be designated as V1b receptors as opposed to the V1a receptors previously characterized on liver and blood vessels.
Adrenocorticotropic Hormone↗
Effects of phencyclidine on active avoidance and escape in rats.
Rats trained to avoid electrical shock in a shuttle box were given phencyclidine (0.0, 1.0, 5.0, or 10.0 mg/kg) prior to testing for 5 consecutive days. There was a dose-dependent increase in both avoidance and escape failures although animals continued to cross the barrier during intertrial intervals, indicating that they were capable of making the appropriate response. Little evidence of tolerance was found during the 5-day testing period.
Animals↗
Association of M13 I-forms and spheroids with lipid vesicles.
Electron microscopy and density gradient centrifugation were used to demonstrate that the coat protein of M13 I-forms and spheroids, but not of filaments, can form some type of association with lipid vesicles in vitro. The association was detected only when the phage particles were incubated with dilauroylphosphatidylcholine (DLPC) or dimyristoylphosphatidylcholine (DMPC) small unilamellar vesicles (SUV) above the phase transition temperature of the lipid. Under these conditions the I-form coat protein was resistant to proteolytic digestion, and the viral DNA was also associated with the vesicles.
Capsid↗
Synthesis and some pharmacological properties of 18 potent O-alkyltyrosine-substituted antagonists of the vasopressor responses to arginine-vasopressin.
Using the Merrifield solid-phase method, we have synthesized 18 new 2-O-alkyltyrosine-substituted analogues (where alkyl = methyl and ethyl) of the arginine-vasopressin (AVP) vasopressor antagonists [1-deaminopenicillamine]-arginine-vasopressin (dPAVP), [1-(beta-mercapto-beta,beta-diethylpropionic acid)]arginine-vasopressin (dEt2AVP), and [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)]arginine-vasopressin (d(CH2)5AVP) and of their 8-D-arginine (d(R2)DAVP) analogues, their 4-valine (dR2VAVP) analogues, and their 4-valine,8-D-arginine (d(R2)VDAVP) analogues [where R = CH3 or C2H5 and 2R = (CH2)5]. These analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor and rat antidiuretic and in vitro rat uterus assay systems. Although many exhibit very low antidiuretic activities, none of the new analogues antagonize antidiuretic responses to AVP. They exhibit no evident pressor activities and are in fact all highly effective antagonists of the vasopressor responses to AVP. They are also potent antagonists of the in vitro oxytocic responses to oxytocin, both in the absence and in the presence of Mg2+. These analogues together with their corresponding antivasopressor pA2 values are as follows: 1. dPTyr(Et)AVP, 8.40 +/- 0.08; 2. dEt2Tyr(Me)AVP, 8.53 +/- 0.06; 3. dEt2Tyr(Et)AVP, 8.46 +/- 0.08; 4. d(CH2)5Tyr(Et)AVP, 8.47 +/- 0.04; 5. dPTyr(Me)DAVP, 8.31 +/- 0.08; 6. dPTyr(Et)DAVP, 8.27 +/- 0.06; 7. dEt2Tyr(Me)DAVP, 8.57 +/- 0.03; 8. dEt2Tyr(Et)DAVP, 8.33 +/- 0.06; 9. d(CH2)5Tyr(Me)DAVP, 8.41 +/- 0.05; 10. d(CH2)5Tyr(Et)DAVP, 8.45 +/- 0.05; 11. dPTyr(Me)VAVP, 8.36 +/- 0.07; 12. dPTyr(Et)VAVP, 8.07 +/- 0.13; 13. dEt2Tyr(Me)VAVP, 8.29 +/- 0.08; 14. dEt2Tyr(Et)VAVP, 8.42 +/- 0.06; 15. dPTyr(Me)VDAVP, 7.84 +/- 0.06; 16. dPTyr(Et)VDAVP, 8.46 +/- 0.03; 17. dET2Tyr(Me)VDAVP, 8.35 +/- 0.10; 18. dEt2Tyr (Et)VDAVP, 8.19 +/- 0.07. Seven of these analogues are clearly more potent vasopressor antagonists than their respective unalkylated tyrosine-containing parents. In the remaining 11, antagonistic potency was not changed significantly. In no instance did 2-O-alkyltyrosine substitution decrease antagonistic potency. With pA2 values equal to or greater than 8.40, nine of these antagonists (numbers 1-4, 7, 9, 10, 14, and 16) are among the most potent vasopressor antagonists reported to date. They could thus serve as additional valuable pharmacological tools in studies on the roles of AVP in the control of blood pressure in normal and in pathophysiological conditions. These findings may also provide useful clues to the design of more potent and selective antagonists of AVP.
Alkylation↗
The use of antagonists of vasopressin in studies of its physiological functions.
Antagonists of the vasopressor response to vasopressin (VP) have proved useful for probing the contributions of endogenous VP to cardiovascular regulation. Studies with such antagonists show that VP can exert substantial cardiovascular effects even when circulating levels are relatively low, as they are after moderate dehydration. Antagonists that also block antidiuretic responses to VP have recently become available. These promise to be equally useful for assessing the importance of VP in limiting water excretion under a variety of circumstances. Although many of the antagonists of the vasopressor response are relatively specific, the early antidiuretic antagonists were not. They block both vasopressor and antidiuretic receptors. Recently we have made progress in designing analogs that are more specific antagonists of the antidiuretic response. This suggests that it should be possible to produce specific antagonists of the antidiuretic response that would provide more incisive pharmacological probes and could become useful therapeutic agents.
Animals↗
Potent and selective antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-D-isoleucine,4- valine]arginine-vasopressin at position 4.
