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Biomedical subjects

M Manning

Publications and source records attributed to M Manning.

At least 91 records · Page 5Linked to original sources
PubMed1991

Cyclic and linear vasopressin V1 and V1/V2 antagonists containing arginine in the 4-position.

Substitution of arginine for glutamine in the 4-position of a vasopressin V1 antagonist has been reported to turn it into an agonist. We resynthesized this 4-arginine analog and synthesized additional cyclic and linear vasopressin antagonists containing a 4-arginine. The presence of a 4-arginine in the resynthesized and new analogs had relatively minor effects on their antivasopressin V1 and V2 antagonistic potencies.

Amino Acid Sequence↗
PubMed1990

Invertebrate neuropeptides resembling vasotocin and some analogues: synthesis and pharmacological properties.

The solid phase synthesis of three invertebrate vasopressin-oxytocin homologs: AVP-like factor, F1(1), ([Leu2, Thr4] AVT)2 isolated from subesophageal and thoracic ganglia of Locusta migratoria3, Arg-conopressin-S4. ([Ile2, Arg4] AVT), Lys-conopressin-G4 ([Phe2, Arg4] LVT), both isolated from the venom of fish-hunting marine snails of the genus Conus and six of their analogues is reported. These analogues are: [Arg4] AVT, [Ile2] AVT, [Leu2] AVT, [Phe2, Arg4] AVT, [Arg4] LVT and [Ile2, Arg4] LVT. All peptides were tested for antidiuretic and vasopressor activities.

Animals↗
PubMed1990

Arithmetic and laterality.

Relationships between arithmetic ability, hand preference and hand skill were investigated in a general population sample of schoolchildren, aged 9-11 years. Incidences of non-right-handedness were highest in the children best at arithmetic and fell progressively through average and below average groups. Strong effects were found for hand skill; level of ability declined linearly from left to right across the R-L continuum in both sexes. Strong dextrality was associated with poor left hand skill and not superior right hand skill. Arithmetic ability was positively associated with left hand skill but not with right hand skill.

Child↗
PubMed1990

Design of potent and selective linear antagonists of vasopressor (V1-receptor) responses to vasopressin.

We report the solid-phase synthesis of 21 linear analogues of A and D, two nonselective antagonists of the vasopressor (V1) and antidiuretic (V2) responses to arginine vasopressin (AVP). A is Aaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2 (where Aaa = adamantylacetyl at position 1). D is the des-Arg9 analogue of A. Nine new analogues of A (1-9) and 12 new analogues of D (10-21) were obtained. The following substitutions either alone or in combination were incorporated in A and/or in D: phenylacetic acid (Phaa) and tert-butylacetic acid (t-Baa) at position 1; D-Tyr2, D-Tyr(Me)2; Gln4; Arg6, Lys6, Orn6, MeAla7. The nine new analogues of A are (1) [Arg6], (2) [Lys6], (3) [Orn6], (4) [Phaa1,Lys6], (5) [Phaa1,Orn6], (6) [D-Tyr2], (7) [D-Tyr2,Arg6], (8) [Phaa1,D-Tyr2], (9) [Phaa1,D-Tyr2,Arg6]. The 12 new analogues of D are (10) [Arg6], (11) [Lys6], (12) [Orn6], (13) [Phaa1,Lys6], (14) [Phaa1,Gln4,Lys6], (15) [Phaa,D-Tyr(Me)2,Lys6], (16) [Phaa,D-Tyr(Me)2,Gln4,Lys6], (17) [Phaa1,D-Tyr2,Gln4,Lys6], (18) [t-Baa1,Lys6], (19) [t-Baa1,Gln4,Lys6], (20) [Arg6,MeAla7], (21) [t-Baa1,Arg6,MeAla7]. All 21 peptides were examined for agonistic and antagonistic potencies in AVP V2 and V1 assays in rats. With the exception of 6, the eight remaining new analogues of A are equipotent or more potent than A as V1 antagonists. Peptides 2-9 are less potent than A as V2 antagonists. Three, 4, 5, and 9, exhibit significant gains in anti-V1/anti-V2 selectivities (selectivity ratio = 41, 14, and infinite, respectively), compared to A (anti-V1, pA2 = 7.75 +/- 0.07; selectivity ratio = 0.44). Peptide 9 is unique in both series. It is a highly potent V1 antagonist (anti-V1 pA2 = 8.62 +/- 0.11 and is the first linear peptide to exhibit substantial antidiuretic agonism (4.1 +/- 0.2 units/mg). With the exception of 12, the remaining 11 analogues of D are 8-40 times more potent than D as V1 antagonists. Eight of these peptides exhibit significant gains in anti-V1/anti-V2 selectivities compared to D (anti-V1 pA2 = 7.43 +/- 0.06; selectivity ratio = 1.6).(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1990