As part of a program in which we are attempting (a) to obtain more potent and/or more selective antagonists of the antidiuretic responses to arginine-vasopressin (AVP) and (b) to delineate the structural features at positions 1-9 required for antidiuretic antagonism, we have synthesized 13 new analogues of the antidiuretic antagonist [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-D-isoleucine,4- valine]arginine-vasopressin [d(CH2)5[D-Ile2]VAVP] in which the valine residue at position 4 has been replaced by the L-amino acids Abu, Ile, Thr, Ala, Ser, Nva, Gln, Leu, Lys, Cha, Asn, Orn, and Phe and two new analogues of the antidiuretic antagonist [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-D-phenylalanine,4- valine]arginine-vasopressin [d(CH2)5[D-Phe2]VAVP] with the Val4 residue replaced by Ser and Orn. These analogues are 1, d(CH2)5[D-Ile2,Abu4]AVP; 2, d(CH2)5[D-Ile2,Ile4]AVP; 3, d(CH2)5[D-Ile2,Thr4]AVP; 4, d(CH2)5[D-Ile2,Ala4]AVP; 5, d(CH2)5[D-Ile2,Ser4]AVP; 6, d(CH2)5[D-Ile2,Nva4]AVP; 7, d(CH2)5[D-Ile2]AVP; 8, d(CH2)5[D-Ile2,Leu4]AVP; 9, d(CH2)5[D-Ile2,Lys4]AVP; 10, d(CH2)5[D-Ile2,Cha4]AVP; 11, d(CH2)5[D-Ile2,Asn4]AVP; 12, d(CH2)5[D-Ile2,Orn4]AVP; 13, d(CH2)5[D-Ile2,Phe4]AVP; 14, d(CH2)5[D-Phe2,Ser4]AVP; and 15, d(CH2)5[D-Phe2,Orn4]AVP. The protected peptide precursors for these peptides were prepared by the solid-phase method, followed by ammonolytic cleavage. The free peptides 1-15 were obtained by deblocking with Na in NH3, oxidation of the resultant disulfhydryl compounds with dilute K3[Fe(CN)6], and purification on Sephadex G-15 in a two-step procedure with 50% HOAc and 0.2 M HOAc as eluants. Analogues 1-15 were tested in rats for agonistic and antagonistic activities by antidiuretic, vasopressor, and oxytocic assays.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparative pathogenicity of auxotrophic mutants of Candida albicans.
An induced mutant of Candida albicans with greatly decreased virulence for mice is described. The mutant was one of five auxotrophic mutants obtained by ultraviolet irradiation of a clinical isolate (strain MY 1044). The five mutants included two methionine auxotrophs, one methionine-cysteine auxotroph, one temperature-sensitive serine auxotroph, and one auxotroph with unknown growth requirements. Each of the mutants produced normal mycelium and had a normal profile of susceptibility to four antifungal drugs. The virulence of each mutant was compared with the parent strain by LD50 determination in mice. Four of the five auxotrophs exhibited LD50's that were not significantly different from the parent strain (mean LD50 = 7.5 x 10(5) cells). However, the temperature-sensitive serine auxotroph was significantly less virulent than the parent strain (LD50 greater than 10(7) cells), even though it grew well in vivo and in mouse serum at 37 degrees C in vitro. Use of this mutant in conjunction with its "isogenic" parent should help to elucidate true virulence factors in C. albicans.
Animals↗
The development of vasopressin antagonists.
Antagonists of the physiological actions of vasopressin can be useful probes for detecting the influences of endogenous vasopressin on cardiovascular regulation. Antagonists that block vascular receptors of the V1 type have been widely used for this purpose. Recently effective antagonists of renal antidiuretic receptors of the V2 type have become available, and we have made progress toward improving their specificity for V2 receptors. Vasopressin antagonists of both types of responses could become useful in the diagnosis and treatment of pathophysiological states in which elevated levels of circulating vasopressin may disturb cardiovascular and renal functions.
Animals↗
Stereoscopic cerebral evoked potentials of Air Force pilots and civilian comparison groups.
Dynamic random-dot stereograms were presented to Air Force jet pilots (N = 14) through a new visual display system. Games which simulated target-detection exercises were included in the test sequence. Event-related potentials were recorded at scalp sites 01, 02, T5, T6, referenced to an anterior midline site. Comparisons were made where possible with the data from recent studies on three civilian groups. A pattern of response was revealed in the event-related potential measures. In general, left-hemisphere amplitudes exceeded right and the predominant response was recorded at the left-temporal site. Amplitudes of responses in subjects able to describe the stimuli in subjective report (perceivers) exceeded those of non-perceivers. Stimuli with definite boundaries evoked stronger and earlier-latency responses than stimuli with nebulous boundaries. The response patterns of subjects make a contribution to normative data on the cerebral electrical indices of stereoscopic vision.
Adult↗
Effect of the vasopressin antagonist d(CH2)5 Tyr(Et)VAVP on diuresis in rat.
The effect of [1-(beta-mercapto-beta,beta- cyclopentamethylene -propionic acid)2-0- ethyltyrosine ,4-valine] arginine vasopressin on the water metabolism was studied in rat. The compound was found to be able to block the antidiuretic action of both exogenous and endogenous vasopressin. A rat model of the Schwartz-Bartter syndrome was created by the administration of a high dose of a posterior pituitary preparation (Pitressin tannate ) together with a forced water intake. The antagonist prevented water retention and averted the enhanced natriuresis and hyponatraemia, and cerebral oedema did not develop. The observations suggest that this vasopressin antagonist might be of use in the future as an effective drug against the Schwartz-Bartter syndrome.
Animals↗