Reading and a balanced polymorphism for laterality and ability.

The idea that reading ability might vary with right-left hand skill, such that children with mild biases to the right hand have advantages for learning, while children at both left and right extremes have disadvantages, was supported by findings for a large sample of primary schoolchildren. Poor readers tended to have weak left hand skills, giving strong right hand preferences in many cases. Those with additionally poor right hand skills tended to be of low intelligence. Good left hand skills and raised incidences of mixed and left hand preference were found only in a small subgroup, "bright dyslexics".

Aptitude↗
PubMed1989

2-O-alkyltyrosine derivatives of 1-deamino-arginine-vasopressin: highly specific and potent antidiuretic agonists.

We report the solid-phase synthesis of eight 2-O-alkyltyrosine analogues of 1-deamino-arginine-vasopressin (dAVP) with enhanced antidiuretic agonistic specificity. These peptides are as follows: 1-deamino[2-O-methyltyrosine]-arginine-vasopressin (dTyr(Me)AVP), 1-deamino[2-O-ethyltyrosine]arginine-vasopressin (dTyr(Et)AVP), 1-deamino[2-O-methyltyrosine,8-D-arginine]vasopressin (dTyr(Me)DAVP), 1-deamino[2-O-ethyltyrosine,8-D-arginine]vasopressin (dTyr(Et)DAVP), 1-deamino[2-O-methyltyrosine,4-valine]arginine-vasopressin (dTyr(Me)VAVP), 1-deamino[2-O-ethyltyrosine,4-valine]arginine-vasopressin (dTyr(Et)VAVP), 1-deamino[2-O-methyltyrosine,4-valine,8-D-arginine]vasopressin (dTyr(Me)VDAVP), and 1-deamino[2-O-ethyltyrosine,4-valine,8-D-arginine]vasopressin (dTyr(Et)VDAVP). All analogues were tested for antidiuretic, antivasopressor, and antioxytocic activities. Deamination, as was expected, significantly enhanced the antidiuretic properties of these analogues relative to their parent N-amino-O-alkyltyrosine peptides. With the exception of dTyr(Me)AVP, all of these analogues are antagonists of the vasopressor responses to AVP and of the uterine response to oxytocin. Thus they all exhibit high antidiuretic agonistic specificity. Due to its remarkable properties, dTyr(Me)VDAVP is a unique compound in this series. It appears to be the most potent antidiuretic agonist (1740 units/mg) and also a vasopressor antagonist and a potent oxytocin antagonist. It is thus a highly specific antidiuretic agonist. In general, all of these new analogues are highly specific and thus are potentially useful as pharmacological tools and clinical agents.

Animals↗
PubMed1989

Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin.

We describe the synthesis and some pharmacological properties of 16 new in vivo antagonists of oxytocin. These are based on modifications of three peptides: A, B, and C. A is our previously reported potent and selective antagonist of the vasopressor (V1 receptor) responses to arginine-vasopressin (AVP)/weak oxytocin antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid), 2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]AVP. B reported here, the Ile3 analogue of A, is d(CH2)5[Tyr(Me)2]AVT (5 below) and C is our previously reported potent nonselective oxytocin antagonist/AVP V1 antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O- methyltyrosine,8-ornithine]vasotocin (d(CH2)5[Tyr(Me)2]OVT). The following substitutions and deletions, alone or in combination, were employed in A, B, and C: 1-deaminopenicillamine (dP); D-Tyr(Alk)2 (where Alk = Me or Et), D-Phe2; Val4, Thr4; delta 3-Pro7; Lys8, Cit8; desGly9, desGly-NH2(9), Ala-NH2(9); Leu-NH2(9); Arg-NH2(9). The 16 new analogues are (1) d(CH2)5[D-Tyr(Me)2]AVP, (2) d(CH2)5[D-Tyr(Me)2, Val4,delta 3-Pro7]AVP, (3) d(CH2)5[D-Tyr-(Et)2, Val4,Lys8]VP, (4) d(CH2)5[D-Tyr(Et)2,Val4,Cit8]VP, (5) d(CH2)5[Tyr(Me)2]AVT, (6) d(CH2)5[Tyr(Me)2,Lys8]VT, (7) dP[Tyr(Me)2]AVT, (8) dP[Tyr(Me)2,Val4]AVT, (9) d(CH2)5[D-Tyr(Me)2, Val4]AVT, (10) d(CH2)5[D-Phe2,Val4]AVT, (11) d(CH2)5[Tyr(Me)2,Thr4]OVT, (12) d(CH2)5[Tyr(Me)2,Thr4,Ala-NH2(9)]OVT, (13) d(CH2)5[Tyr(Me)2,Thr4,Leu-NH2(9)]OVT, (14) d(CH2)5[Tyr(Me)2,Thr4,Arg-NH2(9)]OVT, (15) desGly-NH2(9),d(CH2)5[Tyr(Me)2,Thr4]OVT, (16) desGly9,d(CH2)5[Tyr(Me)2,Thr4]OVT. 1-4 are analogues of A, 5-10 are analogues of B, and 11-16 are analogues of C. Their protected precursors were synthesized either entirely by the solid-phase method or by a combination of solid-phase and solution methods (1 + 8 or 8 + 1 couplings). All analogues were tested in rats for agonistic and antagonistic activities in oxytocic (in vitro, without and with Mg2+, and in vivo) assays as well as by antidiuretic and vasopressor assays. All analogues exhibit potent oxytocic antagonism in vitro and in vivo. With an in vitro pA2 (in the absence of Mg2+) = 9.12 +/- 0.09, dP[Tyr(Me)2]AVT is (7) one of the most potent in vitro oxytocin antagonists reported to date. Fifteen of these analogues (all but 6) appear as potent or more potent in vivo oxytocin antagonists than C (pA2 = 7.37 +/- 0.17). Analogues 1-9 and 14 are potent AVP V1 antagonists. Their anti-V1 pA2 values range from 7.92 to 8.45. They are thus nonselective oxytocin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

The disadvantages of dextrality for intelligence.

The right shift (RS) theory of handedness suggests that the human bias to dextrality has costs as well as benefits. Samples of children from six primary schools were individually tested for hand preference, hand skill and Raven's Matrices. Scores on standardized educational tests recently given by teachers were available for three schools. When children were stratified for ability, the distributions of hand preference and of right minus left (R-L) hand skill were as expected if extent of RS is inversely related to ability. When children were classified for R-L score, the most strongly dextral children were poorer than all others for Matrices, English and several other tests. The trend for ability to decline from left to right across the laterality continuum was consistent for all scores available. Strong dextrality is associated with weak left-hand skill, not good right-hand skill, in accord with the hypothesis that the costs of RS are to the right hemisphere. The findings and their interpretation are discussed in comparison with Geschwind's theory of developmental pathology, and for their implications for theories of hemisphere specialization.

Cerebral Cortex↗
PubMed1988

125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP: iodination and binding characteristics of a vasopressin receptor ligand.

A radioiodinated vasopressin antagonist, d(CH2)5[Tyr(NH2)9]AVP has been prepared. Iodination was carried out at the phenyl moiety of the tyrosylamide residue at position 9, followed by HPLC purification. Non-radiolabelled monoiodinated antagonist was used as a reference for identification. 125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP binding appeared to take place with a dissociation constant of 0.28 +/- 0.09 nM (Kd +/- SD) to V1 vasopressin receptors on rat liver membranes.

Animals↗
PubMed1988

125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT: a selective oxytocin receptor ligand.

An oxytocic antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid,2-O-methyltyrosine,4-threonine, 8-ornithine,9-tyrosylamide]vasotocin (d(CH2)5[Tyr(Me)2, Thr4,Tyr-NH2(9)]OVT [corrected], was monoiodinated at the phenyl moiety of the tyrosylamide residue at position 9. 125I-labelling was performed with 1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenyl-glycoluril. Iodination resulted in an increased affinity for rat uterine oxytocin receptors. A considerably lower affinity for rat vascular V1- and renal V2-receptors was found, resulting in a highly specific oxytocin receptor ligand. 125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT [corrected] was demonstrated to bind selectively to one population of binding sites in rat uterus and ventral hippocampal membrane preparations. Dissociation constants ranged between 0.03 and 0.06 nM. After 3 days of exposure autoradiography revealed binding in regions known to contain oxytocin receptors as well as labelling in some new regions, while no binding was found in the lateral septum, a structure containing mainly [8-arginine]vasopressin receptors. The high specific radioactivity of 125I-labelling allowed important reductions in membrane protein amount, gain in precision of binding analysis as well as considerably lower exposure times for autoradiography.

Animals↗
PubMed1988

Novel linear antagonists of the antidiuretic (V2) and vasopressor (V1) responses to vasopressin.

We report the solid phase synthesis of a series of 16 linear analogues of the cyclic antagonist of the antidiuretic (V2) and the vasopressor (V1) responses to arginine vasopressin (AVP), d(CH2)5[D-Tyr(Et)2, Val4]AVP(A). Peptide 1, the linear precursor of (A), (CH2)5(SH)-CH2-CO-D-Tyr(Et)-Phe-Val-Asn-Cys-Pro-Arg-Gly-NH2 was modified at position six with alpha-L-aminobutyric acid (Abu) to give peptide 2. Further modifications of the Abu6 analogue (No. 2) at position one by substituting cyclohexylacetic acid (Caa), cyclohexylpropionic acid (Cpa), 1-adamantaneacetic acid (Aaa), phenylacetic acid (Phaa), tert.-butylacetic acid (t-Baa), isovaleric acid (Iva), propionic acid (Pa), L-penicillamine (P), tert.-butoxycarbonyl (Boc) or omitting any substituent at this position, and/or in combination with Arg-NH2(9), Ala-NH2(9), D-Arg8-Arg-NH2(9), and desGly9 modifications yielded the remaining 14 peptides. All 16 peptides were examined for agonistic and antagonistic potencies in AVP V2 and V1 assays in rats. Apart from the Cpa analogue and the analogue lacking any substituent in the 1-position, all exhibit substantial V2 and V1 antagonism. A number are as potent as (A) as V2 antagonists. With an anti-V2 pA2 = 8.11 +/- 0.07, Aaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2 (No. 6) is as potent as any cyclic AVP V2 antagonist reported to date. The PaI analogue of No. 6 exhibits promising anti-V2/anti-V1 selectivity. These findings prove conclusively that a ring structure is not a requirement for recognition of or for binding to AVP V2 or V1 receptors. This discovery thus offers a promising new approach to the design of peptide and non-peptide antagonists of AVP and perhaps also to other cyclic peptides such as somatostatin, atrial-natriuretic factor, insulin, and the recently discovered endothelin. Some of these linear antagonists may be of value as pharmacological tools and as therapeutic agents.

Amino Acid Sequence↗
PubMed1988

Strategic pricing: hitting the mark with pricing strategies. Part 1.

Efforts by government and business to reduce healthcare expenditures by fostering competition and reducing utilization have combined to redefine the basic economic structure of the healthcare delivery system. Increased competition among providers has prompted an increased awareness of strategic pricing as a means of achieving institutional goals and objectives. In this article, the first in a three-part series on strategic pricing, the authors examine some of the key theoretical considerations related to pricing strategies for healthcare providers. Future articles will examine practical applications as they relate to package pricing, discounting, per diem systems, and capitation arrangements.

Economic Competition↗
PubMed1988

Discounting and per diem arrangements lock in patient referrals. Part 2.

Discounting and per diem arrangements are the most popular payment methods used by hospitals today because they are relatively simple methods. A properly negotiated discount or per diem contract can provide a hospital with the opportunity to lock in patient referrals from the many healthcare providers in its local markets. This article is the second in a three-part series on the strategic pricing of healthcare services. The final article discusses the intricacies of capitation arrangements, an increasingly popular payment method for healthcare services.

Contract Services↗
PubMed1987

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↗